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Excitability of Dopamine Neurons: Modulation and Physiological Consequences

M. Marinelli*, C.N. Rudick, X-T. Hu and F.J. White
Department of Cellular & Molecular Pharmacology. Rosalind Franklin University of Medicine and Science/The Chicago Medical School. 3333 Green Bay Road, North Chicago, IL 60064, USA
Abstract: This aim of this chapter is to review literature on the excitability and function of dopamine neurons that originate in the midbrain and project to cortico-limbic and motor structures (A9 and A10 dopamine pathways). Electrophysiological studies on rodent or non-human primates have shown that these dopamine neurons are silent or spontaneously active. The spontaneously active neurons show slow regular firing, slow irregular firing or fast bursting activity. In the first section, we will review how neuronal firing is modulated by intrinsic factors, such as impulseregulating somatodendritic dopamine autoreceptors, a balance between inward voltage-gated sodium and calcium currents and outward potassium currents. We will then review the major excitatory and inhibitory pathways that play important roles in modulating dopamine cell excitability. In the second section, we will discuss how, in addition to being modulated by intrinsic and synaptic factors, excitability of dopamine neurons can also be modulated by life experiences. Dopamine neurons change their firing rate throughout the developmental period, their activity can be modified by stressful life events, and the firing mode can change as a consequence of acute or repeated exposure to psychoactive drugs. Finally, these cells change their firing pattern in response to behaviorally relevant stimuli and learning experiences. We will conclude by discussing how changes in the physiology of the dopamine neurons could participate in the development or exacerbation of psychiatric conditions such as drug addiction.

Keywords: Dopamine, electrophysiology, addiction, stress, synaptic, ventral tegmental area. 1. THE MESENCEPHALIC DOPAMINE SYSTEM: BASAL ACTIVITY This section will review the literature on excitability of midbrain dopamine neurons. These neurons originate in the ventral tegmental area (VTA) or the substantia nigra pars compacta (SNc). They project to cortico-limbic and motor structures. We will first discuss how the activity of these neurons can be evaluated using electrophysiological studies. Then, we will review how dopamine neuron activity is regulated by intrinsic neuronal properties as well as by excitatory and inhibitory inputs. 1.1. Evaluating Action Potential Activity of Dopamine Neurons 1.1.a. Techniques and Considerations Electrophysiological studies have uncovered the pattern of activity of midbrain dopamine neurons. In vivo recordings have shown how these neurons function in the context of normal circuitry. In vitro recordings are more reductionistic, but they have provided valuable information to understand the mechanisms regulating neuronal activity. During in vivo extracellular recordings, electrical signals are fed into a high-impedance amplifier, filtered through defined low and high-pass bands that significantly influence
*Address correspondence to this author at the Department of Cellular & Molecular Pharmacology. Rosalind Franklin University of Medicine and Science/The Chicago Medical School. 3333 Green Bay Road, North Chicago, IL 60064, USA; Tel: 847-578-8673; Fax: 847-578-3268; E-mail: micky.marinelli@rosalindfranklin.edu 1871-5273/06 $50. 00+. 00

the shape of the signal, and are visualized on an oscilloscope. Neurons are defined as being dopaminergic if they fulfill several electrophysiological requirements. Among these is a typical dopamine signature, characterized by a triphasic waveform (+/-/+) with a duration >2.5 msec from start to end [106]. Neurons that respond to these criteria have been defined as dopaminergic because they also respond to numerous pharmacological or electrophysiological manipulations in a manner that clearly indicates their dopaminergic identity (for details, see [35, 106]). Recently, the dopamine signature criterion for dopamine neuron identification was revisited [262]. By performing juxtacellular labeling with neurobiotin combined with tyrosine hydroxylase (the rate-limiting enzyme for dopamine synthesis) immunohistochemistry, it was reported that neurons should only be considered dopaminergic if their waveform is longer than the previously-reported ones. It should be noted, however, that the waveform duration (and shape) is largely dependent on the filter settings applied to the recording amplifier. In the above study by Ungless and colleagues, the filter settings were very different from those used in the majority of the studies reported in the literature. Because of this, using such a filter (300 Hz 0.8 kHz), indeed, one should use different criteria. However, using the more classical filters (50 Hz - 0.8 kHz), the long established criteria remain valid. Fig. 1a shows differences in waveform produced by different filter settings. 1.1.b. Firing modes of Dopamine Neurons Most in vivo recordings have been performed in anesthetized rodents. Although there is minor controversy as
2006 Bentham Science Publishers Ltd.

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Fig. (1). (a) In vivo extracellular recordings of a dopamine neuron in the VTA. The same neuron was recorded using different amplifier filter settings. Solid line: 400 Hz - 0.5 kHz (as used in studies by White et al., [79]); dashed line: 50 Hz 0.8 kHz (as often used in studies by Grace and Bunney [106]); dotted line: 300 Hz 0.5 kHz (as used in a recent study by Ungless et al. [262]). Note that, according to the filter settings, the same neuron can exhibit waveforms of different shape and duration so that the start of the signal, the trough of the negative peak, and the end of the signal all appear at different times. Waveforms have been aligned at the onset of the positive peak (shown by the vertical dotted line) to simplify comparisons of waveform duration. (b) Representative traces showing different patterns of rat dopamine neuron activity recorded in vivo (top two traces, ~300g rat) or in vitro (bottom trace, ~120g rat). In vivo, dopamine neurons exhibit bursting activity or irregular firing; in vitro firing is regular and it lacks the irregularity or bursting activity that is typically observed in vivo. Data obtained by M. Marinelli, for the purpose of this review.

to whether neuronal activity in anesthetized conditions parallels that seen in freely-moving animals [86, 96, 122, 148], and whether different anesthetics show similar profiles of neuronal activity [70, 181], there is general consensus that, in vivo , dopamine neurons can be silent, or spontaneously active. Among the spontaneously-active dopamine neurons, action potential output can show slow regular, slow irregular

or fast bursting activity, as illustrated in Fig. 1b. Bursts are characterized by spikes clustered in high-frequency events that generally exhibit spike-frequency adaptation and accommodation [37, 106, 107, 113]. This pattern of activity is unique to the in vivo situation and it is not observed in vitro, as shown in Fig. 1b [108, 141, 219, 234], probably because many of the excitatory synaptic inputs responsible for bursting are severed.

Fig. (2). In vivo extracellular recordings of rat dopamine neurons in the VTA. (a) Firing rate histogram of dopamine neurons showing normal-distribution of firing rates. Average rate = 4.5 0.1 Hz. A very similar pattern of activity was first reported by Grace and Bunney [108]. (b) Distribution of the number of spikes/burst obtained during in vivo extracellular recordings. Note that columns represent the average number of spikes/burst obtained for each cell. Each cell was recorded for a period of at least 3 min. Given that we report averages obtained for each cell, data are not expressed as whole integers (number of spikes/burst: mean= 3.1 0.1, mode=2, median=2.7). The left column shows the percentage of neurons exhibiting bursting consisting uniquely of 2 spikes/burst. The next columns to the right show averages ranging from 2.5 to 8.5 spikes/burst. Note that some burst events had more than 9 spikes/burst, but these were averaged out to lower numbers when taking into consideration the overall activity of the cell. Data expressed as independent observations (i.e. without performing averages for each cell) can be found in previous studies that initially characterized burst firing [107]. Data were obtained by pooling recordings from young adult (300-380g) nave rats across previously published [161, 162, 163, 165] or unpublished experiments by M. Marinelli for a total of 286 neurons (a) or 214 neurons (b).

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In vivo, the firing rate (measured in spikes/sec, or Hz) is normally-distributed across cells, (see Fig. 2a ); it ranges from 0.5 Hz to approximately 10 Hz, with an average around 4.5 Hz [106, 108]. In addition, bursting activity of dopamine neurons can exist to different degrees, from none (only a small percentage of neurons), to moderate (most neurons) to high. It is important to note, however, that the degree of bursting is on a continuum scale, and that sub-divisions into different categories/degrees of bursting are arbitrary. Different aspects of bursting activity can be measured, such as the amount of bursting (e.g. the proportion of spikes emitted in bursts or of the time spent bursting, the number of burst events) or the characteristics of the bursts (e.g. number of spikes/burst, burst duration, frequency of spikes within the bursts). Cells with lowest bursting activity generally display numerous single spikes (i.e. protracted periods of nonbursting activity) and a low proportion of two-spike bursts. Cells with high bursting activity exhibit a small number of single spikes and numerous bursts, either two-spiked or larger. Fig. 2b shows that most cells exhibit burst events characterized by two-three spikes/burst; a smaller percentage of cells exhibit a greater number of spikes/burst. In vitro recordings have been performed with a variety of recording techniques: extracellular, patch clamp (whole cell or cell-attached), or intracellular (with sharp electrodes). The action potential duration during patch clamp or intracellular recordings is long (approximately 2.75 msec); in addition, in response to hyperpolarizing steps, dopamine neurons show a prominent hyperpolarization-activated cation current (Ih) when recorded in voltage clamp, or a voltage sag when recorded in current clamp. Expression of Ih in the VTA is indicative of dopamine neurons [128, 174, 187]. As mentioned above, dopamine neurons in the tissue slice (in vitro) do not spontaneously exhibit bursting activity, (see Fig. 1 b). Bursting has been observed, however in a small percentage of neurons (18.3%) in immature animals in the tissue slice, and so has irregular firing (28.3% of neurons) [180]. In young adult animals, and in other studies on pre-weaning animals, instead, the pattern of output has been shown to be extremely regular (pace-maker activity). In fact, in vitro, neuronal activity displays a very narrow

distribution of interspike intervals on a Gaussian curve (coefficient of variation). Situations that induce bursting activity in the tissue slice (e.g. pharmacological manipulations, see below) broaden the distribution of interspike intervals; therefore, they flatten the Gaussian curve and increase the coefficient of variation (for example, see [286]). This indicates that, in vitro, bursting activity confers irregularity to spike timing. This is the opposite of what is seen in vivo, where neurons with low or no bursting activities exhibit a broad coefficient of variation (and therefore irregular spiking). Instead, cells with greater bursting activity exhibit a tighter distribution of interspike intervals, as shown in Fig. 3 . This points to the difference between natural bursting in vivo and those produced artificially in vitro by pharmacological treatments in the tissue slice and suggests that, in vivo, the temporal variability of spike production during bursting is lower than in pharmacologically manipulated slices. In vivo, bursting activity has been shown to increase the release of dopamine in the terminal regions [103, 199, 243]. However, given the rapid reuptake of the neurotransmitter by dopamine transporters, such phasic increases in peri-synaptic dopamine are only detectable using techniques with good temporal resolution (e.g. fast-scan cyclic voltammetry or chronoamperometry [77, 99, 200]), unless dopamine reuptake is pharmacologically blocked [92]. When dopamine reuptake is experimentally blocked (e.g. by the administration of nomifensine), changes in bursting do result in changes in extracellular levels of dopamine in postsynaptic sites that are detectable with microdialysis techniques. In the absence of changes in dopamine reuptake, the accumulation of extracellular dopamine measurable with microdialysis techniques is the consequence of an increase in the number of active neurons with minimal influence of their bursting pattern. In these circumstances, the increase in population activity results from the activation of silent dopamine neurons after removal or reduction of inhibitory inputs [92]. This indicates that a complex interplay between firing rate, pattern of activity and number of active neurons participate in maintaining phasic and tonic dopamine transmission.

Fig. (3). Distribution of interspike intervals in rat VTA dopamine cells recorded in vivo. Figures are obtained from three different cells with different levels of bursting activity: 80%, 45% or 15% of bursting spikes. Greater bursting activity is associated with a more narrow distribution of interspike intervals (note the narrow distribution of interspike intervals for the cell with 80% of bursting spikes compared with the flattened distribution for the cell firing 15% of bursting spikes). Instantaneous interspike intervals were binned in 10 msec intervals (from 0-10 msec to 2123-2140 msec) and plotted as percentage of observations (Y axis) occurring at each particular bin (in msec on the x-axis; axis truncated at 1000 msec in the above figures). Data obtained by M. Marinelli for the purpose of this review.

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1.2. Regulation of Dopamine Neuron Activity 1.2.a. Intrinsic Modulation of Dopamine Neuron Activity Numerous intrinsic factors regulate impulse activity of dopamine neurons [142, 167, 192]; we will consider some of the most important ones, such as impulse-regulating autoreceptors, calcium-activated potassium channels, calcium channels and Ih. Some receptors located on the somatodendritic area of dopamine neurons require synaptic input to be activated. Therefore, although these receptors are technically intrinsic to the dopamine neuron, they will be discussed in the section on synaptic modulation. Impulse-Regulating Autoreceptors Impulse-regulating autoreceptors play an important role in providing an efficient auto-feedback onto neuronal activity. These receptors are of the D2/D3 dopamine receptor family and are located in the somatodendritic region of VTA dopamine neurons [36, 51, 176]. They are activated by somatodendritically-released dopamine [11, 48, 135] and reduce dopamine neuron activity by activating potassium conductances and thereby hyperpolarizing the cell. More precisely, they activate Gi/o proteins; the
 dimer dissociates from the heterotrimeric protein, binds and activates G-protein-coupled inward-rectifying potassium (GIRK) channels [57, 127, 152, 176, 278]. Although there have been several controversies as to whether somatodendritically-released dopamine acts in a paracrine fashion, and diffuses over some distance prior to exerting its action on dopamine receptors [212], recent evidence shows that dopamine release depends on neuronal depolarization; this exocytotic release can directly inhibit neuron excitability [12]. Nevertheless it is possible that autoreceptors do not exclusively respond to dopamine that is released from the same neuron, because dopamine autoreceptor sensitivity has been shown to occur after partial dopamine lesions [118]. In the in vivo situation, functional sensitivity of dopamine autoreceptors can be determined by examining the dosedependent neuronal inhibition following local (intra VTA) administration of D2/D3 receptor agonists. It can also be tested following systemic (intravenous) administration of autoreceptor agonists, as, when given systemically at appropriate doses, these drugs primarily act at the somatodendritic level [1, 98, 207]. Using these approaches, (see Fig. 4), it was shown that fast-firing dopamine neurons have sub-sensitive impulse-regulating autoreceptors, conversely, slow-firing neurons exhibit greater sensitivity of these receptors [166, 276]. This effect is independent of differences in neuronal inputs because slow-firing cells are more sensitive to autoreceptor-mediated inhibition even when they are driven to a faster rate by local application of glutamate [276]. Overall, these findings suggest that the functional state of somatodendritic dopamine autoreceptors determines the level of activity of dopamine neurons. Calcium-Activated Potassium Channels Potassium channels come in many forms; both voltagegated and calcium-activated small conductance potassium (SK) channels are implicated in midbrain dopamine neuron firing. Intracellular injection of the potassium channel blocker TEA increases the firing rate of dopamine neurons and produces burst-like activity [107]. In addition, by

combining real-time single-cell RT- PCR with slice patchclamp electrophysiology, it was shown that voltage-gated Atype potassium channels play a key role in modulating the pacemaker activity of dopamine neurons [157]. This pacemaker activity is coupled with A-type potassium channel density and number of subunits that make up the potassium channel, indicating that both the amount and the type of gene expression are important in regulating dopamine neuron firing.

Fig. (4). Dopamine neuron activity following the administration of the D2/D3 receptor agonist quinpirole. Quinpirole produces a dosedependent decrease in firing rate in all neurons, however, cells with initially higher baseline firing rates require more quinpirole to be silenced than cells with low firing rates. In this case neurons were divided as high or low firing cells according to the median split (High >4.5 Hz, n=15 cells; Low <4.5 Hz, n=15 cells). Statistical differences between groups in response to the different doses of quinpirole are obtained even when initial differences in baseline firing rates are taken into account [ANCOVA, group x dose interaction: F(9, 243)=2.8, p <0.01]. Data obtained by pooling results from previously-published experiments [161, 162, 163, 165] performed on nave rats (300-380g).

SK channels are found in dopamine neurons, where they contribute to the fast membrane afterhyperpolarization (AHP) that follows a train of action potentials and are largely responsible for modulating burst firing activity [192]. As their name suggests, these channels are selectively permeable to potassium, and they open when the intracellular calcium concentration is elevated. Because of this, they are very sensitive to fluctuations of internal calcium concentrations. An increase in intracellular calcium activates SK channels, whereas a reduction in intracellular calcium prevents their activation. Thus, reducing the intracellular concentration of calcium, by intracellular injection of the calcium chelator EGTA, attenuates the AHP that follows a spike train [108] and increases dopamine neuronal firing [107]. However, application of intracellular EGTA does not produce bursting because this manipulation not only inhibits SK channel activation, but also lowers intracellular calcium concentrations and prevents calcium

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influx from initiating burst firing (see calcium modulation of bursting activity). Physiologically, SK channels are activated by rises in intracellular calcium that can be produced by changes in calcium release from intracellular stores [231] such as those occurring after activation of metabotropic glutamate receptors (see section on synaptic modulation, and [185]). Recently, it was shown that SK channels can also be activated by the calcium influx produced by activation of Ttype calcium channels [286]. Because of this, activation of T-type calcium channels can inhibit, rather than increase, dopamine neuron activity. Another way to study the role of SK channels on dopamine neuron activity is to use SK channel blockers. Application of very low doses of apamin, the calciumactivated SK channel blocker, to dopamine neurons in vitro has been shown to interrupt pacemaker activity of dopamine neurons in the SNc but not in the VTA [285], suggesting that these channels could play a role in modulating dopamine neuron pacemaker activity in the SNc. Most importantly, application of apamin to midbrain dopamine neurons facilitates bursting activity produced by application of excitatory amino acids [129, 229] and can be sufficient to produce burst firing in vitro, in the tissue slice preparation [204, 235]. Burst events produced by apamin consist of long, two to tens of spikes per burst, which resembles natural bursting; in fact, this is possibly the only situation where in vivo-like bursting is partially reproduced in the tissue slice. The transition between the slow irregular firing and bursts is also controlled by fluctuations in membrane potential, which are also modulated by SK channels [2, 280]. Among SK channels, the SK3 subtype is expressed ubiquitously in midbrain dopamine neurons. In addition, its expression in these cells is either exclusive with respect to the other SK subtypes, or at least fourfold higher [285], suggesting that it is the SK3 subtype that plays a major role in modulating burst firing activity in dopamine neurons. Calcium Channels The calcium channel family consists of L-, N-, P/Q-, Tand R-type calcium channels and all of these calcium channels are present in dopamine neurons [42, 248]. Influx of calcium through calcium channels depolarizes the neuronal membrane, which can lead to cell firing. In midbrain dopamine neurons, intracellular injection of calcium (high concentrations), in vivo, increases burst firing whereas the calcium chelator EGTA reduces the depolarization that initiates bursting and thus also greatly reduces bursting [107]. Although it is clear that calcium regulates neuronal firing it is unclear what channel calcium uses to enter the cell. In-vitro studies show that L-type calcium channel blockers greatly reduce the depolarization that initiates bursting and subsequently bursting in midbrain dopamine neurons [42, 78, 175, 204]. Calcium channel blockers for N- and P/Q-type channels also reduce this membrane depolarization but their contribution to the total depolarization is far less than the L-type calcium channels and may not have a large role in dopamine neuron firing [78]. In contrast to L-type calcium channels, T-type calcium channels decrease neuronal firing (by activating SK channels, see above), whereas R-type calcium channels have not been shown to affect neuronal activity. Taken together,

these studies indicate the importance of calcium influx through calcium channels in regulating midbrain dopamine neuron activity. Ih Channels Ih channels are largely expressed by dopamine neurons [187]. As their name implies, these channels are activated when the neuron is hyperpolarized; their opening allows the inward flow of most cations (for review see [97]), which produces membrane depolarization. After hyperpolarizing steps, this is visible as a gradual increase in inward current when measured in voltage-clamp mode, and as a typical sag when recorded in current-clamp; in fact, as mentioned previously, the presence of this current or sag is often used as a marker for dopamine neurons recorded in the tissue slice [110, 128, 174, 187]. SNc neurons express a greater density of Ih channels compared with VTA dopamine cells [187], which is coupled with enhanced Ih current flow in response to hyperpolarizing steps [187]. Ih has been suggested to regulate low frequency pacemaker activity, however only a subset of SNc neurons show altered pacemaker frequency in the presence of the Ih channel inhibitor ZD-7288; therefore, it is debatable whether the expression of this current regulates the overall firing pattern of most midbrain dopamine neurons [174, 187, 230]. Ih does however, regulate amplitude and duration of the afterhyperpolarization that follows action potentials in all subtypes of midbrain dopamine neurons with a possible function of integration of inhibitory input to these cells [187]. 1.2.b. Modulation by Excitatory and Inhibitory Synaptic Inputs The activity of dopamine neurons is strongly modulated by synaptic inputs. Dopamine neurons receive excitatory and inhibitory inputs from a variety of structures whose projection neurons release different excitatory or inhibitory neurotransmitters. We will focus here on glutamatergic and GABAergic input, as these play the major role in modulating dopamine neuronal activity. We refer to excellent reviews for studies on other neurotransmitters [74, 104, 142, 192, 274]. Glutamatergic Input Dopamine neurons in the midbrain receive direct or indirect glutamatergic inputs from different structures such as the prefrontal cortex, the bed nucleus of the stria terminalis, the subthalamic nucleus, the pedunculo pontine nucleus, the laterodorsal tegmental nucleus and possibly the superior colliculus [43, 52, 100, 227]. Glutamatergic input from the prefrontal cortex, once thought to be the major excitatory input, was shown to synapse onto dopamine neurons that loop-back to the prefrontal cortex, but not to those projecting to the nucleus accumbens (NAc) [43, 44, 45]. It is the input from other structures such as the laterodorsal tegmentum that is likely to synapse onto dopamine neurons projecting to the NAc [69, 93, 189, 228]. An increase in glutamatergic drive enhances dopamine neuronal activity and produces the characteristic bursting pattern expressed in vivo; increased firing and bursting activity are also evident following local application of

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glutamate [172, 190, 191]. Glutamate acts via three general groups of receptors that are expressed on dopamine neurons: AMPA, NMDA and metabotropic [46, 239, 252]. Both AMPA and NMDA receptors are ion channels that are opened by glutamate binding and allow inflow of sodium and calcium, whereas metabotropic glutamate receptors (mGluRs) bind glutamate and modulate ion channel activity via second messenger systems. AMPA and NMDA receptors mediate the majority of excitatory input to dopamine neurons [167, 192, 270, 271]. In vivo studies have shown that application of both AMPA and NMDA receptor agonists ( via microiontophoresis) increases the firing rate of spontaneously-active dopamine neurons of the SNc and VTA. Both AMPA and NMDA receptor activation increases bursting activity in the SNc, however, bursting activity in the VTA appears to be independent of AMPA receptors [49, 50, 190, 292]. In vitro studies in the tissue slice also show the excitatory role of these receptors on dopamine neurons; both application of AMPA and NMDA evokes an inward current and increase neuronal firing in a dose-dependent manner [177, 270, 271, 287, 288]. NMDA receptor activation has been shown to increase bursting activity only in certain conditions, particularly in the presence of hyperpolarizing currents or when calcium-activated potassium currents are blocked [129, 130, 229]. Together, these findings underline the important excitatory role of AMPA and NMDA glutamate receptor activation in dopamine neuron regulation; however, as pointed previously, it should be noted that this type of bursting produced in the slice does not resemble the naturally-occurring one in vivo. Activation of mGlu receptors can have either an excitatory or inhibitory role on dopamine neurons, depending on how the receptors are activated. Fast activation of group 1 mGlu receptors located on dopamine neurons, via synaptically-released glutamate, produces inhibitory postsynaptic currents and mediates a slow inhibition of dopamine neurons [90]. These inhibitory currents are the consequence of mobilization of intracellular calcium stores, which in turn activates inhibitory calcium-dependent potassium currents. However, with prolonged activation, the inhibitory response produced by mGlu receptor activation desensitizes. Therefore, continuous activation of these receptors induces a slowly-developing sodium-dependent excitation, which can lead to an increase in impulse activity of dopamine cells [90, 173, 178, 294]. It has also been suggested that activation of mGlu receptors modifies dopamine neuron activity indirectly, by acting on presynaptic glutamatergic terminals so as to modify glutamate release. As for the post-synaptic effects, these pre-synaptic ones can also be either stimulatory or inhibitory (according to the level of activation of the phospholipase C pathway) and produce, respectively, enhanced or reduced NMDA-mediated excitatory currents in post-synaptic cells [18, 101, 116]. On a similar line, at high doses, bath application of glutamate to isolated dopamine neurons has been shown to enhance the spontaneous firing, but also to temporarily inhibit firing through two distinct calcium-dependent mechanisms: via activation of NMDA and AMPA receptors or mGluRs [140]. Recently, it has also been shown that the action of mGluRs is linked to activation of transient receptor potential channels [13].

Together, these findings indicate that bursting may be ascribed, at least in part by a complex combination of glutamate receptors. Activation of these receptors can exert both excitatory and inhibitory roles, either directly, or indirectly, by modifying glutamate release or the activity of other channels. Measuring Excitatory Synaptic Strength and Plasticity Given the important role of excitatory glutamatergic synapses onto dopamine neurons, recent studies have addressed the question as to whether these synapses can undergo synaptic plasticity. A classic way to determine synaptic plasticity is to determine long term potentiation (LTP) of excitatory inputs using in vitro patch clamp recordings that evaluate excitatory post synaptic currents (EPSCs) or potentials (EPSPs). In these experiments, a change in the strength of synaptic input is indicated by an increase in evoked EPSC or EPSP amplitude following the pairing of synaptic stimulation with post-synaptic depolarization. Using perforated whole-cell patch clamp recordings, LTP was demonstrated in midbrain dopamine, but not GABAergic neurons [19, 193]. The increase elicited at excitatory synapses on dopamine neurons was NMDA receptor dependent and mGluR independent. Further studies demonstrate that long-term depression (LTD) is also a form of synaptic plasticity exhibited by VTA dopamine neurons [132, 133, 253]. The LTD that is elicited at excitatory inputs to dopamine neurons depends on NMDA receptor activation and requires an increase in intracellular calcium, but is Ltype calcium channel independent. Similarly, this LTD does not rely on activation of mGluRs but can be blocked by activation dopamine D2-class receptors, further underscoring the role of these autoreceptors in modulating neuronal excitability [132, 133, 253]. GABAergic Input GABA, the major inhibitory neurotransmitter, is responsible for most synaptically-induced inhibition of dopamine neuron activity. GABAergic inputs arise mostly from the striatal complex; it includes inputs from the NAc, caudate nucleus, globus pallidus and ventral pallidum (for review, see [112, 237, 238, 266, 274]). Another important GABAergic input arises from local neurons in the midbrain [10, 115, 150]. GABA afferents from the striatal complex are often defined as a long-loop GABAergic pathway. Whereas this inhibitory pathway plays an important role in certain conditions, such as after administration of psychostimulant drugs [32, 34, 79, 206], the extent to which it operates under anesthetized basal states is controversial. Hemitransection of the long-loop pathway fails to modify basal impulse activity of both VTA and SNc dopamine cells [79, 207]. During the acute phase of kainic acid injections into the dorsal striatum, there is a transient (< 12h) decrease in the percentage of active of SNc dopamine cells due to depolarization inactivation, as revealed by iontophoretic administration of GABA [25]. Similar kynurinic acid lesions of the NAc produce a transient decrease in firing rate and burst firing of VTA dopamine neurons [91]. The presence of GABA neurons within the VTA explains many biphasic effects produced by stimulation of brain structures projecting to the midbrain, or by systemic

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pharmacological treatments. Thus, stimulation of afferents onto dopamine neurons can have an initial response that is immediately followed by an opposite effect [109, 195, 258]. This is because afferents can form synapses onto both dopamine and GABA neurons. Synapses onto dopamine neurons produce direct neuronal excitation or inhibition. Synapses onto GABA neurons will have the opposite effects; they will change the activity of GABA neurons, which in turn will modify the activity of the dopamine neurons. On the same line, due to this anatomical arrangement, systemic administration of GABAergic drugs can have a paradoxical excitatory effect on dopamine neurons [105, 272]. Direct inhibition of dopamine neurons by activation of GABAA receptors occurs on a fast time scale. Systemic or local (intra VTA) application of the GABAA receptor agonist muscimol increases dopamine neuron firing while reducing the burst firing pattern and regularizing the firing pattern [80, 83]. On the other hand, GABAA receptor antagonists bicuculline and picrotoxin enhance both firing and bursting activity. Studies show that the GABAA receptor agonists modulate dopamine neuron activity by opening ionotropic receptors which directly allows chloride influx, thereby hyperpolarizing the cell membrane [128, 244]. In contrast to GABAA receptors, GABAB receptors mediate inhibition of midbrain dopamine neurons via a slower time course. Local administration of the GABAB receptor agonist baclofen reduces firing and burst firing and regularizes dopamine neuron firing rhythm [82, 84]. Conversely, application of GABAB receptor antagonists increases dopamine firing and bursting, and prevents the effects produced by GABAB receptor activation [47, 81, 82, 197]. Experiments using brain slices show that GABAB receptor agonists modulate the activity of dopamine neurons by activating Gi/o proteins; the
 dimer dissociates from the heterotrimeric protein and binds to GIRK channels, which are differentially expressed by dopamine and non-dopamine (GABAergic) neurons within the VTA [54]. The consequent opening of these channels allows potassium outflow, which hyperpolarizes the cell membrane thereby inhibiting neuronal activity [54, 273]; this mechanism of neuronal inhibition produced by activation of metabotropic GABAB receptor activation is similar to the one produced by activation of dopamine D2 receptors (see above). 2. THE MESENCEPHALIC DOPAMINE SYSTEM: CHANGES DURING LIFE This second section will review how dopamine neurons can be modulated during the lifespan of an individual. We will first give a brief overview of naturally-occurring changes in dopamine neuron impulse activity. These include changes over time, during development or naturallyoccurring differences in dopamine neuron activity across individuals. We will then focus on changes in neuronal activities induced by life events, such as exposure to stressful conditions or to addictive drugs or to behaviorally relevant (rewarding) stimuli and learning experiences. In these sections, we refer to basal activity of dopamine neurons to denote the general level of activity of these cells (as seen in the previous section, this is composed

of regular and bursting firing patterns). Instead, we refer to phasic activity of these neurons to denote rapid changes in firing pattern in response to specific stimuli. 2.1. Naturally-Occurring Differences in Dopamine Neuron Activity 2.1.a. Dopamine Neurons During Development During development, the dopamine system undergoes important changes. Dopaminergic innervations to the forebrain and dopamine receptors in the NAc and striatum increase rapidly from birth to reach a peak during adolescence, around postnatal day (PND) 40 and decrease gradually thereafter [5, 249]. Dopamine levels in the striatum increase from birth to adolescence, although it is unclear whether such differences are present in the NAc [3, 4, 155, 250]. Concerning impulse activity of midbrain dopamine neurons, developmental changes have been studied over different time periods. Firing and bursting of midbrain neurons increases progressively from birth to early (PND 2835) adolescence [205, 251], when autoreceptors in the midbrain appear to be functionally mature [268]. Activity during mid adolescence (PND 35-42) was not assessed in these experiments, but, recent findings from our group, (see Fig. 5 ), indicate that dopamine neuron activity (firing and bursting) is higher during this time than during adulthood (PND 75-90). Additional studies have also shown that dopamine neuron activity declines progressively during adulthood [95, 154]. Taken together, we can infer that dopamine neuron activity exhibits and inverted U-shaped curve over an individuals lifespan. Activity is low at birth, it shows a gradual increase during early adolescence, a possible peak during mid adolescence, and a gradual decline thereafter to return to low levels during old age.

Fig. (5). Dopamine neuron activity in Adult (PND 75-90, n=14 cells) and Adolescent (PND 35-45, n=15 cells) rats. Adolescent rats exhibit enhanced neuronal activity compared with Adult rats (T test, p<0.001). In addition to increased firing rate, adolescents show higher bursting activity (data not shown). Preliminary unpublished data from M. Marinelli.

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2.1.b. Inter-Individual Differences in Dopamine Neuron Activity Dopamine neuron activities are not identical across individuals. As shown in Fig. 2a, firing rates show a normal distribution and range from low (0.5 Hz) to high (10 Hz). As for most biological parameters, differences are in part dues to inter-individual variance. It was recently shown that action potential output (both firing and bursting) varies across individuals that exhibit strong vs . low locomotor activity when placed in a novel environment. Animals with high reactivity to a novel environment have high-levels of dopamine neuron activity, whereas animals with a low reactivity to the same environment have reduced dopamine activity [166]. This enhanced dopamine neuronal output is paralleled by enhanced dopamine levels in the NAc [22, 119, 202, 216]. Interestingly, these differences in dopamine neuronal activity across individuals are predictive of differences in susceptibility to acquire cocaine selfadministration behavior [166]. This suggests that the level of activity of dopamine neurons can be a predisposing factor that could favor addiction. This is not surprising, given the important role of these neurons in addictionassociated behaviors [275, 281] and will be discussed more extensively in the next sections. 2.2. Life Events-Induced Changes in Dopamine Neuron Activity 2.2.a. Dopamine Neurons and Addictive Drugs Effects of Addictive Drugs on Dopamine Neuron Activity As mentioned above, the dopamine system is one of the major players mediating the rewarding effects of addictive drugs [85, 214, 275, 281]. Different addictive drugs have the common action of increasing dopamine in the striatal complex [23, 65, 121], however, their action on dopamine neuron excitability varies. Acute administration of psychostimulant drugs such as cocaine [38, 79, 153], amphetamine [209, 269], methylphenidate [24, 88, 209] and caffeine [241] decreases dopamine neuron activity. This effect is likely due to the fact that psychostimulant drugs enhance extracellular concentrations of dopamine (either by enhancing neurotransmitter release or by preventing its reuptake) in the somatodendritic region of dopamine neurons [23]. This increase in dopamine activates somatodendritic impulse-regulating autoreceptors that inhibit neuronal activity. Evidence also exists for amphetamine to have two actions on dopamine neurons: direct via autoreceptors, and indirect via feedback from forebrain structures via different neurotransmitters [33, 196, 198]. Although psychostimulant drugs decrease dopamine neuronal activity while the drugs are onboard, withdrawal from repeated administration of these drugs has opposite effects and produces a transient increase in the firing and bursting activity of dopamine neurons. This is seen both after repeated non-contingent drug exposure, via experimenteradministered injections, or voluntary drug exposure, via intravenous self-administration, (see Fig. 6 ) [163, 275]. Because of its transient nature, the enhancement in dopamine cell excitability produced by withdrawal from drug exposure should not influence the expression of addictive behaviors

Fig. (6). Dopamine neuron activity after self-administration of saline or at different withdrawal time points from cocaine selfadministration (500
g/kg intravenously for 7 days, average daily intake  15 mg/kg). Compared with animals that self-administered saline (n=54 cells), animals that self-administered cocaine show a transient increase in the firing rate of VTA dopamine cells at early withdrawal times from the self-administration procedure [ANOVA Group effect F(4,179)=9.13, p<0.001]. This effect was greatest on withdrawal day 1 (p<0.01, n=34), and decreased in a timedependent manner on withdrawal day 3 (p<0.05, n=24), 10 (ns, n=11) and 30 (ns, n=27). Modified from [163].

(which persist long after dopamine cell activity has recovered). However, it appears to be critical for their development [265, 284]. This short-lived increase in dopamine cell activity is believed to serve as a driving force for transferring information to the forebrain, which exhibits more persistent drug-induced neuroadaptations. When this increase is prevented by pharmacological manipulations, treatment and withdrawal from psychostimulant drugs does not produce long-lasting neuroadaptations in the forebrain, and no longer produces behavioral sensitization [284]. Further evidence for a role of the VTA in the initiation of addiction-associated behaviors comes from studies showing that behavioral sensitization, as well as increases in drug self-administration behavior, can also be induced by psychostimulant infusion into the VTA but not in the NAc [265]. Again, such an increase in drug responding is blocked by intra-VTA administration of drugs (glutamate receptor blockers) [246] that are known to inhibit dopamine neuronal activity. Interestingly, animals with greater predisposition to develop and maintain cocaine selfadministration exhibit prolonged enhancement in dopamine cell activity after withdrawal from cocaine selfadministration compared with the more transient increase observed in animals with reduced addiction liability [161].

Sensitization refers to the progressive increase in behavioral effects of drugs following their repeated administration. This phenomenon reflects druginduced changes in the brain reward system that could underlie certain aspects of addiction [215].

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These differences in the duration of the neuroadaptation induced by cocaine self-administration and withdrawal may indicate that drug-vulnerable individuals have decreased capacity for recovery after exposure to drugs; given the data presented above, it is possible that such a profile could facilitate the development of addiction. Exposure to other drugs of abuse, such as alcohol, cannabinoids or opiates has opposite effects as those seen for psychostimulant drugs. These drugs acutely increase dopamine cell activity [30, 102, 114, 179], when the drug is onboard, and then decrease it following withdrawal from their repeated administration [8, 71, 72, 73]. The increase in dopamine neuron activity produced by acute administration of opiates is due to activation of
opioid receptors; this inhibits local GABA neurons thereby removing tonic inhibition of dopamine cells [114, 128]. In fact, animals lacking
opoid receptors exhibit enhanced GABAergic input to dopamine neurons as shown by increased frequency of spontaneous inhibitory post-synaptic currents [168] as well as reduced dopamine neuron activity [169]. Overall, these data indicate that dopamine neurons respond to addictive drugs with either excitation or inhibition, according to the mechanism of action of the drugs. The effects observed while the drug is onboard are usually the opposite of those produced during withdrawal from repeated drug treatment. It is possible that these neuroadaptations represent a compensatory response such that repeated administration of drugs that reduce impulse activity produces rebound increase in cell activity upon discontinuation, whereas repeated administration of drugs that increase impulse activity has opposite effects. Nevertheless, enhanced dopamine neuron excitability associated with exposure and withdrawal to addictive drugs (either acute, or repeated) appears to be important for the induction of addiction-associated behaviors such as behavioral sensitization. Effects of Addictive Drugs on Plasticity of Excitatory Inputs onto Dopamine Neurons The increase in dopamine cell activity observed after the discontinuation of psychostimulant drugs mentioned above is coupled with increased reactivity of these cells to glutamate [293]. This suggests that changes in the strength of glutamatergic input to dopamine neurons could be responsible for such an increase in dopamine neuron activity. Thus, excitatory synaptic inputs to dopamine cells have been shown to undergo plasticity [19, 193], and the manner in which these inputs are integrated after exposure to drugs of abuse has been the focus of numerous recent studies. One way to evaluate the status of synaptic plasticity for excitatory inputs onto dopamine neurons has been to quantify the ratio of AMPA to NMDA receptor-mediated synaptic currents (AMPA/NMDA ratio). Higher AMPA/NMDA ratios have been shown to correlate directly with the relative degree of synaptic potentiation [217, 264]. In addition, paired-pulse stimulation assays, whereby one measures the ratio between the amplitude of two EPSCs evoked at brief intervals, are a good method to evaluate release probability [75, 94, 188, 226]. Thus, the ratio between the amplitude of the second and first EPSC evoked

at brief intervals reflects whether there is facilitation of transmitter release (ratio >1), depression (ratio <1), or no change (ratio =1). When synapses display paired-pulse facilitation, the probability of transmitter release is thought to be low and residual calcium in the terminals leads to more release during the second stimulus. The opposite is thought to underlie paired-pulse depression. Using these approaches, it was shown that exposure to psychostimulant drugs increases the strength of excitatory synapses onto dopamine neurons (the AMPA/NMDA ratio), without modifying probability of release (i.e. the paired-pulse ratios [87, 254, 255, 264]. Interestingly, the time-course for these effects parallels the one seen on dopamine neuron activity: increased plasticity is seen at early withdrawal times from psychostimulant administration and return to baseline values after ten days of withdrawal from the drug treatment [20]. This further suggests that changes in the strength of excitatory inputs onto dopamine neurons could be a mechanism underlying enhanced neuronal excitability of dopamine neurons seen in vivo . In addition to psychostimulant drugs, plasticity at excitatory synapses onto dopamine neurons have also been observed at short intervals after the exposure to other drugs of abuse such as morphine, nicotine and ethanol as well as by exposure to stress [217], illustrating that a variety of addictive drugs and stress share the common property of enhancing dopamine neuron reactivity to excitatory synaptic input. The fact that addictive drugs produce a common neuronal adaptation in the reward system by enhancing plasticity of excitatory synaptic input onto dopamine neurons is an important finding; synaptic transmission is the fundamental way in which neurons communicate and changes in synaptic strength have been implicated in normal learning and memory formation. Therefore, drug-induced enhancement of excitatory synaptic strength onto dopamine neurons could strengthen transmission in the reward circuit [17, 131, 138] and facilitate the development of addiction [139, 158, 283]. Effects of Changing Dopamine Neuron Excitability on Addiction Liability The data reviewed above indicate that there is a positive relationship between dopamine neuronal activity and addiction liability. To explore the causal relationship between these factors, we will review work showing the effects of manipulating dopamine neuron activity on drugassociated behaviors. Changes in dopamine neuronal activity can be obtained with electrical stimulations, or with a variety of drugs discussed extensively in the first section of this review. We will limit ourselves to a few examples of the effects produced by these treatments. Administration of the GABAB receptor agonist baclofen, at doses that inhibit dopamine neuron activity and release, have been shown to reduce self-administration of amphetamine and cocaine [26]. These effects are apparent on simple schedules of reinforcement (one response triggers one drug infusion [28, 67]) as well on progressive ratio schedules where the amount of responses required to trigger one infusion increase progressively over time [27]. In addition to this, baclofen has also been shown to decrease cocaine responding on second order schedules of reinforcement [67],

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indicating a decrease in cue-controlled drug-seeking as well. In addition to decreasing responding to psychostimulant drugs, other studies have also shown that activation of GABAB receptors can inhibit certain aspects of heroin selfadministration behavior [67, 289, 290]. Together, these findings indicate that activation of GABAB receptors attenuates the reinforcing properties of the drugs as well as the conditioned reinforcing properties of the drug-associated conditioned stimuli. These effects are not attributable to a general decrease in motor activity or motivational drive, because similar doses of baclofen do not modify responding for food and do not impair locomotor activity [213, 236]. In these studies, the receptor agonists were administered systemically; therefore, it is possible that these drugs acted on brain substrates different from dopamine neurons; nevertheless, similar findings were reported after direct infusion of baclofen into the VTA [29], indicating that the effects are, at least in part, attributable to an effect in the midbrain dopamine region. Another way to test the effects of decreases in dopamine neuron activity on self-administration behavior is to use drugs that modify excitatory glutamatergic transmission, which, in turn, is known to modify dopamine neuron activity. These results, however, are not always clear, probably given the non-selective or the non-specific effects of some of the systemically-administered receptor agonists or antagonists (see [15, 123, 208, 220]). More selective studies with local infusions, however, show that direct administration of ionotropic glutamate receptor blockers into the VTA decreases heroin self-administration [291], consistent with the idea that the level of activity of dopamine neurons could modulate self-administration behavior. In addition to being important for self-administration behavior during the self-administration session, dopamine neuron activity also appears to have an important role in drug seeking behavior. Seeking behavior is an important aspect to study because it represents a valid model of drug relapse in humans [137, 232]. Such studies have shown that administering drugs that putatively decrease dopamine neuron activity, such as autoreceptor agonists [163], or drugs that inactivate the VTA [21, 67, 68, 171], both reduce drugseeking behavior in animals that were trained on selfadministration tasks, (see Fig. 7 ). This suggests that an experimentally-induced decrease in dopamine neuron activity could be responsible for decreasing seeking behavior. On the other hand, treatments that are known to enhance dopamine neuron activity, such as stimulation of afferent structures or the local infusions of glutamate or morphine, increase seeking behavior [240, 267]. It should be noted however, that direct stimulation of the medial forebrain bundle with repetitive 3-spike bursts, does not produce an increase in drug seeking behavior [267]. This suggests a physiological increase in bursting, such as that obtained with synaptic stimulation, i.e. several spikes/burst followed by long pauses as shown in Fig. 1b , might be necessary to enhance seeking behavior. Despite the positive relationship between experimentallyinduced increases in dopamine neuron activity and enhanced seeking behavior, there is no relationship between the enhanced dopamine neuron activity observed at short withdrawal times from psychostimulant self-administration

and drug seeking behavior. In fact, seeking behavior increases over time, and is usually lowest at short withdrawal times from drug intake [111, 259] when, instead, neuronal activity is highest [163]. This dissociation could be explained by the fact that at early withdrawal times, increased impulse activity is often accompanied by an upregulation of dopamine transporter levels and might not translate into a functional increase in dopaminergic transmission [203]. In addition, we do not know the timecourse for the development of increased impulse activity in dopamine cells after cocaine self-administration so it is likely that sudden changes from baseline are important to trigger seeking behavior. Relationship Between Phasic Changes in Dopamine Neuron Activity and Operant Responding for Drugs We will further examine the relationship between dopamine neuron activity and addiction by investigating how dopamine neurons fire in response to or anticipation of drug rewards (i.e. during self-administration tasks). As with all operant responding, caution should be taken in interpreting the results, because changes in firing rates prior to performing a response could signal increased incentive wanting, expectation or anticipation, or simply motor activation. In addition, once the drug is onboard, neuronal activity will be influenced by the pharmacological properties of the drug, thereby potentially masking the activity of dopamine neurons during initiation of drug responding. Nevertheless, careful analysis of the timing of neuronal activity during responding to drugs that do not normally dampen neuronal firing can still give us important insights on the role of these neurons in reward-responding. Recording dopamine neurons in freely moving small animals such as rodents, while they are engaged in operant responding has only been attempted by a few investigators. We are aware of only two studies performed during heroin self-administration [147, 149]. These careful studies clearly show that neuronal activity peaks right before each selfinfusion. More precisely, for the first self-infusion, discharge rate increased before the first lever-press to obtain the drug and then remained elevated after the infusion. After the second infusion, phasic increases were only seen prior to lever pressing, whereas infusion delivery produced inhibition of neuronal activity. The inhibition was followed by a gradual increase in firing rate, which peaked again just prior to the next heroin infusion. The nature of the decrease in neuronal activity following the reward itself is unclear, and could be related to behavioral (freezing behavior) or pharmacological factors; however, it is clear that phasic increases in dopamine neuron activity are associated with the activational-motivational-drive towards the reward, but not with the reward itself. This suggests that dopamine neuron activity could be a driving force for goal-directed behavior. We are not aware of studies examining firing patterns of VTA dopamine neurons during self-administration of cocaine. However, recent studies monitoring changes in brain temperature (which reflect neuronal activity [146]) have shown that, similar to heroin self-administration, activity (temperature) in the VTA increases prior to cocaine self-infusions [144, 145] and decreases about one minute after the reward itself. As for the heroin self-administration

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Fig. (7). Effects of autoreceptor-selective doses of D2/D3 receptor agonist quinpirole on drug seeking behavior tested 10 days after the end of cocaine self-administration training (500
g/kg intravenously for 7 days, average daily intake  15 mg/kg). Animals were submitted to a 1hour extinction test (responding is measured in the absence of the reinforcer) followed by a 1-hour reinstatement test (where non-reinforced responding is measured after administration of saline or cocaine). Quinpirole, administered at doses that are known to reduce dopamine neuronal activity, decreased drug seeking behavior in both the extinction [ANOVA group effect F(2,37)=20.9, p<0.001; n= 8-16/group] and cocaine-induced reinstatement phase [ANOVA group effect F(2,25)=6.0, p<0.01; n= 8-10/group] without modifying saline-induced responding [ANOVA group effect F(1, 10)=0.09, ns; n=6/group]. These effects were not due to non-specific changes in motor activity because doses that modified behavior did not modify locomotor activity (data not shown). Modified from [163].

studies, the first infusion of cocaine is not followed by neuronal inhibition (decrease in temperature), but by continuous activation. To assess the relative behavioral and pharmacological component of this effect, the authors studied temperature changes in animals that received noncontingent cocaine infusions at the pattern mimicking selfadministration. These animals show similar patterns of activity as those performing operant responding, but they do not show neuronal activation preceding their first daily drug infusion. Again, these results indicate that neuronal activation coincides with drug-seeking behavior that precedes the actual drug intake. Together with the above studies, these findings suggest that dopamine neuron activity is associated with motivational arousal, or drug seeking, rather than with rewards per se. The concept that an increase in dopamine neuron activity could favor goal-directed behavior is in line with our findings showing that heightened baseline firing and bursting activity of midbrain dopamine cells is associated with enhanced acquisition of cocaine selfadministration behavior; conversely, decreased cell activity is associated with resistance to develop this behavior [161, 166]. 2.2.b. Dopamine Neurons and Natural Rewards Studies examining changes in firing patterns of dopamine neurons during presentation of rewards indicate that temporal changes in action potential activity of dopamine cells may exert a critical function in reward-related behaviors [53, 104], however whether such changes in firing rate increase learning, the impact of the reinforcer, the

associative reward-learning, the conditioned reinforcement, the attention towards such salient stimuli, the incentive salience of a stimulus, or a combination of these all, is still a question of debate [14, 64, 218, 221]. We will discuss briefly such studies and will limit our analysis to work centered on dopamine neuron excitability. We refer to excellent, more thorough reviews on the role of dopamine transmission in general on different aspects of reward responding [14, 41, 120, 143, 224, 282]. Relationship Between Phasic Changes in Dopamine Neuron Activity and Pavlovian Conditioning Numerous studies have examined the response of dopamine neurons using Pavolovian conditioning. Animals are presented with a conditioned stimulus (e.g. an image or light), which is followed by a reward (e.g. juice). These studies show that a large percentage of dopamine neurons increase firing rate after the initial presentation of the reward (when the reward is unexpected). During the early phases of the Pavlovian task, when the animal is learning the association between the conditioned stimulus and the reward, dopamine neuron activity increases phasically during both the reward and the conditioned (reward-predicting) stimulus. Once the task is fully learned, presentation of the reward ceases to elicit increases in neuronal activity; such increases are transferred entirely to the conditioned rewardpredicting stimulus [221, 222] so that dopamine cell activity increases prior to a reward but not with the reward itself. This does not depend on a time-dependent decrease in sensitivity to the reward because modifying the predictability

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of the reward (by presenting it earlier than expected) still produces a phasic increase in dopamine neuronal activity. In addition, omitting an expected reward depresses neuronal activity at the exact time when the reward was predicted. This suggests that dopamine neurons are sensitive to the unpredictability of the timing and occurrence of rewards. In other words, dopamine neurons are error predictors. This coding for prediction errors resembles that employed in conditioning theories [211] and is strikingly similar to the temporal difference model of Pavlovian learning proposed by Sutton and Barto [247]. Simplistically, such theories indicate that reinforcers that occur better than predicted will induce learning; those that are fully predicted do not contribute to learning, and those that are worse than predicted (i.e. they are omitted) produce the extinction of the learned behavior. Accordingly, it has been suggested that dopamine neurons could act as a teaching signal that could facilitate the learning of reward-related responses [222]. Although Pavlovian conditioning and the temporal difference model compute predictive signals, such prediction is not translated into action and it does not improve or influence reward delivery. Several other theories have therefore been proposed to determine the relevance of changes in dopamine neuron activity produced during Pavlovian conditioning in reward-related behavior. Recently, a variation of the temporal difference algorithm was proposed; this was based on an internal model approach that uses learning experiences to make predictions of future rewards. This theoretical model allows for Pavlovianinduced changes in dopamine neuron activity to code for the planning of goal directed behavior [245]. Other studies, instead, have argued that the short-latency dopamine response during Pavlovian conditioning is too short to be able to signal reward and it was therefore proposed that phasic increases in neuronal activity in response to conditioned stimuli could play a different role in associative learning: they could help orient attention and behavior towards subsequent salient stimuli [210]. This could facilitate associative learning [31] and could prepare the organism for the appropriate reaction to a significant event [210]. On a similar line, because conditioned stimuli predicting rewards increase dopamine neuron activity, they could acquire the capacity to elicit a conditioned attentional orienting response that facilitates goal-directed behavior [117]. This was further corroborated by more recent studies [76] showing that the superior colliculus (a primitive visual structure in the monkey), is the primary source of shortlatency visual information to dopamine neurons. It is also possible that dopamine neuron changes during such Pavlovian tasks are responding to the incentive value of the conditioned stimulus, which predicts the reward, or that they code for expectation of the reward. Arguments against the latter hypothesis are provided by results obtained using a delayed alternation task. After having learned this task, dopamine neurons increase activity when exposed to the instruction cue (which provides special information for task performance) and the trigger stimulus (which predicts reward), but they do not increase their activity during the lapse (delay) between the instruction and the trigger stimulus. Because of the lack of sustained activation during the delay period, changes in neuron activity are not likely to code for expectation of a reward, or even preparation of

movement but, rather, for attentional and motivational processes that are involved with learning and cognitive behavior [223]. Nevertheless, in situations where reward probability is uncertain, dopamine neurons show an increase in activity preceding a reward that increases from the time of the conditioned stimulus predicting reward to the expected time of reward itself, indicating that activity can be related to reward expectation, or at least to uncertainty of expectation [89]. It should be noted that all of these theories are not mutually exclusive. In fact, additional studies, based on existing electrophysiological, neurochemical and neuroimaging data propose that dopamine neuron activity signal reward prediction as well as the incentive salience of a reward [170, 183]. Furthermore, recent studies from Schultzs group, indicated that dopamine neurons show responses related to motivational salience, because they can code the reward value, which is a hallmark of a motivational system [257]. Therefore, increases in dopamine neuron activity could represent a mechanism by which rewards increase their incentive value or salience, thereby facilitating their addictive potential. Relationship Between Phasic Changes in Dopamine Neuron Activity and Operant Responding More information on the role of dopamine and reward come from operant conditioning studies. During operant conditioning, an animals response is directly paired with an outcome, and goal-directed behavior is a consequence of the animals intention to obtain a reward (or to seek for one). Such studies could give us information on anticipation of an outcome, the drive towards the outcome, the value of the predictive cues, or of the reward itself. Initial indirect evidence for a facilitatory role of dopamine neuron activity on goal-directed behavior can be extrapolated from studies examining behavior after treatments known to modify dopamine neuron activity. The infusion of GABA into the VTA, which is known to decrease dopamine cell activity (see previous sections), has been shown to disrupt appetitive behavior. Interestingly, this treatment only impairs approach to an appetitive reward (sucrose), without modifying its consumption [124]. This suggests that impulse activity of dopamine neurons is associated with approach, or wanting behavior, without having much relevance to the liking of the reward itself. Studies measuring dopamine neuron activity during operant responding are scarce. One study measured dopamine neuron activity during operant responding for a sucrose reward in rats [151]. This study showed variable responses across neurons, which exhibited excitations or inhibitions during different phases of the reward-related test (approach, responding and consummatory phases). Other operant-based studies have been performed in monkeys, using spatial choice tasks, instructed spatial tasks, and spatial alternation delayed tasks that use Pavlovian conditioning and operant responding [223]. It should be noted that all stimuli that predict reward in some way, even during operant conditioning, are Pavlovian conditioned. As mentioned previously, these studies show that dopamine neurons activate phasically in response to the instruction cue or the trigger stimulus, however, dopamine neuron activity is not

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sustained between the lapse of time that predicts the reward and the reward itself, nor during the motor task that is required to obtain the reward. The authors thus suggested that changes in the activity of these neurons do not code for goal-directed behavior or reward expectation [223]. In these tests, although animals did perform operant responses, they could not control when they would obtain a reward; they were always given an instruction, after which they could perform the correct operant response that would result in reward delivery. Although a correct operant response probably reflects the animals intention to obtain the reward, it would also be interesting to perform operant tasks where animals can choose when to respond for a reward. Such tests could give us insight on how different patterns of drug-seeking behavior are linked with dopamine neuron activity; alas such tests would not be free of confounds, since they would not be able to distinguish between incentive 'wanting', expectation, or motor activation. 2.2.c. Dopamine Neurons and Stress Defining Stress Stress is a complex term that usually carries negative connotations. Under a biological point of view, it is widely accepted that stressful events have the common feature of elevating blood levels of glucocorticoids, the major stress hormones (for review, see [7, 16, 56, 58, 186]). Under a psychological point of view, it is generally conceived that stressful stimuli are something that will be avoided by animals. However, such a vision might need some revisiting. For example, in humans, it is classically accepted that some individuals show preference for situations that enhance stress levels (e.g. sensation-seekers [295]). In animals, similar traits exist as well [59]. Rats with enhanced stress reactivity (glucocorticoid secretion) in response to certain situations have been shown to spend more time in these stressful situations (e.g. a novel environment, or the open arms of a plus maze) compared with rats with reduced stress reactivity [134]. In other words, some animals choose to spend time in stressful situations that promote the release of stress hormones. This self-administration of stress is further corroborated by studies showing that rats will self-administer corticosterone, the major glucocorticoid hormone in the rat [63, 201]. In addition to there being individuals that seek stressful situations (indicating that stress is not necessarily an avoided condition), one must consider that there are different degrees of stress. Stressors could have different effects according to their intensity, duration and predictability. Mild stressors, such as reduction in food availability or changes in the social environment can increase arousal and produce a state of activation, whereas intense stress such as the "chronic mild stress" procedure produces learned helplessness, and depressive-like symptoms [39, 40, 125, 279]. Indeed one could view stress as having an inverted U-shaped curve, where low to moderate stressors may produce the excitation of a system, whereas higher levels could inhibit the same system. This notion is corroborated by behavioral findings showing such an inverted U-shaped curve in response to increasing doses of the stress hormone corticosterone [60].

Effects of Stress on Dopamine Neuron Excitability Information discussed above suggests that stress exhibits an inverted U-shaped curve, where low to moderate stressors are activating whereas stronger stressors are inhibitory. This is particularly true for the dopamine system. Dopamine levels in the nucleus accumbens have been shown to increase following acute or repeated mild stress [9, 126, 136, 256]; instead they decrease following intense, chronic or unpredictable stress [66, 159]. Although most studies focused on the effects of stress on dopamine levels, a few have analyzed the effects of stress on the impulse activity of midbrain dopamine neurons. These studies are consistent with each other as they show that stress increases dopamine neuronal transmission. Chronic exposure to cold stress, although reducing the number of detectable neurons, also enhances the proportion of neurons showing high levels of bursting activity [184]; this suggests that stress could facilitate the switch from regular-firing to burst-firing activity. A similar effect is also observed following changes in food availability or restraint stress (such conditions are considered stressful because they increase glucocorticoid levels [55, 61, 62, 233]). Thus, repeated food-restriction, (Fig. 8a), or a single day of complete food deprivation, (Fig. 8b), enhances both bursting and firing activity of dopamine neurons in the VTA of anesthetized rats. In addition, in awake rats, a 30-min restraint stress increases firing in all dopamine neurons and bursting in 80% of the neurons; interestingly, bursting activity is preferentially increased in those neurons with high burst rates under resting conditions [6]. In awake behaving cats, the exposure to the stress of a conditioned emotional reaction, which also produces an increase in glucocorticoid hormones, also increases dopamine neuron activity [260]. Finally, administration of glucocorticoid hormones, in the range between low and high peaks of the circadian cycle, increases glutamate-induced bursting activity in VTA dopamine neurons [194].

Fig. (8). Effects of stress on dopamine neuron activity. (a) Compared with ad-libitum-fed controls (n=24 cells), animals whose daily ration of food was decreased over 12-22 days to produce a 10%-decrease in body weight (n=25 cells) show heightened firing activity of dopamine neurons (T test, p<0.001). (b) Similar effects are produced by acute food deprivation (24h of food removal). (n=27-30 cells/group, T test, p<0.01). Fig. (a) is modified from [162]; Fig. (b) is preliminary unpublished data from M. Marinelli and C.N. Rudick.

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In addition to modifying dopamine neuron activity, stress has also been shown to enhance excitatory synaptic input onto dopamine cells [217]. Thus, exposure to cold swim stress enhances the AMPA/NMDA ratio recorded from dopamine neurons following synaptic stimulation [217]; this effect is probably mediated by a stress-induced increase in corticotropin-releasing factor, as administration of this hormone induces a potentiation of NMDA receptor-mediated synaptic transmission in VTA dopamine neurons [263]. This increase in excitatory synaptic transmission could be one of the mechanisms by which stress is able to increase dopamine neuron activity. Effects of Brief Aversive Stimuli on Dopamine Neuron Excitability While the above-listed forms of stressors have been shown to increase dopamine neuron activity or excitability, brief exposure to mildly aversive situations (that might not be stressful and might not produce an increase in glucocorticoid levels, nor in dopamine release [156, 277]) either increase neuronal activity, have no effects on dopamine neuron activity or more generally produce a transient decrease in their firing rate. In awake cats, the brief presentation of aversive stimuli (such as brief tail pinch, immersion of paws in cold water, inaccessible food or white noise) do not seem to produce major changes in neuronal firing [242]. In rats, the pinching paw while the animal is anesthetized has been shown to slow down dopamine neuron firing in 10/12 neurons [262]. Pinching of the tail in similar conditions also depresses activity in 25% of dopamine neurons projecting to cortical regions, but increases it in 65% of this mesocortical population [160]. In monkeys a similar pinching stimulus has been shown to decrease dopamine neuron activity in 50% of the entire neuronal population, but to increase it in 25% of the cells or to have no effects in the remainder of the neuronal population [225]. A decrease in dopamine neuron activity is also seen when monkeys that are trained to expect a juice reward are not offered such a reward, which represents an aversive stimulus [222, 224]. Non-noxious airpuffs, however, do not produce significant changes in dopamine cell activity [182], suggesting that aversive stimuli might require greater intensity to produce any effects or that dopamine neurons do not respond to aversive stimuli [182]. Differences Between Aversive and Stressful Stimuli Overall, these findings, together with those described in the previous paragraphs, indicate that acute and short aversive stimuli (e.g. air puffs, 15 sec paw pinch) can produce increases, decreases or no effects in neuronal activity and neurotransmitter release. Instead, exposure to repeated mild stress (e.g. repeated or prolonged exposure to cold, restraint, food deprivation) increases dopamine neuron activity. It is unlikely that such increases are artifacts due to recording techniques [261] because similar stressors induce a parallel increase dopamine levels in terminal regions [164, 261]. It is therefore likely that stimuli need to be presented repeatedly, or require long periods of time in order to become stressful and produce increases in dopamine neuronal firing. In addition stressors and aversive stimuli could be different in nature, and prolonged increases in stress hormones (glucocorticoids) might be required for

stimuli to modify dopamine neuron activity. Consistent with this idea are the findings that stress-induced increases in dopamine neuron excitability are prevented by the administration of glucocorticoid receptor antagonists [217]. In addition, for stress to increase dopamine levels, it needs to be moderate and presented repeatedly or for a prolonged period of time (for review see [164]). Possible Relevance of Stress-Induced Increases in Dopamine Neuron Excitability Putting aside the mechanism by which stress could increases dopaminergic transmission and taking into account its relevance, it is puzzling how the effects of stress are similar to those produced by situations that are considered rewarding (e.g. the unexpected presentation of a reward [224]). It is possible that stress-induced increases in dopaminergic transmission could be viewed as coping mechanism that helps reduce the aversive effects of stress and thus increases the individuals ability to cope with the stressful situation. Similar to what has already been proposed for stress hormones [164], this increase in dopamine could reduce the aversive properties of stressors, and possibly even make some stressors reinforcing. With repeated or intense stress, however, dopaminergic transmission could decrease and lead to depressive-like states [39, 40, 125, 279] and offset an individuals homeostatic state. In addition to this, the fact that dopamine cells of stressed animals show stronger responsiveness to excitatory synaptic inputs [217] could possibly result in the animals heightened reactivity to environmental stimuli. After stressful conditions, such a phenomenon could serve as a survival mechanism allowing animals to increase their attention towards behaviorally-relevant stimuli. Finally, sustained increases in dopamine neuron activity have been suggested to reinforce risk-taking behavior [89]. Although very speculative, it is possible that stress-induced prolonged increases in dopamine neuron activity could facilitate risktaking behavior and thereby broaden the animals ability to respond to stressful situations. 3. SUMMARY AND CONCLUSIONS Dopamine neurons in the midbrain are spontaneously active and show regular, irregular and bursting patterns of activity. Neuronal activity is regulated by intrinsic and synaptic factors. As for the intrinsic factors, the binding of dopamine to impulse-regulating dopamine D2/D3 autoreceptors located on the dopamine cell body activates GIRK potassium currents, hyperpolarizes the cell, and thereby inhibits neuronal activity. Activation of SK channels, produced by slight rises in intracellular calcium, increases SK potassium currents responsible for the AHP, and thereby produces the neuronal inhibition that is typical after a train of spikes. Differences in the strength of excitatory or inhibitory synaptic input also produce changes in neuronal excitability. As for most systems, glutamatergic synapses are excitatory and produce their effects by activating AMPA and NMDA receptors. GABAergic synapses are largely inhibitory, and can act on ionotropic GABAA or metabotropic GABAB receptors to produce fast or slower inhibitions of neuronal activity respectively.

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Changes in neuronal activity of dopamine neurons are observed throughout an individuals life. Activity is low at birth, peaks during the adolescent period, and decreases thereafter. Changes in the basal activity of these neurons can also be induced by life experiences, such as exposure to drugs or stress. These are manifested as enhanced neuronal firing, bursting, and in the strength of excitatory synapses onto these cells. Such increases in neuronal activity are associated with greater responding for cocaine, suggesting that increases in the baseline activity of these neurons could favor addiction liability. This hypothesis is supported by observations that reductions of dopamine cell activity are coupled with decreases in self-administration and drugseeking behavior. In addition to changes in the basal activity of these cells induced by life events, neuronal activity can also be modulated phasically. Phasic increases in impulse activity are observed in all forms of reinforcement-learning. In operant responding for drugs, neuronal activity has been shown to increase prior each voluntary self-infusion, suggesting that phasic increases in dopamine cell activity are associated with goal-directed behavior, or possibly the motivational drive to seek the drug. In Pavlovian conditioning for natural rewards these neurons increase bursting when presented with reward-predicting cues, or unexpected rewards, indicating that these neurons signal reward prediction errors. Such phasic increases in dopamine neuron activity during the presentation of reward-predicting cues could increase attention towards these stimuli. Overall, the phasic increases in dopamine neuron activity that precede rewards could be a potential mechanism that facilitates learning, or the incentive value of the reward-associated cues. Repeated or prolonged exposure to mild stressors (such as restraint, food restriction or cold stress) has been shown to produce increases in the basal activity of dopamine neurons. On the other hand, presentation of brief aversive stimuli (such as brief paw or tail pinches, or air puffs), produces variable effects on dopamine neuron firing. It is possible that stressors need to be presented repeatedly or in a prolonged manner to produce increases in dopamine neuron activity. It is, however, surprising how stressors could produce similar effects as those produced by rewarding stimuli. It is possible that such increases could serve as a coping mechanism that could decrease the aversive nature of the stress, increase attention towards the environment, or possibly even increase risk behavior. Such effects could in the short run facilitate the individuals coping responses to the environment in conditions of stress. In conclusion, dopamine neurons are spontaneously active neurons whose activity can be modulated by diverse life events, ranging from exposure to drugs, stress, or unpredictable rewards. Ultimately if prolonged, these changes could lead to the development of dopamineassociated disorders, such as drug addiction. Several hypotheses have been put forward to explain the mechanism by which addiction liability or the learning of reward-related tasks could be facilitated by increases in dopamine neuron activity (either changes in the basal firing rate, or phasic changes in response to stimuli). These include changes in

learning, the impact of the reinforcer, the associative reward-learning, the conditioned reinforcement, the attention towards such a salient stimulus, the incentive salience of a stimulus, or a combination of these. ACKNOWLEDGEMENTS We thank: Frdric Ambroggi, Kristin Anstrom, Kent Berridge, Lionel Dahan, Patricia DiCiano, Eugene Kiyatkin, Wolfram Schultz and Anthony West for very useful input, discussion, comments or the sharing of data and information that helped us write sections of this review. Preparation of this review was supported in part by USPHS grant DA O4093 (X-TH and FJW) and a Senior Scientist Award (DA 00456) to FJW. ABBREVIATIONS AHP AMPA EGTA EPSC EPSP GIRK Ih LTP LTD NAc PND SK SNc TEA VTA = Afterhyperpolarization = Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid = Ethylene glycol-bis(2-aminoethylether)-N,N,N_, N_-tetraacetic acid = Excitatory post synaptic current = Excitatory post synaptic potential = G-protein-coupled inward-rectifying potassium = Hyperpolarization-activated cation current = Long term potentiation = Long-term depression = Nucleus accumbens = Postnatal day = Calcium-activated small conductance potassium = Substantia nigra, pars compacta = Tetraethylammonium = Ventral tegmental area

mGluRs = Metabotropic glutamate receptors NMDA = N-methyl-D-aspartate RT-PCR = Reverse transcriptase polymerase chain reaction

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Received: July 7, 2005

Revised: November 18, 2005

Accepted: November 18, 2005