TINS 1344 No.

of Pages 18

Feature Review

Rebalancing the Addicted Brain: Oxytocin

Interference with the Neural Substrates of
Addiction
Michael T. Bowen1,2 and Inga D. Neumann3,*

Drugs that act on the brain oxytocin (OXT) system may provide a much-needed Trends
treatment breakthrough for substance-use disorders. Targeting the brain OXT The brain OXT system is emerging as
one of the most exciting new treatment
system has the potential to treat addiction to all major classes of addictive
targets for substance-use disorders.
substance and to intervene across all stages of the addiction cycle. Emerging
evidence suggests that OXT is able to interfere with such a wide range of Drugs acting on the brain OXT system
ameliorate a range of addictive beha-
addictive behaviours for such a wide range of addictive substances by reba- viours for all major classes of addictive
lancing core neural systems that become dysregulated over the course of substance, including alcohol, stimu-
addiction. By improving our understanding of these interactions between lants, opioids, and nicotine.

OXT and the neural substrates of addiction, we will not only improve our OXT inhibition of drug consumption,
understanding of addiction, but also our ability to effectively treat these dev- drug reward, and prime- and cue-
induced relapse involves interference
astating disorders.
with brain reward circuitry, in particular
with dopaminergic systems within the
striatum.
Oxytocin: A Modulator of the Brain Circuitry Subserving Drug Addiction and
A Potential Therapeutic Target Synthetic OXT can interfere with stress
Substance-use disorders, or addictions, are chronic, relapsing brain disorders (reviewed in [1]). responses and socioemotional impair-
ments during protracted withdrawal.
They are among the most prevalent and devastating diseases, with a staggering 15% of all
The effectiveness of synthetic OXT in
deaths worldwide each year attributed to the harmful use of tobacco, alcohol, and illicit inhibiting stress-induced relapse likely
substances [2,3]. Despite this enormous burden, treatment options for substance-use dis- involves its ability to compensate for
orders are severely limited, with currently available pharmacological and psychosocial inter- impaired OXT functionality and to
rebalance specific dopaminergic path-
ventions marred by a lack of effectiveness, dangerous adverse effects, and poor compliance in
ways as well as the hypothalamic and
the community [4,5]. extrahypothalmic stress systems.

Addiction is characterised by a vicious cycle of bingeing, intoxication, and reward, followed by The ability of OXT to enhance connec-
tivity between frontal cortical regions,
withdrawal and negative affect, and finally periods of intense preoccupation with drug seeking
as well as between the amygdala and
and anticipation for drug consumption and/or reward that precede relapse [1]. These three the nucleus accumbens (NAc), is
stages of the addiction cycle are underpinned by severe disruption and imbalance in neural another factor likely to be critical to
circuits involved in reward, learning, motivation, stress, socioemotional regulation, and higher- its effects on relapse, by improving
inhibitory control over craving and
order cognitive abilities (such as inhibitory control) [1,6]. cue reactivity.

There is a growing body of evidence that suggests targeting the brain OXT system [526_TD$IF]could
provide a much-needed treatment breakthrough for addiction. The neuropeptide OXT is
perhaps best known for its role in the hormonal regulation of reproductive functions, such 1
The University of Sydney, Faculty of
as birth, lactation, and sex [7]. Accompanying and supporting these peripheral functions, the Science, School of Psychology,
brain OXT system is heavily involved in the promotion of corresponding social behaviours, and Sydney, NSW, Australia
2
the regulation of stress, anxiety, and fear. The brain OXT system comprises projections from The University of Sydney, Brain and
Mind Centre, Sydney, NSW, Australia
hypothalamic OXT neurons to several brain regions, and there is wide distribution of OXT 3
Regensburg Center of Neuroscience,
receptors (OXTRs) throughout the brain (Box 1) [7]. Department of Behavioural and

Trends in Neurosciences, Month Year, Vol. xx, No. yy https://doi.org/10.1016/j.tins.2017.10.003 1

© 2017 Elsevier Ltd. All rights reserved.
 TINS 1344 No. of Pages 18

Box 1. The Endogenous OXT System Molecular Neurobiology, University of

The nonapeptide OXT is primarily synthesised in magnocellular neurons of the hypothalamic supraoptic nucleus (SON), Regensburg, Regensburg, Germany
paraventricular nucleus (PVN), and accessory nuclei, which have major projections to the neurohypophysis. Neu-
rohypophyseal OXT terminals form neurohaemal contacts with local capillaries that lack the blood–brain barrier,
allowing secretion of OXT into the blood stream. Physiological stimuli for the peripheral secretion of OXT include birth, *Correspondence:
suckling, and sexual stimulation in both male and female mammals. Other stimuli that induce OXT release into the blood inga.neumann@biologie.uni-
include exposure to various physical or psychosocial stressors. regensburg.de (I.D. Neumann).

Hypothalamic magnocellular and parvocellular OXT neurons also have axon collateral and/or axonal projections
targeting various parts of the forebrain, limbic, and reward systems, including the central and medial amygdala, lateral
septum, bed nucleus of the stria terminalis, hippocampus, prefrontal cortex, anterior olfactory nucleus, and nucleus
accumbens (NAc). Using intracerebral microdialysis in conjunction with sensitive and specific detection assays, OXT
release was found in limbic regions, and in the SON and PVN, where OXT can be released somatodendritically (reviewed
in [110]) in response to birth, suckling, sexual stimulation, and various kinds of stress (reviewed in [7]). However, although
the same stimuli trigger peripheral and intracerebral release of OXT, the temporal dynamics of release patterns can
differ.

Numerous behavioural and physiological functions have been attributed to centrally released OXT. OXT acts within the
central amygdala (CeA) and PVN to reduce anxiety, and inhibits stress responses of the hypothalamo–pituitary–adrenal
(HPA) axis, likely via inhibition of the hypothalamic corticotropin-releasing factor (CRF) system (reviewed in [7,60]). OXT
also acts within the CeA to promote extinction of context fear [9], and within the lateral septum to reverse social fear [61].
OXT has important actions in several regions involved in the reduction of food intake [111], regulation of sexual behaviour
[112], and the promotion of numerous prosocial behaviours, including social preference behaviour [53] and pair bonding
in monogamous species [7,113]. Moreover, parvocellular OXT neurons of the PVN project to the brainstem, where OXT
is involved in autonomic regulation and antinociception [114]. Brain OXT has also been shown to regulate many facets of
addictive behaviour (see the main text).

At physiological concentrations, OXT interacts with one type of G-protein-coupled OXTR, which results in activation of a
variety of intraneuronal signalling cascades and the regulation of intracellular calcium levels or gene transcription (e.g.,
[65]; reviewed in [115]). At pharmacological concentrations, OXT has also been shown to act at the closely related
vasopressin V1AR to exert some of its social effects [27,29] as well as at least one submember of the Cys-loop family of
receptors [17]. In humans, synthetic OXT can be administered intranasally, affecting a variety of neuronal and
behavioural functions, especially in the context of socioemotional behaviour (reviewed in [7,116]).

A robust body of preclinical evidence and emerging clinical studies show that OXT may have
beneficial effects at each stage of the above-described addiction cycle, across all major classes
of substances of abuse (SOAs, see Glossary; Table 1; reviewed in [8]). Briefly, OXT not only
reduces drug consumption and drug reward, but also restores normal responding to at least
some natural reinforcers, reduces [527_TD$IF]heightened emotionality and stress reactivity during
withdrawal and abstinence, and prevents reinstatement to drug seeking.

Given that OXT has effects across different stages of the addiction cycle, and for a range of
addictive substances, it follows that it is likely to interact with several of the core neurobiological
systems involved in the development and maintenance of addiction [1,6]. Here, we review
existing evidence for the capacity of OXT to modulate these neurobiological systems, to
promote the reinstatement of their physiological balance, and, thus, to interfere with addictive
behaviours driving drug consumption and reward, protracted withdrawal, and relapse.

Oxytocin Interferes with Systems Involved in Drug Consumption,

Intoxication, and Reward
The initial stage of the addiction cycle, which is often referred to as the bingeing and intoxication
stage, involves the consumption of high levels of [528_TD$IF]the SOA and is largely driven, at least initially,
by the positive reinforcing effects of the SOA [1]. During this stage, OXT and specific OXT
fragments administered both peripherally and centrally in rodent studies reduced consumption
and the rewarding effects of alcohol, opioids (including heroin and morphine), and stimulants

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Table 1. The Effects of OXTa Administration during Different Stages of the Addiction Cycle for each Major Glossary
Class of Addictive Substances in Both Preclinical and Clinical Studies Anxiogenic: anxiety-increasing, that
Substance of Abuse Stage of Addiction Cycle Study Type OXT Interferencee[513_TD$IF] Refsg[514_TD$IF] is, an anxiogenic situation results in
increased anxiety-related behaviour.
Alcohol Consumptionb Preclinical [34–36,69,87–90]
Anxiolytic: anxiety-reducing, that is,
Withdrawalc[51_TD$IF] Preclinical [51_TD$IF][11] an anxiolytic drug lowers anxiety-
related behaviour.
Clinical [516_TD$IF][91]
Dopamine utilisation: refers to the
Relapsed Preclinical [34] rate at which dopamine is used in a
particular brain region. Utilisation can
Clinical [91,92]f[517_TD$IF]
be impacted by a range of factors,
[92]f including changes in receptor density
d and affinity, and circulating levels of
Cannabis Relapse Clinical [93]
hormones. Greater dopamine
Nicotine Withdrawalc[51_TD$IF] Preclinical [51_TD$IF][94] utilisation in the NAc has been
b associated with increased sensitivity
Opioids Consumption Preclinical [11]
to the reinforcing effects of SOAs.
[95] Drug cue: a stimulus experienced
during drug self-administration that
Withdrawalb[518_TD$IF] Preclinical [51_TD$IF][11,43]
becomes paired with the effects of
d
Relapse Preclinical [43,96] the drug and the drug-taking
Clinical [519_TD$IF][97] behaviour. Drug cues can become
powerful triggers of drug-seeking
[98] behaviour and, thus, are heavily
Stimulants Consumptionb[51_TD$IF] Preclinical [51_TD$IF][14,70,99–105] involved in many cases of relapse.
Drug prime: exposure to a small
c
Withdrawal Preclinical [44,106] amount of the substance to which an
Relapsed[51_TD$IF] Preclinical [51_TD$IF][70,75,76,99–109] individual is addicted. Exposure to a
drug prime is one of the main
Clinical [520_TD$IF][74,97]f triggers of relapse.
[74]f Dysphoria: pronounced
dissatisfaction and unease that often
a leads to emotional distress.
Here, OXT refers to the administration of synthetic OXT, OXT fragments, or other OXTR agonists.
b
Consumption refers to studies examining OXT effects on drug consumption and their rewarding properties. Executive functions: cognitive
c
Withdrawal refers to studies examining OXT effects on acute and protracted withdrawal. processes that allow for the cognitive
d
Relapse refers to studies examining OXT effects on craving, reinstatement of drug seeking, and enduring-treatment control of behaviour. They include:
effects.
inhibitory control (the ability to inhibit
e
, positive interference (reduction in addictive behaviours); [52_TD$IF], negative interference (increase in addictive behaviours); [523_TD$IF],
impulses); cognitive inhibition (the
no interference (no change in addictive behaviours).
f
[92] showed a positive effect of intranasal OXT in patients with alcohol use disorder with an anxious attachment style, and a ability to ignore stimuli not relevant to
negative effect in those without. [74] showed intranasal OXT disrupted the positive relationship between anger and desire the task at hand); attentional control
to use cocaine but increased baseline desire to use and cue-induced excitability[524_TD$IF]. (an individual’s ability to choose what
g
Reviewed in [8]. they pay attention to); cognitive
flexibility (the ability to think about
multiple concepts simultaneously and
to shift between thinking about
(including methamphetamine and cocaine). Beyond this, OXT and OXT fragments reduce some different concepts); and the higher-
of the acute intoxicating effects of alcohol, cocaine, and methamphetamine, and inhibit the order functions facilitated by these
processes that allow reasoning,
development of tolerance to some of the acute effects of opioids, cocaine, and ethanol. For
problem solving, and rational
more information on these studies, see Table 1 and [8]. thinking.
Hypohedonia: a reduced ability to
Oxytocin Interferes with Drug Actions within Dopaminergic Reward Pathways derive pleasure from activities that
are normally enjoyable.
The mesolimbic dopamine pathway connecting the ventral tegmental area (VTA) to the nucleus
Hypothalamo–pituitary–adrenal
accumbens (NAc) is perhaps the best-characterised addiction pathway and is heavily involved (HPA) axis: a major neuroendocrine
in the bingeing and intoxication stage of the addiction cycle. The mesolimbic dopamine system system comprising the
has a key role in the rewarding properties of almost all SOAs. When a rewarding drug is hypothalamus, pituitary gland, and
adrenal cortex, which become
consumed, it causes a swift and pronounced increase in dopamine release within the NAc. This activated during stressor exposure.
powerful release of dopamine not only mediates the rewarding effects of SOAs, but also leads Malfunctioning of the HPA axis has
to incentive salience being attributed to originally neutral cues that are associated with the been implicated in a range of
drug, and the development of powerful motivation to consume the substance (reviewed in [1]).

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Oxytocinergic projections originating within the hypothalamic paraventricular nucleus (PVN; disorders, including anxiety, mood,
Box 1) terminate within the dopamine-rich brain regions that are critically involved in addiction, and substance-use disorders.
Incentive salience: ‘wanting’ or
including the NAc [9]. Furthermore, recent work confirmed that OXTRs are expressed on ‘desiring’ a rewarding stimulus is the
dopamine neurons that project from the VTA to the NAc, prefrontal cortex (PFC), prelimbic result of incentive salience. It is a
cortex, and amygdala [9,10]. Accumulating evidence suggests that the ability of OXT to reduce cognitive process that leads to
drug consumption and reward, as well as some of the dopamine-driven acute effects of powerful motivational resources (e.g.,
attention and approach behaviours)
stimulant drugs, is due to its interference with the actions of SOAs on these dopamine being directed toward a rewarding
pathways. stimulus.
Positive reinforcement: leads to an
increase in the rate of a particular
For instance, OXT blocked cocaine-induced increases in dopamine utilisation in the NAc,
behaviour when that behaviour leads
and microinfusion of OXT into the NAc inhibited heroin self-administration in rats (reviewed in to a desirable or pleasant outcome.
[11]). Similarly, intracerebroventricular (ICV) OXT inhibited both methamphetamine-induced Natural reinforcers/rewards: a
locomotor hyperactivity and reduction in dopamine turnover in the NAc [12]. Peripherally stimulus that is inherently reinforcing.
Food, water, and positive social
administered OXT also decreased methamphetamine-induced activation of the NAc and
contact are examples of natural
subthalamic nucleus [13]. Baracz and colleagues [14] extended on these findings by demon- reinforcers.
strating that microinfusion of OXT directly into the NAc or subthalamic nucleus attenuated the Negative reinforcement: leads to
formation of a methamphetamine-conditioned place preference (CPP). In support of a central an increase in the rate of a particular
behaviour when that behaviour
OXTR-mediated action of peripherally administered OXT, suppression of motivation to con- removes an aversive or unpleasant
sume methamphetamine by intraperitoneal (IP) OXT was blocked by bilateral infusion of an stimulus.
OXTR antagonist (OXTR-A) directly into the NAc [15]. Moreover, ICV administration of OXT Neurohaemal contact: the direct
completely prevented the increase in dopamine release within the NAc that was induced by contact between neuronal structures,
mainly terminals, and blood
acute or repeated ethanol administration in rats, and this blockade was associated with capillaries, where neurohormones,
reduced alcohol consumption and preference [16]. such as oxytocin or vasopressin, are
released into the blood.
Neurohaemal contact zones, such as
Oxytocin Interactions with GABA-A, 5-HT, and MC4R Receptor Systems
those found in the neurohypophysis,
In the case of ethanol, OXT also appears to directly interfere with one of its substance-specific lack a blood–brain barrier.
mechanisms of action. The ability of OXT to reduce ethanol consumption (Table 1), to inhibit Neurohypophysis: the posterior
ethanol intoxication [17], to prevent the development of rapid tolerance to some of the acute lobe of the pituitary gland, which is
of neuronal origin and stores and
effects of ethanol (reviewed in [11]), and to block ethanol-induced dopamine release within the
releases OXT and vasopressin into
NAc shell [16] may involve a direct interaction with a specific GABAergic system. Potentiation of the bloodstream via neurohaemal
GABA-gated activation of d subunit-containing GABAA receptors by ethanol has been impli- contact zones.
cated in all the aforementioned effects of ethanol [18–24]. In this context, OXT completely Stress reactivity: the tendency of
an individual to respond to a stress
blocked the positive allosteric modulation of these receptors by ethanol, without interfering with
and/or the magnitude of their
their normal functioning under physiological conditions [17]. This provides a compelling response to that stressor.
possible mechanism underlying the aforementioned in vivo OXT–ethanol interactions (Figure 1). Substance of abuse (SOA): a
Interestingly, OXT exerted these effects by acting directly on extrasynaptic d subunit-containing psychoactive substance that can
lead to addiction and harmful mental
GABAA receptors, uncovering a new molecular target for pharmacological concentrations of and/or physical health outcomes.
OXT. This adds to a growing body of evidence showing that OXT binds directly to other
receptors in the brain, including vasopressin receptor subtypes, especially at pharmacological
concentrations [17,25,26], possibly helping to explain its effects on such a broad range of
behaviours [17,27–29].

In the context of drug consumption and reward, OXT also likely interacts with the brain
serotonergic (5-HT) system ([529_TD$IF]the involvement of the serotonergic system in addiction is reviewed
in [30]). 5-HT1B receptor agonists potentiate drug reward and also lead to social impairments,
with OXT shown to reverse the latter effects ([31], but see [32]). Conversely, activation of 5-HT1A
and/or 5-HT2C receptors inhibits drug consumption and reward. Interestingly, OXT has been
shown to lead to downstream activation of 5-HT2C receptors [33], suggesting that it acts to
inhibit some aspects of drug reward through this mechanism. By contrast, the prosocial effects
of a 5-HT1A receptor agonist were shown to involve downstream release of OXT (reviewed in

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 TINS 1344 No. of Pages 18

(A) (B)
0.5 Ethanol preference 350

VEH ICV VEH/OXT

300
0.4 OXT
250

Dopamine [% baseline]
Preference rao

0.3 ICV VEH/OXT

200
IP EtOH
150
0.2

100

0.1
50

0.0 0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 –40 to –20 –20 to 0 0 to +20 +20 to +40 +40 to +60 +60 to +80 +80 to +100 min
24-h drinking session
Baseline Post treatment
Microdialysate samples

(C) Immobile (D)

1250
ICV VEH
ICV OXT (1 μg) 3 nM GABA
1000
30 mM EtOH
750
10 μM OXT
Time (s)

300 s
500
200 nA

250

0
VEH EtOH
IP drug
(E)

Extrasynapc Oxytocin
δ-GABAA receptor
Ethanol

CI- CI- GABA

CI- CI-

Synapc GABAA
receptor

Figure 1. Oxytocin (OXT)–Ethanol Interactions: A Possible Role for OXT Effects at Extrasynaptic d Subunit-Containing GABAA Receptors.[507_TD$IF] In rats,
OXT blocks ethanol consumption and preference (A: *P < 0.05 vs. VEH) (preference shown), ethanol-induced dopamine release within the nucleus accumbens (NAc)

(Figure legend continued on the bottom of the next page.)

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 TINS 1344 No. of Pages 18

[34]). Thus, it is compelling to consider that the reduction in drug consumption and reward
observed following the administration of 5-HT1A receptor agonists might also involve this
downstream release of OXT.

Downstream effects on endogenous OXT release may also be involved in the inhibitory effects
of melanocortin-4 receptor (MC4R) agonists on ethanol consumption [35,36]. The MC4R is part
of the leptin > MC4R > single-minded homolog 1 > OXT pathway, with MC4R activation
leading to downstream release of OXT (reviewed in [37]). Briefly, leptin stimulates proopiome-
lanocortin neurons originating in the arcuate nucleus and projecting to the PVN and supraoptic
nucleus (SON) of the hypothalamus, where these neurons release a-melanocyte-stimulating
hormone. This hormone then activates MC4Rs expressed on OXT neurons in the PVN and
SON, resulting in OXT release. Similar to OXT, the MC4R agonist melanotan-II, administered
either centrally or peripherally, reduced alcohol consumption in mouse models [35,36]. MC4R
signalling in the hypothalamus, where OXT neurons are abundant in distinct nuclei, appears to
be particularly important for these effects [38]. Moreover, MC4R agonists also have OXT-
dependent prosocial effects [39–41]. Given that MC4R agonists and OXT share several
behavioural functions, it is likely that MC4R agonists exert their effect on alcohol consumption
via activation of the OXT system.

Oxytocin Interference with Systems Involved in Drug Withdrawal

When an individual ceases drug [530_TD$IF]use following extended periods of drug consumption, they
enter into what is often referred to as the withdrawal and negative affect stage of addiction [1].
This stage is characterised not only by the acute withdrawal from the SOA, lasting days or
weeks after last consumption, but also by a protracted withdrawal syndrome that can last
months or even years into abstinence. Core behavioural components of protracted withdrawal
include reduced sensitivity to natural reinforcers, heightened emotionality (including increased
aggression), and exaggerated anxiety and stress responsivity. These behavioural changes
during protracted withdrawal present one of the greatest challenges to the maintenance of
abstinence and are underpinned by a multitude of alterations in brain systems that mediate
reward, motivation, stress, and socioemotional responses (reviewed in [1,6]). Due to its
capacity to promote social behaviours and to attenuate emotional and physiological stress
responses, OXT appears to be a particularly promising treatment for this stage of addiction.

OXT has been shown to inhibit both acute and protracted withdrawal from several SOAs in both
animals and humans (for references, see Table 1). In rodents, OXT: (i) reduced the severity of
alcohol withdrawal-induced convulsions and reduced subsequent mortality (although, at low
doses, OXT was reported to make withdrawal-induced seizures more severe); (ii) blocked the
somatic symptoms of nicotine withdrawal (e.g., facial fasciculations and abdominal constric-
tions); (iii) inhibited acute morphine withdrawal-induced hypothermia and loss of body weight;
(iv) alleviated anxiety, depression, and social impairment during protracted morphine with-
drawal; (v) inhibited anxiety induced by cocaine cues during withdrawal; and (vi) reversed social
deficits induced by chronic amphetamine exposure.

(B[508_TD$IF]: *P < 0.01 vs. OXT; #P < 0.05 vs. baseline), and the acute motor-impairing effects of ethanol (C: ***P < 0.001 vs. ICV VEH + IP VEH; #[509_TD$IF]P < 0.05 vs. ICV VEH + IP
EtOH) (blockade of sedative effects of ethanol in an open field test shown). While ethanol has many molecular targets in the central nervous system, at the doses
administered or consumed in these studies, ethanol potentiation of GABA-gated current at extrasynaptic d subunit-containing GABAA receptors is critically involved.
Using two-electrode voltage-clamp electrophysiology, it was shown that OXT prevents ethanol from acting at recombinant d subunit-containing GABAA receptors
expressed in Xenopus oocytes (D). Thus, OXT effects on ethanol consumption, ethanol actions in the NAc, and ethanol intoxication, may involve its ability to inhibit
ethanol potentiation of GABA effects at d subunit-containing GABAA receptors (E). An important discovery in this study was that OXT acts directly at d subunit-
containing GABAA receptors, uncovering a new receptor target for OXT, and one that might be particularly relevant for its interference with the effects of alcohol.
Adapted from [16,17]. Abbreviations: [510_TD$IF]EtOH, ethanol; ICV, intracerebroventricular; IP, intraperitoneal; Veh, vehicle.

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Some of these findings have begun to be translated into humans. In a small randomised
double-blind placebo-controlled trail, alcoholics who were treated with intranasal OXT while
undergoing medical detoxification required less lorazepam during treatment, and had less-
severe withdrawal symptoms (including lower levels of anxiety and tension) and reduced
alcohol craving. For more information on these studies, see Table 1 (reviewed in [8]). Here,
we focus primarily on the neurobiological mechanisms that may be driving the effects of OXT on
protracted withdrawal symptoms.

Reduced Sensitivity to Social Reward

In response to chronic stimulation by SOAs, the activity of the brain reward system is down-
regulated at several levels [1]. This downregulation persists throughout withdrawal and can last
well into periods of prolonged abstinence, resulting in reduced sensitivity to a range of natural
reinforcers. However, arguably the most devastating aspect of this hypohedonic state is
reduced interest in social interactions, which is compounded by impairment of social skills
as a result of long-term substance abuse [42]. Impaired functioning of the brain OXT system as
a result of chronic exposure to SOAs [43–49] is likely to contribute to this dysfunctional social
behaviour (Box 2).

The social impairment that results from chronic substance abuse has an enormous impact on
the addicted individual and their social environment and is a major hindrance to recovery.
Positive social interactions and a strong social support network can have immense benefits in
the treatment of addiction [50,51]. Thus, the major challenge is motivating addicted individuals
to re-engage with a positive social support network and helping them to overcome the social
impairments that can hinder their integration into that network.

Box 2. Changes in the Endogenous OXT System following Chronic Substance Abuse
Numerous studies reported abnormalities, in particular a reduction in activity, in the endogenous OXT system following
chronic exposure to a range of SOAs. For instance, rats repeatedly exposed to cocaine had reduced OXT plasma
concentrations, accompanied by reduced OXT content in the hypothalamus and hippocampus, which may reflect
reduced OXT synthesis and local release. Moreover, these rats developed tolerance to some of the behavioural effects
of cocaine that was prevented by replacement of hippocampal OXT by local infusion of synthetic OXT [58]. Similarly,
mice repeatedly exposed to morphine had decreased OXT levels in the hippocampus [46], and rats given chronic
morphine had decreased OXT levels in the SON and NAc accompanied by decreased OXT synthesis in the SON [45].
Chronic ethanol appears to cause major degeneration of the OXT-producing neurons in the hypothalamus. Silva and
colleagues [48] reported a marked decrease in magnocellular OXT-producing neurons in the PVN after 6 and 10 months
of chronic ethanol exposure in rats that still remained 4 months after alcohol withdrawal. Similar findings have been
reported in prairie voles after 7 weeks of continuous alcohol self-administration [49]. Consistent with these findings in
rodents, postmortem examinations of the brains of alcoholic men found evidence of significant degeneration of OXT-
containing magnocellular neurons [47]. Therefore, these effects of alcohol on the endogenous OXT system also appear
to be relevant for human addiction.

Reduced brain OXT levels in morphine-abstinent mice were accompanied by increased OXTR expression as well as
heightened anxiety, impaired social behaviour, and depression-like behaviour that was corrected by peripheral
administration of the OXT analogue carbetocin [43]. This same group reported a similar regional elevation of OXTR
binding following chronic exposure to a range of SOAs [43,55,57,117], including upregulation in the amygdala (nicotine,
methamphetamine, cocaine, and morphine), lateral septum (cocaine and morphine) and hypothalamus (methamphe-
tamine). The authors argued that this is likely a compensatory response to the reduced endogenous OXT levels that
result from exposure to SOAs (detailed above).

Finally, findings of increased OXTR density after chronic substance abuse are not consistently reported across all of the
relevant literature; thus, it is likely that such changes are region, and possibly species, dependent. For instance,
monogamous prairie voles chronically exposed to amphetamine showed long-term abnormalities in social behaviour
and reduced, rather than increased, OXTR levels in the medial PFC. Moreover, infusion of OXT into the medial PFC
restored normal social behaviour in these animals, and this was dependent on OXTR binding in this region [44].

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Accordingly, one hypothesis proposes that at least some of the potential therapeutic effects of
OXT in addiction might stem from an ability to shift focus away from drug reward and back onto
social reward [34] through increasing the salience of social stimuli [52]. Indeed, there is direct
evidence for endogenous OXT being essential for naturally occurring social preference behav-
iour and for reinstating stress-impaired social preference behaviour in rats and mice [53].
Importantly, there is also growing evidence that OXT is able to refocus behaviour on social
engagement following chronic drug exposure. For example, chronic amphetamine adminis-
tration impaired the expression of partner preference in monogamous prairie voles [44], and
OXT administered directly into the PFC re-established normal partner preference in parallel to
restoring normal baseline functioning of the NAc dopamine system. Of interest, partner
interaction had important stress-buffering effects in these voles [54]. In another study, periph-
eral administration of the OXT analogue carbetocin reversed social deficits in mice that had
been chronically administered morphine and led to parallel reductions in morphine-seeking
behaviour [43].

Thus, OXT reduces drug consumption and drug reward on the one hand, but promotes
positive social interactions and social reward on the other. Therefore, these contrasting
reward type-dependent effects of OXT might be mediated through actions on the separate
dopaminergic pathways believed to underlie drug versus social reward. These are the striatal
dopamine D1 receptor (D1R) pathways, which are critical for drug reward, and the striatal
dopamine D2 receptor (D2R) pathways, which are critical for social reward (for more details,
see Box 3). Moreover, OXT actions on these two pathways are likely involved in some of its
inhibitory effects on addictive behaviours (Box 3 and Figure 2). In particular, the contrasting
effects of OXT on the D1R versus D2R pathways in the NAc might underlie the ability of OXT to
shift focus from drug seeking onto seeking out social reward and possibly also other natural
reinforcers.

Box 3. Dopaminergic Pathways Mediating Drug versus Social Reward

Emerging evidence suggests that different neural pathways exist for drug versus social reward. Drug reward depends
on drug-induced phasic dopamine release, which leads to the high levels of extracellular dopamine required to stimulate
low-affinity D1Rs in the NAc. By contrast, high-affinity D2Rs, and possibly OXTR-D2R heteroreceptor complexes in
particular, appear to have an especially important role in social reward, and may act to limit the reinforcing effects of
drugs [1]. For instance, mating-induced partner preference in female prairie voles required activation of both D2R and
OXTRs in the NAc (reviewed in [118]). OXTR-D2R heteroreceptor complexes have been characterised in several brain
regions, including the NAc [119–122]. OXT acts via an allosteric receptor–receptor interaction to substantially increase
the affinity of dopamine for D2Rs in these complexes. This then enhances D2R-mediated inhibition of the adenyl
cyclase–PKA–pCREB signalling cascade and increases PLC beta–IP3–calcineurin pathway activity. These findings
have been implicated in not only the effects of OXT–dopamine interactions in social salience, but also the regulation of
anxiety responses.

Importantly, D2R activation has been shown to reduce consumption of SOAs in rodent addiction models, and D2R
pathway activation is reduced following chronic drug exposure (reviewed in [1,123]). Briefly, rodent and nonhuman
primate studies have found reduced D2R levels in the NAc and other parts of the striatum following chronic exposure to
SOAs and have also reported lower D2R levels in these regions in animals that more readily self-administer SOAs.
Similar findings have been reported in human imaging studies examining D2Rs in the striatum of chronic drug users.
Furthermore, chronic substance abuse leads to lower basal/tonic levels of striatal dopamine, which results in less
activation of the high-affinity D2Rs. Reduced D2R pathway activation has been implicated in the switch to compulsive
drug taking. However, we propose that impairment of the striatal D2R pathway and a subsequent increase in the D1R:
D2R activation ratio is also likely involved in social impairment in addiction. Indeed, the evidence indicates that an
increased ratio of D1R:D2R activation biases behaviour toward seeking out drug rewards over social rewards [1],
whereas an increased ratio of D2R:D1R activation biases behaviour toward seeking out social rewards over drug
rewards [118]. Importantly, OXT may serve to rebalance the activity in these two striatal dopamine pathways. Figure 2 in
the main text illustrates the dual mechanisms through which OXT might rebalance the activity of the D1R and D2R
pathways and subsequently reduce sensitivity to drug rewards and restore sensitivity to social rewards.

8 Trends in Neurosciences, Month Year, Vol. xx, No. yy

 TINS 1344 No. of Pages 18

OXT effects on
(A) Drug-smulated (B) drug-smulated
dopamine release
dopamine release

OXT
VTA SOA VTA SOA

NAc NAc

Key: Dopamine
OXT
Basal and natural reward-
(C) Basal and natural reward- (D) smulated dopamine release D1R
smulated dopamine release
aer chronic drug abuse
OXTR–D2R
heteromer
VTA VTA

NAc NAc

Figure 2. The Dual Mechanisms through which Oxytocin (OXT) Might Rebalance the Activity of D1R and
D2R Dopamine Pathways. Substances of abuse (SOAs) increase the release of dopamine from dopaminergic neurons
projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), allowing activation of the low-affinity
D1Rs that have a critical role in drug reward (A). Exogenous OXT has been shown to inhibit increased dopaminergic activity
induced by SOAs (B) (see the main text), preventing their ability to stimulate D1Rs. Furthermore, exogenous OXT may
counteract the reduced D2R pathway activity that results from chronic drug abuse by further increasing the affinity of the

(Figure legend continued on the bottom of the next page.)

Trends in Neurosciences, Month Year, Vol. xx, No. yy 9

 TINS 1344 No. of Pages 18

Stress, Anxiety, and Emotional Impairment

In addition to hypohedonia (in particular, lack of social interest), heightened stress respon-
sivity, anxiety, and emotional impairment can also persist for months or even years into
abstinence. Chronic drug abuse- or drug withdrawal-induced changes in the endogenous
OXT system, including alterations in OXT release and OXTR binding, are likely involved in these
aspects of protracted withdrawal [43–49,55–59] (Box 2). Importantly, administration of OXT or
OXT analogues restored normal behaviour in relevant preclinical models [43,44,58], probably at
least partly by compensating for the abnormalities in the brain OXT system.

These findings are in line with the general anxiolytic properties of OXT, especially under
conditions of stress [60]. Indeed, similar alterations in the endogenous OXT system to those
seen following chronic exposure to SOAs were associated with sustained states of heightened
fear and anxiety in rodents [61,62]. Importantly, administration of OXT reversed the behavioural
and physiological symptoms of these states [61,63]. For example, in a mouse model of social
phobia, social fear-conditioned mice had increased OXTR levels and impaired OXT release in
the lateral septum (similar to what is observed following chronic exposure to [531_TD$IF]SOAs; Box 2)
during social interactions, indicating impaired OXT signaling [61]. Here, infusion of OXT ICV or
into the lateral septum completely reversed the conditioned social fear. Given that increased
OXTR expression has been repeatedly associated with decreased OXT levels, it has been
hypothesised that the increased receptor expression may be a compensatory response to
reduced ligand levels [43,61,64].

Anxiolytic and fear-reducing effects of endogenous and synthetic OXT have been described not
only in the lateral septum, but also within the hypothalamic PVN [65] and the amygdala [9] of
male and female rats (reviewed in [7,60]), as well as within the medial PFC [66], which provides
downstream inhibition of the central amygdala (CeA). Within the CeA, which orchestrates
behavioural responses to both negative (anxiogenic and fearful) and positive (rewarding)
stimuli, synthetic OXT or optogenetically induced local OXT release [9] was found to reduce
behavioural fear responses in rats. Imaging studies have also linked the anxiolytic effects of
intranasal OXT in humans to actions in the amygdala [67].

OXT also appears to regulate other systems involved in stress and anxiety that become
dysfunctional following chronic substance abuse, including the hypothalamo–pituitary–
adrenal (HPA) axis. Elevated levels of corticotropin-releasing factor (CRF), an anxiogenic
neuropeptide and major stimulator of the HPA axis, in the CeA and bed nucleus of the stria
terminalis have a critical role in heightened stress and dysphoria during withdrawal (reviewed in
[6]). It is also believed that this dysregulation of the extrahypothalamic stress system following
chronic substance abuse emerges due to initial activation and subsequent dysregulation of the
HPA axis by SOAs [6]. When a drug is consumed again it provides some transient relief from this
negative state, which acts as a powerful form of negative reinforcement that drives com-
pulsive drug-seeking behaviour. Of particular interest here, OXT has been repeatedly reported
to reduce the activity of the HPA axis under basal conditions as well as its physiological stress
responsiveness [7,9,60,65,68], possibly via OXTR-mediated actions in the CeA and PVN [7,9].
OXT was found to directly attenuate the stress-induced synthesis of CRF within the PVN via
identified intracellular signalling pathways [65]. Combining these findings, OXT–CRF

D2Rs in OXT receptor (OXTR)–D2R heteroreceptor complexes for dopamine (C,D). OXT may reduce sensitivity to drug
rewards and restore sensitivity to social rewards by rebalancing the activity of these two dopaminergic pathways (see Box
3 in the main text).

10 Trends in Neurosciences, Month Year, Vol. xx, No. yy

 TINS 1344 No. of Pages 18

interactions, especially within the amygdala and PVN, are likely to have a critical role in
mediating the ability of OXT to reduce heightened anxiety and stress responses during
withdrawal [43].

Oxytocin Interference with Neurobiological Systems Involved in Drug

Relapse
The stage of the addiction cycle that immediately precedes relapse is often referred to as the
preoccupation and/or anticipation stage [1]. During this stage, increased salience of drug-
related cues combines with reduced sensitivity to natural reinforcers, emotional impairment,
and heightened stress reactivity (detailed above) to produce intense cravings and motivation for
drug consumption. Impaired executive functioning reduces the individual’s ability to resist
the powerful drug-seeking drive and relapse often occurs as a result of this ‘perfect storm’ of
factors.

There are three main triggers for relapse: drug primes, drug cues, and stress. Box 4 provides
a more-detailed description of these three main types of relapse and gives examples of how
they are modelled in rodents. Importantly, preclinical and clinical studies (Table 1; reviewed in
[8]) have demonstrated that OXT has the potential to reduce the incidence of all three types of
relapse.

In preclinical studies, OXT has been shown to inhibit prime-, cue-, and stress-induced
reinstatement of methamphetamine-seeking behaviour, stress-induced reinstatement of opi-
oid-seeking behaviour, and prime- and cue-induced reinstatement of cocaine-seeking behav-
iour. OXT also inhibited cocaine cue-induced anxiety, suggesting that the ability of OXT to inhibit
cue-induced reinstatement of cocaine seeking, and perhaps also other SOAs, is related to its
well-characterised anxiolytic effects [7,60], discussed above. Finally, suppression of alcohol
and methamphetamine consumption in rats by IP OXT was shown to last well beyond the
cessation of treatment [34,69,70]. This lasting inhibition of drug-seeking behaviour is associ-
ated with the emergence of an enduring addiction-resistant phenotype characterised by
increased social motivation, pain tolerance, and reduced anxiety and stress responses
[69,71–73].

Evidence for the potential of OXT to promote abstinence also comes from a few human clinical
trials (see Table 1 for references), which have shown that intranasal OXT: (i) reduced stress-
induced craving in cannabis-dependent humans; (ii) inhibited craving during detoxification in
alcoholics; (iii) reduced cue-induced craving in nondependent alcohol users with an anxious
attachment style; (iv) inhibited cocaine craving in patients with comorbid cocaine- and opioid-
use disorder; and (v) prevented the escalation of heroin craving over periods of heroin absti-
nence in comorbid heroin and cocaine users. However, some trials have yielded contrasting
results (Table 1; reviewed in [8]). The findings of Lee and colleagues [74], in particular, highlight
the mixed and sometimes-complex effects of intranasal OXT reported in the small trials
completed to date. In their study in cocaine-dependent men undergoing in-patient rehabilita-
tion, intranasal OXT treatment slightly but significantly increased the baseline desire to use
cocaine and cue-induced excitability, had no effect on other measures of cue-induced craving
and arousal, but inhibited the positive correlation between anger and desire to use cocaine.

Here, we present evidence that the ability of OXT to interfere with all three major triggers for
relapse, to reduce craving, and to exert enduring effects on consumption of SOAs is mediated
through the actions of OXT on neural systems involved in motivation, reward, stress, and
behavioural control.

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 TINS 1344 No. of Pages 18

Box 4. Drug Prime-, Cue-, and Stress-Induced Relapse

As discussed in the main text and Box 3, chronic substance abuse leads to reduced sensitivity to natural reinforcers,
while SOAs maintain their ability to stimulate reward circuitry. With prime-induced relapse, these factors combine to
produce a drug-reward hypersensitivity, whereby subthreshold levels of drug exposure can lead to reinstatement of
drug seeking. In the case of cue-induced relapse, over time drug cues develop their own motivational properties as the
relationship between these conditioned reinforcers and the rewarding outcome strengthens. As part of this process, the
cues can control the stimulation of not only the mesolimbic pathway, but also the mesostriatal and nigrostriatal
pathways projecting from the VTA and substantia nigra to the dorsal striatum. Consequently, evidence from both animal
and human studies has demonstrated that exposure to drug-related cues can stimulate dopamine release within the
NAc, dorsal striatum, amygdala, hippocampus, and PFC, and this cue-induced stimulation is believed to have a critical
role in the establishment of habitual, compulsive drug-taking behaviour [1,124–126]. In the case of stress-induced
relapse, heightened stress, especially unpredictable and uncontrollable stress, increases craving and reactivity to drug
cues and drug primes [127].

In commonly used rodent models of relapse (Figure I), subjects initially learn to self-administer high levels of the SOA by,
for example, pressing a lever to receive IV infusions of the drug. SOA self-administration is generally paired with a cue,
such as a light, that the subjects come to associate with the drug-taking behaviour. Once the subjects are consistently
self-administering high levels of the SOA, the SOA is removed, such that pressing the lever no longer results in access to
the SOA, and the cue is no longer presented. Gradually, over several sessions, the subjects will stop pressing the lever.
Once this drug-seeking behaviour has subsided, reinstatement, or relapse, of drug taking is induced by a drug prime, a
drug cue, or stress. In prime-induced reinstatement paradigms, the subject is given a small amount of the SOA, and this
exposure, called a prime, causes a pronounced reinstatement of the drug-seeking behaviour. In cue-induced
reinstatement paradigms, the cue (such as a light) that was initially paired with the drug-taking behaviour is once
again presented and exposure to this cue reinstates the drug-seeking behaviour. In stress-induced reinstatement
paradigms, exposure to a stressor, such as a foot shock, causes relapse to drug seeking. Reinstatement is indicated by
a marked increase in attempts to gain access to the drug (e.g., by pressing the lever that originally provided access to
the SOA).

No
drug

Prime-induced
reinstatement

Self-administraon Exncon
Drug No No
drug drug

Cue-induced
reinstatement

No
drug

Stress-induced
reinstatement

Figure I. Rodent Models of Drug Relapse. This figure depicts a common method of modelling the three main
triggers of drug relapse (drug prime-, drug cue-, and stress-induced relapse) using a rodent drug self-administration
paradigm. Further details are provided in the text of Box 4.

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 TINS 1344 No. of Pages 18

Prime- and Cue-Induced Relapse Outstanding Questions

As is the case with OXT effects on consumption of addictive substances, its ability to prevent SOAs induce dopamine release from
prime- and cue-induced relapse to drug seeking also appears to be mediated, at least in part, neurons that project from the VTA to
the NAc, and this release is inhibited by
by its capacity to interfere with the effects of SOAs and drug cues in the NAc. For instance, OXT OXT. How does OXT act to inhibit
decreased both cocaine and methamphetamine cue-induced activation of the NAc [15,75], SOA-induced dopamine release in
and infusion of OXT directly into the NAc inhibited both prime- and cue-induced relapse to the NAc? Given that OXTR activation
is excitatory, OXT likely acts via an
methamphetamine seeking [14,15,76]. In a recent study, the effect of peripherally administered
indirect mechanism (e.g., increasing
OXT on cue-induced reinstatement of methamphetamine seeking in rats was blocked by GABAergic inhibition of these neu-
bilateral infusion of an OXTR-A directly into the NAc [15]. rons), but the specifics remain to be
elucidated.
Prime- and cue-induced reinstatement are also thought to be, at least partly, mediated by
OXT infused directly into the NAc inhib-
projections from the PFC to the NAc and VTA [1]. More specifically, excitatory glutamatergic
its drug consumption and drug
projections from the infralimbic PFC control dopamine neuron firing in the NAc [77]. Interest- reward. How, specifically, does OXT
ingly, OXT is able to supress basal levels of glutamatergic transmission in the infralimbic PFC exert these influences? It may act,
[78], providing a possible mechanism of how OXT interferes with prime- and cue-induced for instance, to increase GABAergic
inhibition of D1R-expressing neurons
reinstatement of drug seeking. OXT was also recently shown to prevent cocaine cue-induced
that mediate drug reward. It may also
activation of the medial PFC in rats [75]. act to increase activation of D2R-
expressing neurons that mediate
Stress-Induced Relapse social reward and are protective
against drug reward. Allosteric
In contrast to prime- and cue-induced reinstatement of drug seeking, stress-induced rein- receptor–receptor interactions are of
statement involves activation of CRF and other stress-related neurotransmitter systems and particular interest, given the presence
brain regions, such as the extended amygdala [1]. The interaction of OXT with these systems of OXTR–D2R heteromers in the NAc.
was discussed in the previous section. However, the direct effects of OXT on stress-induced
activation of CRF in the context of relapse have not yet been studied. The effects of OXT on Is intranasal OXT sufficient to translate
effects from animal studies to clinical
stress-induced relapse shown in animal models may also involve its ability to enhance populations? Animal studies largely
connectivity between the frontal cortex and amygdala [79–81]. This enhanced connectivity used central administration or very
may improve the ability of frontal regions to exert control over the drug-focused behavioural high peripheral doses that are not
practical in humans and only small clin-
impulses generated in response to heightened activity in the extended amygdala during
ical trials have been run with intranasal
protracted withdrawal [6]. OXT, with mixed results. Concerns
about brain uptake, lack of dose–
Behavioural Control response information, and small sam-
ple sizes must be addressed in future
More broadly, reduced connectivity between frontal cortical regions and subcortical regions
clinical studies with intranasal OXT. It is
has a critical role in the development of chronic substance-use disorders by contributing to likely that small-molecule [532_TD$IF]OXTR ago-
poor decision-making and a lack of behavioural control. The general lack of inhibitory control of nists and/or OXT circuit stimulators will
behaviour is believed to have a major role in the inability of drug users to prioritise other critical be required to unlock the full potential
of targeting the brain OXT system to
behaviours, such as social interaction, over their drug-seeking behaviour and to resist cravings.
treat addiction.
Thus, it is interesting that OXT is able to enhance connectivity between the frontal cortex and
various subcortical regions, including the striatum [82–85], and to restore some of the behav- 5-HT1A receptor agonists and MC4R
iours mediated by these pathways that become disturbed in addiction. agonists cause downstream release of
OXT and have prosocial and antiaddic-
tive effects. This release of endoge-
Concluding Remarks nous OXT is involved in the prosocial
The ability of synthetic OXT treatment to ameliorate addictive behaviours across all three stages effects of these compounds and might
of the addiction cycle, and for all major classes of SOA, appears to be underpinned by also be involved in their ability to
interactions with key neural systems that underlie these behaviours (Figure 3). In this review, reduce addictive behaviours. Is the
stimulation of intracerebral release of
we have mapped the effects of OXT on specific addictive behaviours onto its ability to interfere endogenous OXT involved in the ther-
with the specific neurobiological systems that underlie these behaviours. However, given the apeutic mechanism of action of other
complex, multifaceted nature of addiction, and the complex, multifaceted actions of OXT in the drugs (e.g., 5-HT1A agonists and
MC4R agonists) that have potential
central nervous system, there are likely many other interactions that are also of relevance that
for the treatment of addiction?
will emerge from future research.

Trends in Neurosciences, Month Year, Vol. xx, No. yy 13

 TINS 1344 No. of Pages 18

How broadly involved are changes in

the endogenous OXT system in the
development of addiction? More work
is needed to mechanistically tie the
changes in specific parts of the endog-
enous OXT system that occur in
PFC response to chronic exposure to SOAs
to changes in specific addictive behav-
iours. Given the work to date, and the
broad effects of pharmacologically
enhancing brain OXT activity, it is pos-
VTA and SN sible that alterations in endogenous
OXT systems are critically involved in
[53_TD$IF]a range of addictive behaviours.
S

Hypothalamus
(incl. PVN and
SON)
Amygdala
ippocampus

Figure 3. The Neural Substrates of Addiction Overlap with the Brain Oxytocin (OXT) and Stress Systems.
This diagram provides a schematic representation of the overlap between brain addiction pathways and the brain OXT and
stress systems. OXT receptor (OXTR)-expressing regions of the brain reward system (green), of the stress system (red),
and in regions involved in behavioural control and memory (blue) are indicated. Arrows with solid black lines represent
projections between these regions that are known to be involved in addiction. Arrows with broken blue lines represent the
known projections of OXT neurons from the paraventricular nucleus (PVN) and/or supraoptic nucleus (SON). As can be
seen, OXT fibres project to regions critically involved in addiction, and there is a rich network of OXTRs expressed within
these brain regions. Mounting evidence demonstrates that OXT interferes with the effects of substances of abuse (SOAs)
within these brain regions and on these pathways (see the main text). For simplicity, these brain regions have been
designated as part of the reward, stress, or behavioural control and/or memory pathways, but several of these regions
have multiple roles across these systems. Placement of brain regions on the diagram of the brain is only approximate, so as
to allow easier visual representation of the addiction and OXT pathways that connect these regions. Abbreviation: PFC,
prefrontal cortex; NAc, nucleus accumbens; SN, substantia nigra; VTA, ventral tegmental area.

That said, preclinical evidence strongly indicates that OXT inhibition of drug consumption and drug
reward involves interference with the brain reward circuitry, in particular with dopaminergic systems
within the NAc. OXT interference with drug actions at specific GABA-A receptor subtypes, as well as
with serotonergic systems involved in drug consumption and reward, also appear to be of relevance.
These studies highlight the complex array of the molecular targets of OXT in the brain.

Moreover, OXT interferes with at least three key components of the protracted withdrawal
syndrome that often emerges following chronic substance abuse: hypohedonia, impaired emo-
tional regulation, and heightened stress responding. Effects of synthetic OXT during this stage of
addiction likely involve its ability to compensate for the reduced functionality of the endogenous
OXT system that results from chronic substance abuse. Thus, OXT treatment is likely to increase
the availability of OXT in the extracellular fluid of the brain and, thus, OXT signalling within distinct

14 Trends in Neurosciences, Month Year, Vol. xx, No. yy

 TINS 1344 No. of Pages 18

brain regions. OXT actions within the PFC, hypothalamic and extrahypothalmic stress systems,
and specific dopaminergic pathways are likely of particular importance.

Finally, the potential of OXT to prevent relapse to drug seeking involves direct OXTR-mediated
actions in the NAc to inhibit both prime- and cue-induced reinstatement to drug seeking,
whereas, by contrast, its effects on stress-induced relapse likely involve the aforementioned
interactions with brain stress systems. In this context, enhanced functional connectivity
between frontal cortical regions and the amygdala and the NAc may contribute to its effects
on relapse through improving inhibitory control over craving and cue reactivity.

While the evidence clearly supports the considerable and growing interest in synthetic OXT or
drugs that stimulate the brain OXT systems as a novel treatment options for addiction, there is
still much work to be done (see Outstanding Questions). The preclinical evidence demonstrat-
ing effects of OXT on behavioural components of addiction is robust, but future studies must
continue to establish the mechanisms driving OXT effects on different aspects of addiction.

In terms of clinical evidence, only a limited number of human trials of intranasal OXT in addicted
populations have been completed, with the results thus far being mixed. In addition, there is an
ongoing debate regarding: (i) the efficacy of the intranasal route of OXT administration to target
the brain OXT system due to poor brain penetration and unknown mechanisms of brain uptake;
(ii) lack of dose–response information; and (iii) the small sample sizes and low statistical power
of most clinical trials to date [86].

Ultimately, there appears to be great potential in targeting the brain OXT system to treat
substance-use disorders. However, the ability to fully harness this potential may depend on the
development of OXT agonists and/or oxytocin circuit stimulators that reach the brain in
sufficient amounts after peripheral application. Given that some OXT effects on addictive
behaviours do not appear to be mediated via actions at OXTRs, the ability to develop such
drugs will be greatly assisted by gaining a more-detailed, nuanced, and mechanistic under-
standing of how the numerous and significant interactions of OXT with the neural substrates of
addiction lead to changes in specific addictive behaviours.

Conflict of Interest
M.T.B. holds USA (9119805), EU (20100819736) and AU (2010302945) method of use patents entitled Therapy and
Prevention of Problem Drinking, which focus on the use of OXT for the treatment of problem drinking. M.T.B. holds a PCT
patent application (WO2017004674 A1) entitled Therapeutic Compounds and Compositions for Treating Social Disorders
and Substance Use Disorders, which focuses on a series of novel therapeutic small molecules, at least one of which
activates OXT -containing neurons in the hypothalamus.

Acknowledgements
This work was supported by: a common travel grant from the Deutscher Akademischer Austausch Dienst and Group of
Eight; grants from the Deutsche Forschungsgemeinschaft, BMBF, and EU (I.D.N.); and an Australian National Health and
Medical Research Council Fellowship (M.T.B.) and project grant (M.T.B. and I.D.N.).

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