The Anti Reward Brain System

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The Neuroscience of Chemical Dependence 2012: The Anti-Reward Brain System
The Neuroscience and Pharmacology of Chemical Dependence 2012
Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D Clinical Associate Professor University of Georgia College of Pharmacy Athens, Georgia mnorton@rx.uga.edu
Merrill Norton Pharm.D.,D.Ph.,ICCDP-D
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Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D
Chemical Dependence is a Complex Illness
The Addicted Brain- 2012
with biological, sociological and psychological components

Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D 11/27/12 Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D 11/27/12
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Street Drugs-2012

Absinthe Alcohol* Bath Salts* Caeine Cannabis* Cocaine DXM GHB Heroin Inhalants Ketamine
LSD MDMA Mescaline Meth Mushrooms Nutmeg Opiates* Peyote Salvia* Spice* Tobacco
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Bath Salts
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Methylenedioxypyrovelerone (MDPV)
Street names:
MDPV Bath Salts

Eects: similar to cocaine, amphetamine, or
Bath Salts, Ivory Wave, Plant Fertilizer, Plant Food, Vanilla Sky, Energy-1 Designer drug developed to get around drug control laws
Merrill Norton Pharm.D.,D.Ph.,ICCDP-D 11/27/12
MDMA
Positive: mental and physical stimulation, euphoria,
creativity, feelings of empathy, increased sociability and productivity, sexual arousal Negative: tightened jaw muscles, grinding teeth, loss of appetite, disturbed sleep patterns, involuntary body movements, confusion, GI disturbance, muscle tension, headache, harsh comedown eects, tachycardia, hypertension, vasoconstriction, psychotic behavior, residual depression, anxiousness/paranoia
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MDPV Bath Salts

Routes of Administration: most often insuated
MDPV Bath Salts

Prevalence of use: Information is currently
(snorted), but can be smoked, injected, or ingested orally; usual amounts 5 mg or less (active ingredient) Duration of action: 3 to 4 hours for subjective eects, 6 to 8 hours for side eects Legal status: Not federally controlled, several states have banned either bath salts or chemicals used to make MDPV. Georgia has proposed a bill to ban sale of bath salts, but they have been commonly available in convenience stores and head shops
very limited, data is not yet reported by any national drug study programs due to relative newness of drug Used predominantly in youth population Increasingly cases are being reported of overdose on MDPV leading to death 2 men in Pennsylvania and 1 woman in Illinois in April 2011, and 1 man in Michigan in May 2011
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MDPV Bath Salts

Chemistry and Pharmacology
Related in chemical structure to MDMA and
MDPV Bath Salts

Availability: Typically
cathinone
MDPV administered to mice increased dopamine
levels 60 minutes after administration, though not as markedly as increases induced by methamphetamine or MDMA Has a cousin mephedrone: also found in bath salts with same eects and dangers
sold in smoke shops or convenience stores as a bath salt under the product names Ivory Wave or Vanilla Sky. It is marked for novelty use only and has no instructions on dosing. Also sold online as Energy 1 on UK based websites or as Plant Food
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MDPV Bath Salts

Addiction Potential: No studies have shown
MDPV Bath Salts

Long-term eects: Unknown Bath salts
addiction potential as of yet, but self-report from users indicate the high is so addictive they can not stop using.
Intense cravings have been reported Some users have sought professional help after
have only come into spotlight within last 2 years, so no studies are available Toxicity and overdose:
Severe and life-threatening toxic eects that do
not respond to conventional medical treatment
only one month of abuse
No information available on withdrawal or
tolerance
Usually non-responsive to sedatives When users present with psychosis, psychotic state returns when sedatives and antipsychotics withheld, even after days
Toxic and lethal doses are unknown
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MDPV Bath Salts

Drug Testing
Not commonly tested for in standard and
Cannabis- Tetrahydrocannabinols
extended drug screens
Redwood Toxicology Lab has a 2-panel urine drug
screen that tests for MDPV and mephedrone, as well as an extended 14-panel screen that includes these drugs
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Cannabis Effects by Erowid
Onset Coming Up Plateau Coming Down After Effects

0-10 minutes 5-10 minutes 15-30 minutes 45-60 minutes 30-60 minutes
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Opiates(Opium
Poppy Extracts/Modifed Extracts) Morphine(Various) = 1.0 Codeine(Tylenol #3) = 0.4 Opium(Paregoric) = 0.8 Diacetylmorphine(Heroin) = 1.5 Hydrocodone(Vicodin) = 3.0 Oxycodone(Oxycontin,Percodan) = 4.0 Hydromorphone(Dilaudid) = 5.0
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Meperidine(Demerol) = 1.0 Propoxyphene(Darvon) = 0.7 Pentazocine(Talwin) = 0.5 L acetyl alpha methadol(LAAM)= 2.0 Methadone (Dolophine) = 3.0 Levomethadyl acetate HCl (Orlaam) = 3.0 Fentanyl(Sublimase) = 50.0 Sufentanyl(Various) = 100.0 Alpha Sufentanyl (Various) = 200.0

A Dangerous Legal High
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Salvia Divinorum
Street names: Salvia,
Salvia Divinorum
Eects: Psychedelic experiences causes
Diviners Sage, Ska Maria Pastora, Seers Sage, The Sheperdess Perennial herb in mint family, native to areas of Sierra Mazateca region of Oaxaca, Mexico
dramatic changes in perception and sometimes frightening hallucinations that often deter users from repeated use 20 minute acid trip primary eects last 5 to 15 minutes, followed by 20 40 minutes of comedown period
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Salvia Divinorum
Salvia Divinorum
Routes of administration: smoking out of a
pipe or bong, vaporization, extracting juices to make a tea, or sublingual consumption by chewing the leaves (much larger doses: ~20 leaves vs. 1 leaf for smoking) Legal status: not federally controlled; however 15 states have placed Salvia on Schedule I lists Georgia and 8 other states restrict its distribution, but it remains legal to possess
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Salvia Divinorum
Prevalence of use: In 2008, estimated 1.8
Salvia Divinorum
Chemistry and Pharmacology:
Salvinorin A (or Divinorin A) is compound
million persons aged 12 or older have used Salvia in their lifetime; approx. 750,000 in past year. More common among young adults aged 18 to 25 than those over 25, and more common in males than females
responsible for hallucinogenic eects receptor agonist
Salvinorin A is a potent and selective kappa opioid
Other drugs that act at this receptor produce hallucinogenic eects and dysphoria similar to Salvinorin A Does not activate serotonin 2A receptor, which mediates the eects of other Schedule I hallucinogens
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Salvia Divinorum
Availability: Sold as
Salvia Divinorum
Long-term eects: No overall consensus;
dried leaf ($50 - $100 per ounce), concentrated extracts ($20 - $50 per gram), and live plants (prices vary) Sold in smoke shops or online
studies in rats show depression-like eects

One report of salvia precipitating psychosis in a No hangover eects reported by most users Low toxicity Feelings of dj vu have been reported in long-
patient genetically predisposed to schizophrenia
term
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Salvia Divinorum
Addiction potential: not
Salvia Divinorum
Toxicity and Overdose
No reports of either toxicity or overdose Danger comes from need for babysitters to
currently known to be physically addicting or cause psychological dependence Withdrawal eects have not been reported Appears to be no tolerance experience can be extended or amplied with increased dose
watch over rst time users

Can have frightening experiences that mimic psychoses Can also precipitate psychotic episodes in those predisposed to schizophrenia
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Salvia Divinorum
Drug Testing
Salvia is not commonly tested for in standard drug
Spice
tests or extended drug tests
It can be detected by liquid chromatography/mass
spectrometry and gas chromatography/mass spectrometry; however these tests are expensive and impractical Elimination half-life of Salvinorin A is very short (less than an hour), so the detection window is likely less than 12 hours
A Dangerous Legal High
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Synthetic Cannabinoids
Street names: K2 and
Spice
Eects: has marijuana-like psychoactive
Spice Marketed as herbal incense; claims to be a blend of traditionally used medicinal herbs but instead is laced with synthetic cannabinoids that are not naturally in the herbs it is labeled to possess
eects in humans decreased activity, analgesia, decreased body temperature, euphoria, anxiety, altered perception Does not induce the munchies in most users When used with alcohol, exacerbates hangovers and causes headaches at base of skull that last for hours
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Spice
Routes of Administration: smoking in pipes,
Spice
Prevalence of use:
bongs, or joints Duration of Action: the high lasts an average of 10 minutes, and no longer than 30 minutes Legal status: As of March 1, 2011, synthetic cannabinoids have been temporarily placed in Schedule I federally, but has been illegal on a state level in Georgia since May 2010
primary abusers are youth purchasing these substances from Internet sites, gas stations, convenience stores, and smoke shops
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Spice
Chemistry and Pharmacology
The chemical structure of synthetic cannabinoids
Spice
Comparison of chemical structure of THC
shares similarities with THC as seen on the next slide, but is not classied as a THC Synthetic cannabinoids bind to the brain cannabinoid receptor CB1 and peripheral receptor CB2 with higher anity than THC, suggesting it would have the same eects as THC in vivo
(left) and HU-210, a synthetic cannabinoid (right)
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Spice
Availability: With the temporary Schedule I
Spice
Addiction potential: unknown, though based
status federally, it should no longer be possible to purchase these compounds in retail stores; however many websites still operate that sell these drugs Cost: More expensive than real marijuana one gram is sold for about $25, as opposed to $14/gram for potent marijuana on the street
on the similarity to THC in vivo it can be supposed that the addiction potential is likewise similar to marijuana No ocial information available on withdrawal or tolerance, though one case of withdrawal after daily use of Spice Gold for 3 months is reported; physicians treating the user noted his use showed signs associated with addiction
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Spice
Long-term eects: as yet unknown; still
Spice
Drug Testing
Spice and the synthetic cannabinoids do not cause
relatively new (Spice rst appeared in 2004)

As with any smoked product, has detrimental
eect on lungs reported to cause more burning in throat and aching in lungs than marijuana
Toxicity and overdose:

Extremely large doses may cause negative eects
in humans that are generally not noted in marijuana users increased agitation and vomiting Potential for overdose unknown
a user to test positive for cannabis or other illegal drugs on a standard or extended drug screen, or even with gas or liquid chromatography/mass spectrometry testing Dominion Diagnostics and NMS Labs have developed tests that identify metabolites of some of the synthetic cannabinoids as of September 2010
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DEFINITIONS OF PSYCHOACTIVE CHEMICAL USE, ABUSE, AND DEPENDENCE

" Psychoactive Chemical Use " This term can be applied to a single episode of
Psychoactive Chemical Use

" Single episode " May have consequences-allergic reactions " May lead to abuse , addiction , and
psychoactive chemical self-administration. Psychoactive chemical use can have adverse consequences that require treatment, and it can lead to psychoactive chemical abuse or dependence, but it may also be self-limiting and have no adverse effects. Psychoactive chemical use has no diagnostic criteria in the DSM-IV.
dependence
Endorphins/Dopamine Receptors 1 USE Cortex
Psychoactive Chemical Abuse

" Failure to meet a role obligation " Placing yourself or others in physically
hazardous situations
" Legal problems " Repeat of the above " 12 Month Period " Estimate 50% Population US meet criteria
DSM IV TR Criteria
Merrill Norton Pharm.D.,D.Ph.,ICCDP-D Merrill Norton Pharm.D.,D.Ph.,ICCDP-D
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Physical Dependence
Psychoactive Chemical Dependence

" Tolerance " Physical Withdrawal " Chemical taken longer/larger amounts than
ABUSE
Midbrain
intended
Physical and Psychological Dependence
" Preoccupation " Time acquiring,using,recovering from drug " Important people,places,things become less
important
" Compulsivity
DSM IV TR Criteria
Factors Contribu.ng to Vulnerability to Develop a Specic Addic.on

use of the drug of abuse essential (100%)"
Biology/genes
Genetic (25-50%)" Biology/ Environment Interactions

DNA" SNPs" other " polymorphisms"
Environmental (very high)"

prenatal" postnatal" contemporary" cues" comorbidity"
Environment
mRNA levels" peptides" proteomics"

Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D 11/27/12
Drug-Induced Effects (very high)"
neurochemistry" behaviors"
Kreek et al., 2000"
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We know that despite" their many differences, most abused substances enhance the dopamine and serotonin pathways"
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Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D"
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GABA
Alcohol Benzodiazepines Valium Xanax Ativan Non benzodiazepine Ambien Sonata Barbiturates Fiorinal Soma
Norepinephrine Serotonin
Cocaine Amphetamine Methamphetamine Ephedrine Ritalin LSD Psilocibin DMT Ibogaine
CannabinoidAnandamide
Marijuana
The Necessary Nine

Norepinephrine/Epinephrinestimulant,anger,fear,anxiety,fight,flight Serotonin-depressant,sleep,calm,pleasure GABA-relaxant,stress reduction,seizure threshold Endorphins-pain relief,pleasure Acetylcholine-involutary actions,memory,motivation Anandamide-memory,new learning,calmness Glutamate-organization of brain signaling,memory,pain Dopamine-perception,movement,pleasure PIP- loving of ones self,others,GOD
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Acetylcholine
Nicotine
NMDA
Ecstasy Mescaline DOM PCP Ketamine
Opiate
Opioids Opiates Heroin Buprenex Oxycontin
GHB
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Human Doing Neurotransmitters of Dependence Dependence PIP Dopamine Glutamate Acetylcholine Anandamide Endorphins / Enkelphins GABA Serotonin Epinephrine / Norepinephrine
Human Being
Recovery
Depletion may take less than 12 months
Replenishment may take 5 to 7 years
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Schick Shadel Hospital, 2009

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The An.-Reward Brain

1. A key element of addic.on is the development of a nega.ve emo.onal state during drug abs.nence. 2. The neurobiological basis of the nega.ve emo.onal state derives from two sources: decreased reward circuitry func.on and increased an.-reward circuitry func.on. 3. The an.-reward circuitry func.on recruited during the addic.on process can be localized to connec.ons of the extended amygdala in the basal forebrain. 4. Neurochemical elements in the an.reward system of the extended amygdala have as a focal point the extrahypothalamic cor.cotropin- releasing factor system. 5. Other neurotransmiOer systems implicated in the an.-reward response include norepinephrine, dynorphin, neuropep.de Y, and nocicep.n. 6. Vulnerability to addic.on involves mul.ple targets in both the reward and an.-reward system, but a common element is sensi.za.on of brain stress systems. 7. Dysregula.on of the brain reward system and recruitment of the brain an.- reward system are hypothesized to produce an allosta.c emo.onal change that can lead to pathology. 8. Nondrug addic.ons may be hypothesized to ac.vate similar allosta.c mechanisms.
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ANTI-REWARD The concept of an an.-reward system was developed to explain one component of .me-dependent neuroadapta.ons in response to excessive u.liza.on of the brain reward system. The brain reward system is dened as ac.va.on of circuits involved in posi.ve reinforcement with an overlay of posi.ve hedonic valence. The neuroadapta.on simply could involve state-shiXs on a single axis of the reward system (within- system change; dopamine func.on decreases). However, there is compelling evidence that brain stress/emo.onal systems are recruited as a result of excessive ac.va.on of the reward system and provide an addi.onal source of nega.ve hedonic valence that are dened here as the an.-reward system (between-system change; cor.cotropin- releasing factor func.on increases). The combina.on of both a decit in the reward system (nega.ve hedonic valence) and recruitment of the brain stress systems (nega.ve hedonic valence) provides a powerful mo.va.onal state mediated in part by the an.-reward system. (Koob & Le Moal 2005).
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Why Do People Abuse Prescription Drugs?

% of Basal Release
Why Do People Abuse Prescription Drugs?

% of Basal Release
These prescription drugs, like other drugs of abuse (cocaine, heroin, marijuana) raise brain dopamine levels
frontal cortex
Dopamine
Neurotransmission

1100 1000 900 800 700 600 500 400 300 200 100 0
AMPHETAMINE
These prescription drugs, like other drugs of abuse (cocaine, heroin, marijuana) raise brain dopamine levels
frontal cortex
1 2 3 4 Time AXer Amphetamine
5 hr
Dopamine
Neurotransmission

1100 1000 900 800 700 600 500 400 300 200 100 0
AMPHETAMINE
1 2 3 4 5 hr Time After Amphetamine
% of Basal Release
nucleus accumbens
150 100 50 Empty Box Feeding 0 0 60
% of Basal Release
200
FOOD
nucleus accumbens
120 180
200 150 100 50 Empty Box Feeding 0 0 60
FOOD
VTA/SN
VTA/SN
Time (min)
Di Chiara et al.
Time (min)
120
180
Di Chiara et al.
BUT dopamine is also elevated by natural re-enforcers
BUT dopamine is also elevated by natural re-enforcers
CNS Actions of Corticotropin Releasing Factor (CRF)
Stages of the Addiction Cycle
Merrill Norton D.Ph.,NCAC II,CCS
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Neurobiology of Addiction
Binge/Intoxication Stage
Koob, G. F. and Volkow. N. D. Neurocircuitry of Addiction, Neuropsychopharmacology reviews 35 (2010) 217-238
Withdrawal/Negative Affect Stage
Preoccupation/Anticipation Craving Stage
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Non-dependent
Positive Reinforcement
Brain Arousal-Stress System Modulation in the Extended Amygdala
Dependent
Negative Reinforcement
From: Koob, G.F. 2008 Neuron 59:11-34
Allostasis - Definition
The ability to achieve stability through change To obtain stability, an organism must vary all of the parameters of its internal milieu and match them appropriately to environmental demands.
Merrill Norton D.Ph.,NCAC II,CCS
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From: Sterling P and Eyer J, Allostasis: a new paradigm to explain arousal pathology. In Fisher S and Reason J (eds), Merrill Norton D.Ph.,NCAC II,CCS Handbook of Life Stress, Cognition and Health, John Wiley, New York, 1988, pp. 629-647.
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The Brain has a Hedonic Set Point
Another set point in the brain . . .
High stress hormone levels reset the brains pleasure set point
Change in Hedonic Set Point:" Old pleasures dont show up
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Anhedonia: Pleasure deafness

The patient is no longer able to derive normal pleasure from those things that have been pleasurable in the past Addiction is a stress-induced hedonic dysregulation
Hedonic Allostasis Theory (Koob & LeMoal)

With continued drug use and withdrawal, the anti-reward system is recuited to counterbalance excess Dopamine (with the stress hormone CRF) Brain is unable to maintain normal homeostasis So the brain reverts to allostasis - change of the hedonic set point under stress in a desperate attempt to maintain stability Current Rx/Tx focus: CRF1-antagonists as anticraving drugs
Pharmacokinetics in Human Brain

[11C]Cocaine
[11C]Methylphenidate

Relationship Between Drug Pharmacokinetics and the High

[11C]Cocaine
100
[11C]Methylphenidate
100 80 60 40 20
% Peak
80 60 40 20 0 0 10 20 30 40 50 60 70 80
"High"

"High"

0 10 20 30 40 50 60 70 80
Time (min)
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Addic.on = Depression 2012
Denitions"
cAMP- Cyclic adenosine monophosphate used for intracellular signal transduction" BDNF- Brain-derived neurotrophic factor-encourage the growth and differentiation of new neurons and synapses." CREB-(cAMP Response Element Binding)-neuronal plasticity and longterm memory formation in the brain."
BDNF
cAMP CREB
Brain Derived Neurotrophic Factor and neuronal plasticity
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CHROMOSOME 11
11p13
11p14
PROMOTER
5
297
468
492
681
1040
1353 BP
This is your brain"

This is your brain" Thanks to balanced" BDNF"
Think of it like fertilizing and pruning your rose bushes"
START CODON MAY BE EXTRACELLULARLY ACTIVE AT TrkB RECEPTORS
G492 A492 Val66 Met66
STOP CODON
proBDNF (32 kDa)

CLEAVED IN TRANS-GOLGI NETWORK AND/OR IMMATURE VESICLES
CLEAVED IN ENDOPLASMIC RETICULUM
Val66
SIGNAL PEPTIDE
Met66
OR
Val66
Met66
TRUNCATED proBDNF (28 kDa)
SIGNAL PEPTIDE
MATURE BDNF (14 kDa)
ACTIVITY UNKNOWN
ESSENTIAL ROLE IN DEVELOPMENT, SURVIVAL AND FUNCTION OF NEURONS
Molecular Biology of Addiction:

Addiction is a form of drug-induced neural plasticity
THE RECEPTOR SENSITIVITY HYPOTHESIS

Supersensitivity
Upregulation of cAMP pathway

Occurs in response to chronic administration of drugs Resulting activation of transcription factor CREB (cAMP response element-binding) Both mediate aspects of tolerance and dependency
and up-regulation of postsynaptic receptors leads to depression Suicidal and depressed patients have increased 5HT-2 receptors
Induction of another transcription factor, d FosB

Exerts opposite effects May contribute to sensitized responses to drug exposure
Ref: Nestler, Eric - Molecular Biology of Addiction. Am J of Addictions 10:201-217, 2001
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Basis for Plasticity: Summary

Drugs enter the brain and bind to an initial protein target Binding perturbs synaptic transmission which in turn cause the acute behavioral effects of the drug Acute effects of the drug do not explain addiction by themselves
Basis for Plasticity: Summary

Drugs enter the brain and bind to an initial protein target Binding perturbs synaptic transmission which in turn cause the acute behavioral effects of the drug Acute effects of the drug do not explain addiction by themselves
The Neurochemistry of Recovery and Discovery

Addiction produces a change in brain structure and function (adaptation to the drug) molecular and cellular changes in particular neurons alter functional neural circuits This leads to changes in behavior consistent with addicted states Addiction is therefore a form of drug induced neural plasticity
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Precursor" Synthesis" Storage"
= vesicle
" " "
= neurotransmitters = receptor
Degradation"
Reuptake" Release" Synaptic Cleft"
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Neural Communication"
Action Potential "
a neural impulse; a brief electrical charge that travels down an axon" generated by the movement of positively charged atoms in and out of channels in the axons membrane"
Threshold "
the level of stimulation required to trigger a neural impulse"
Merrill Norton Pharm.D.,D.Ph.,ICCDP-D Merrill Norton
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Synapse [SIN-aps]"
junction between the axon tip of the sending neuron and the dendrite or cell body of the receiving neuron" tiny gap at this junction is called the synaptic gap or cleft!
Neurotransmitters"
chemical messengers that traverse the synaptic gaps between neurons" when released by the sending neuron, neurotransmitters travel across the synapse and bind to receptor sites on the receiving neuron, thereby inuencing whether it will generate a neural impulse"
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Cell body end of axon"

Merrill Norton Pharm.D.,D.Ph.,ICCDP-D Direction of neural impulse: toward axon terminals
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Serotonin Pathways
Merrill Norton
Dopamine Pathways
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The Nervous System"

Nervous system
Peripheral
Central (brain and spinal cord)
Autonomic (controls self-regulated action of internal organs and glands)
Skeletal (controls voluntary movements of skeletal muscles)
Sympathetic (arousing)
Parasympathetic (calming)
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The Nervous System"
The Nervous System"
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The Nervous System"

Reex"
a simple, automatic, inborn response to a sensory stimulus"
Brain Sensory neuron (incoming information)
The Nervous System"

Neurons in the brain connect with one another to form networks
Neural Networks"
interconnected neural cells " with experience, networks can learn, as feedback strengthens or inhibits connections Outputs that produce certain results " computer simulations of neural networks show analogous learning"
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Interneuron Inputs
Muscle Skin receptors
Motor neuron (outgoing information)
Spinal cord
The brain learns by modifying certain connections in response to feedback

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The Endocrine System"

Endocrine System"
the bodys slow chemical communication system" a set of glands that secrete hormones into the bloodstream"
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Major Classes of Psychoactive Chemicals

CNS Depressants CNS Stimulants Narcotics Hallucinogens Cannabis Solvents/ Inhalant Steroids Psychotropics
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CENTRAL NERVOUS SYSTEM (CNS) STIMULANTS SUMMARY

Pharmacological Actions ! effects" " Constricted blood vessels decreased vessel tone" " Increased blood pressure decreased pressure" " Increased energy " "Fatigue" " Increased strength " " Euphoria " " "Depression, anxiety" " Increased alertness " concentrating" " Decreased appetite " appetite" ! " " " " " " " ! " " " " " " " !Withdrawal "Normal or "Normal or " "Weakness" " "Trouble "Increased
NARCOTICS
. Naturally Occurring - Codeine, Morphine, Opium, Thebaine" B. Semisynthetic - Dilaudid, Heroin (Horse, Junk, Smack, Skag), Percodan , Oxycontin" C. Synthetic - Darvon, Demerol, Fentanyl, Methadone"
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NARCOTIC SUMMARY
Symptoms of users - Drowsiness, lethargy, euphoria, slurred speech, bobbing head (nodding), ushing of skin of face, neck, chest, pinpoint pupils, constipation, and nausea. The duration of psychoactive chemical effect varies from 3-6 hours for Codeine to 12-36 hours for methadone." How used - Injected - (I.V. or skin popping)" Orally or Smoked (Opium)" Physical dependence - YES (Very Rapid)" Psychological dependence - YES (High Degree)" Tolerance - YES (Very Rapid)"
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HALLUCINOGENS
Examples" LSD, MDSA, MDMA (Adam, Ecstasy), MDEA (EVE), MBDB, DMT, STP, Mescaline, Psilocybin, etc." Spice" Bath Salts" Salvia"
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HALLUCINOGENS SUMMARY
Physical and Mental Effects" Distortions in perception;" Euphoria;" Impaired short-term memory;" Increased pulse;" Disturbed judgement;" Withdrawal and tolerance;" Method of ingestion;" Specic effects of PCP;" Severe adverse effects possible:" Anxiety reaction;" Depression;" Schizophrenia-like episode, usually paranoid; sometimes long-lasting and difcult to treat;" Accidents;" Flashbacks" Extremely low effective dose;" Taken sporadically."
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CANNABIS: MARIJUANA, HASHISH

(Cannabis Sativa and Indica) Called Pot, Reefer, Dope, Weed, or Grass. Usually a mixture of the leaves, owering tops, stems and seeds of the cannabis plant. The plant contains about 60 cannabinols to which the intoxicating properties are attributed. " Tetrahydrocannabinol, or THC, is the most prevalent and most potent of the cannabinols found in the marijuana plant. The potency of marijuana is usually measured by the concentration of THC in the plant, cigarette or extract. There has been a dramatic increase in the potency of marijuana conscated over the last 15 years."
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CANNABIS SUMMARY
Concentrations of THC" " Marijuana- (4-8 % THC) Hashish (up to 12% THC) Hash Oil (up to 30% THC)" Symptoms of usersAltered time sense (time appears slow), reddening of the eyes, confusion, paranoia, increased appetite, mood swings, drowsiness, vision may seem sharper and sounds may seem more distinct, increased reaction time, increased heart rate." How used" When smokedOnset of effect is within minutes, peak intensity is within 70 minutes, decline is within 2 hours, clearing of the effects within 6 hours. " When eatenOnly 1/3 to 1/4 of THC reaches the blood stream. Onset is from 30-120 minutes; duration of effect is 8-12 hours. " Physical dependenceSuggested" Psychological dependenceYES" TolerancePlasma half-life of THC is shorter in chronic users than in non-users. Users tend to increase daily intake by shortening the interval between highs or by increasing total numbers of cigarettes used. " Withdrawal symptomsIrritability, restlessness, nervousness, insomnia, dysphoria."
Merrill Norton
SOLVENTS AND INHALANTS

Organic Solvents (hydrocarbons) are industrial solvents and aerosol sprays " Volatile Nitrates" Nitrate poppers are used to enhance sexual behavior performance. It is now a prescription substance. Butyl and Isobutyl, Locker Room, Rush, Bolt, Quick Silver and Zoom are used to enhance sexual pleasure." Nitrous Oxide "
117"
Merrill Norton
118"
"STEROIDS (Anabolic)
These psychoactive chemicals are male hormones that increase muscle mass. Names are: Testosterone, Dianabol. Effects include: elevated mood, aggressiveness, high risk of injury because muscle mass is all that increases while tendon strength remains the same; masculinization of women (body hair and baldness), feminization of males (atrophy of the gonads), and liver cancer. These compounds are currently on the Control Substance Schedule III listing."
Merrill Norton
119"
OVER-THE-COUNTER PSYCHOACTIVE CHEMICALS

Allergy Treatment Products/Cough/Cold Remedies containing Caffeine, Codeine, Pseudoephedrine derivatives. " Antidiarrheal products containing Paregoric." Antitussives containing Codeine and Pseudoephedrine." Sedatives and Sleep Aids/Appetite Suppressants containing Codeine and Pseudoephedrine ." Appetite Suppressants/Diet Control Medications containing Caffeine, Codeine, Psuedoephedrine and Phenylephrine derivatives. "
Merrill Norton
120"
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USE OF PHARMACEUTICALS
These are some precautions that will help avert problems with prescribed psychoactive medications:" Avoid any medications that contain alcohol such as prescription cough syrups, liquid vitamin supplements, and any other preparations containing alcohol." Avoid any medications that contain any central nervous system stimulants such as prescription appetite suppressants and antihistamines." Avoid any medications that contain a narcotic that is used for pain relief or as an anti-diarrheal." Avoid any medications that contain a central nervous system depressant used for anxiety or as a sedative-hypnotic."
121"
CENTRAL NERVOUS SYSTEM (CNS) DEPRESSANTS

Alcohol- Ethyl alcohol, Ethanol (Beer, Liquors, Wine)" B. Barbiturates- Amytal, Nembutal, Phenobarbital, Seconal, Tuinal" C. Benzodiazepines- Valium, Librium, Ativan, Serax, Xanax, Tranxene, Klonopin" D. Other CNS Depressants- Ambien, Chloral Hydrate, Doriden, Meprobamate, Noludar, Paraldehyde, Placidyl, Quaaludes"
122"
CENTRAL NERVOUS SYSTEM DEPRESSANT SUMMARY

Physical and Mental Effects" Tolerance" Generally useful only for brief therapy" Other effects" Varying lengths of action and medical uses" Withdrawal" Potentiation with other depressants" Release inhibition, hostility, agitation" Depression, brain damage with chronic use" Habituation" Neuroadaptation"
123"
CENTRAL NERVOUS SYSTEM STIMULANTS

Amphetamines (Synthetic)-d,l amphetamine, Dextroamphetamine, Methamphetamine" B. Naturally Occurring-Caffeine, Cocaine, Nicotine" C. Synthetic Agents Like Amphetamines - Methylphenidate, Phentermine HCl"
124"
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Natural Rewards"
Food" Sex" Excitement" Comfort"
Dopamine Spells REWARD"
Release
Recycle
Activate
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125"
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126"
Brain Reward Pathways"
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127"
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Activation of Reward"
Drug-induced Craving
High Craving
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11/27/12" Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D" 129"
130
I want a beer
GABA and Glutamate Role in Motivation"

Thinking Brain Judgment Brain Ins.nctual Brain Basolateral Amygdala" Prefrontal Cortex" Mediodorsal Thalamus"
It makes me feel goooood Pleasure Brain Miller Lite Nucleus Accumbens" Ventral Pallidum"
Dopamine"
Ventral Tegmental Area"
Motor Nuclei"
GABA "" Glutamate"

Adapted from Kalivas and Nakamura, Curr. Opin. Neurobiol., 1999.!
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Marijuana Spect Scans Stimulant Spect Scans
4 Years
7 Years
9 Years
12 Years
Cocaine Use 3 years
Methamphetamine Use 1 Year
With Permission Amens Clinics

11/27/12 Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D 133 11/27/12 Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D 134
Opioids Spect Scans
Alcohol Spect Scans
Hydrocodone 3 Years Normal Brain- 25 years old Oxycodone 2 Years
Alcohol Use of 7 Years
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135
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136
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Dopamine D2 Receptors are Lower in Addiction

Cocaine

DA" DA" DA
DA DA " "
DA D2 Receptor Availability
Science has generated much" evidence showing that " prolonged drug use changes" the brain in fundamental" and long-lasting ways"
DA DA "
"
DA" DA
" DA " DA " " DA "
Meth
Reward Circuits
Non-Drug Abuser
Alcohol
DA DA " "
DA" DA" DA" DA
"
Heroin
11/27/12" Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D" 137" 11/27/12"
Reward Circuits ControlDr. Merrill Norton Addicted Pharm.D.,D.Ph.,ICCDP-D"
Drug Abuser
138"
Dopamine Transporter Bmax/Kd
2.0 1.8 1.6 1.4 1.2 1.07
Motor Task"
Loss of dopamine " transporters in the meth " abusers may result in " slowing of motor " reactions."
Implication:" Brain changes resulting from " prolonged use of drugs " may compromise " mental and motor functions
Normal Control
Time Gait (seconds)
9 10 11 12 13
2.0 1.8 1.6 1.4 1.2 1.0 16 14 12 10 8
Memory task" Loss of dopamine transporters " in the meth abusers may result " in memory impairment."
Delayed Recall (words remembered)
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Methamphetamine Abuser Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D"
Volkow et al., Am. J. Psychiatry, 2001.
."
139" 11/27/12" Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D" 140"
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Cross Addic.on
Many people who begin the process of becoming clean and sober cling to the idea that they can con.nue to hold on to some parts of their drinking/using lifestyle, especially their friends who might s.ll be using.
Though each class of addic.ve drugs has its own unique area, or nucleus, in which it exerts its ac.ons, there is a common nerve pathway that acts to increase the release of dopamine in the pleasure center of the brain, following the use of any of these drugs. Interes.ngly, the pleasure center of the brain is a group of nuclei located in the same area in which the drive for survival resides. The nucleus accumbens and the Ventral tegmental areas are the primary sites responsible for dopamine release causing pleasure and relaxa.on. This release of dopamine in the reward center of the brain creates a desire, or reinforcement to repeat a par.cular ac.vity. In the same fashion that certain pleasurable ac.vi.es cause a surge of dopamine, drugs of abuse in certain individuals trigger a far greater release and/or response to the dopamine release. We think this is one reason some people may be more predisposed to addic.ve behavior than others.
141
Cross-addiction can occur by different mechanisms. A person in solid alcohol recovery, for instance, may go to the dentist and be prescribed some pain medicine along with an antibiotic. He may take this exactly as prescribed thinking nothing of it. He may then, without considering what is happening, begin to increase the dosage and/or frequency of the medication and may even seek a refill although the pain does not warrant a narcotic.This person, who was previously doing well as a recovering alcoholic may be on the path to developing a dependency on narcotics or, at very least, is on a slippery slope for an alcohol relapse.
11/27/12
Cross addiction or Cross-tolerance means that when you develop a tolerance to a drug you will also have a tolerance to closely related drugs--but not to totally dissimilar drugs. The more closely related the two drugs are the stronger the cross tolerance effect will be. For example,Valium, Librium, Xanax, Ativan and Klonopin are all closely related drugs which belong to the benzodiazepine family of drugs.These drugs all affect the GABA receptors in your brain. If you become addicted to any one of these benzodiazepines then you can substitute any other because there is crosstolerance. Since alcohol also affects GABA receptors there is some cross-tolerance with alcohol but not as much with each other since alcohol affects many different receptors. However you cannot substitute heroin for Valium because heroin does not affect the GABA receptor.There is no cross tolerance between heroin and Valium.
Brain Reward Pathways
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144
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Cocaine Craving:
Population (Cocaine Users, Controls) x Film (cocaine, erotic)
Cingulate
Signal Intensity (AU)
Ant. Cing.
Cocaine Film
IFG
Controls Cocaine Users

11/27/12" Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D" 145" 11/27/12" Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D"
Garavan et al., Am. J. Psychiatry, 2000.

146"
Drug Addiction: A Complex Behavioral and Neurobiological Disorder"

Historical"
- Prior experience - Expectation - Learning"
Drugs" Brain Mechanisms" Behavior" Environment"
Physiological"
- Genetics - Circadian rhythms - Disease states - Gender"
Environmental"
- Social interactions - Stress - Conditioned stimuli"
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147"
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148"
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Addiction Changes Brain Circuits"

Non-Addicted Brain
Addicted Brain

Control

Control

Saliency
Drive

NOT
GO

Saliency

Drive
GO

Memory

Full recovery is a challenge but it is possible "
Memory

Source: Adapted from Volkow et al., Neuropharmacology, 2004.!

11/27/12" Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D" 149" 11/27/12" Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D" 150"
The Neurochemistry of Recovery and Discovery
ANTI-REWARD The concept of an an.-reward system was developed to explain one component of .me-dependent neuroadapta.ons in response to excessive u.liza.on of the brain reward system. The brain reward system is dened as ac.va.on of circuits involved in posi.ve reinforcement with an overlay of posi.ve hedonic valence. The neuroadapta.on simply could involve state-shiXs on a single axis of the reward system (within- system change; dopamine func.on decreases). However, there is compelling evidence that brain stress/emo.onal systems are recruited as a result of excessive ac.va.on of the reward system and provide an addi.onal source of nega.ve hedonic valence that are dened here as the an.-reward system (between-system change; cor.cotropin- releasing factor func.on increases). The combina.on of both a decit in the reward system (nega.ve hedonic valence) and recruitment of the brain stress systems (nega.ve hedonic valence) provides a powerful mo.va.onal state mediated in part by the an.-reward system. (Koob & Le Moal 2005).
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152
38
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I want a beer
Thinking Brain Judgment Brain Ins.nctual Brain
It makes me feel goooood Pleasure Brain Miller Lite
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153
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154
GABA and Glutamate Role in Motivation"
Basolateral Amygdala"
Prefrontal Cortex"
Mediodorsal Thalamus"
A Major Reason People Take a Drug is They Like What it Does to Their Brains
Nucleus Accumbens"
Ventral Pallidum"
Dopamine"
Ventral Tegmental Area"
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Motor Nuclei"
GABA "" Glutamate"
Dr. Merrill Norton Adapted Pharm.D.,D.Ph.,ICCDP-D 155 from Kalivas and Nakamura, Curr. Opin. Neurobiol., 1999.!
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Increased cAMP produced in post-synap.c cell
Circuits Involved In Drug Abuse and Addiction"
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All of these must be considered" in developing strategies to Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D effectively treat addiction "
158
Natural Rewards Elevate Dopamine Levels "

200
% of Basal DA Output" DA Concentration (% Baseline)"
" " "

Empty
FOOD"
NAc shell
200
" " "
SEX"
150
150
Copulation Frequency"
100
100
15 10 5 0
Female Present"
50
"
Box Feeding
"
"
" "
"
120 180
"
"
60
" Time (min)"
"
"
Sample" 1 Number
" "
"
" 2" 3" 4" 5" 6" 7" 8"
Mounts" Intromissions" Ejaculations"
Di Chiara et al., Neuroscience, 1999.! 11/27/12
Fiorino and Phillips, J. Neuroscience, 1997.! Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D 159 11/27/12 Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D 160
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Effects of Drugs on Dopamine Release"

1100" 1000" 900" 800" 700" 600" 500" 400" 300" 200" 100" 0" Accumbens"
AMPHETAMINE"
400"
% of Basal Release"
% of Basal Release"
Accumbens"
COCAINE"
DA" DOPAC" HVA"
DA" DOPAC" HVA"
300" 200" 100" 0"
0"
1" 2" 3" 4" Time After Amphetamine"
5 hr"
0"
1"
2" 3" 4" Time After Cocaine"
5 hr"
% of Basal Release"
250" 200" 150" 100"
% of Basal Release"
NICOTINE"
Accumbens" Caudate"
250" Accumbens" 200" 150" 100"
MORPHINE"
Dose (mg/kg) "
0.5" 1.0" 2.5" 10"
0" 0" 11/27/12
0" 1" 2" 3 hr" 0" 1" Time After Nicotine" Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D
2" 3" 4" Time After Morphine"
5hr" 11/27/12 Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D 162
161 Di Chiara and Imperato, PNAS, 1988!
Science has generated much" evidence showing that " prolonged drug use changes " the brain in fundamental " and long-lasting ways "
11/27/12 Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D 163 11/27/12
This is your brain

This is your brain AXer drugs
Think about it as what happens when you fail to fer.lize, water, and prune your garden.
Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D 164
41
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Questions?????????"
11/27/12"
165"
42

The Anti Reward Brain System

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11/27/12

The Neuroscience of Chemical Dependence 2012: The Anti-Reward Brain System

The Neuroscience and Pharmacology of Chemical Dependence 2012

Merrill Norton Pharm.D.,D.Ph.,ICCDP-D

Dr. Merrill Norton Pharm.D.,D.Ph.,ICCDP-D

Chemical Dependence is a Complex Illness

The Addicted Brain- 2012

with biological, sociological and psychological components

Merrill Norton Pharm.D.,D.Ph.,ICCDP-D

Merrill Norton Pharm.D.,D.Ph.,ICCDP-D

MDPV Bath Salts

Positive: mental and physical stimulation, euphoria,

MDPV Bath Salts

MDPV Bath Salts

MDPV Bath Salts

MDPV Bath Salts

MDPV administered to mice increased dopamine

Merrill Norton Pharm.D.,D.Ph.,ICCDP-D

MDPV Bath Salts

MDPV Bath Salts

not respond to conventional medical treatment

only one month of abuse

No information available on withdrawal or

Merrill Norton Pharm.D.,D.Ph.,ICCDP-D

MDPV Bath Salts

extended drug screens

Redwood Toxicology Lab has a 2-panel urine drug

Merrill Norton Pharm.D.,D.Ph.,ICCDP-D

Merrill Norton Pharm.D.,D.Ph.,ICCDP-D

Cannabis Effects by Erowid

Onset Coming Up Plateau Coming Down After Effects

A Dangerous Legal High

Merrill Norton Pharm.D.,D.Ph.,ICCDP-D

Merrill Norton Pharm.D.,D.Ph.,ICCDP-D

Merrill Norton Pharm.D.,D.Ph.,ICCDP-D

Merrill Norton Pharm.D.,D.Ph.,ICCDP-D

responsible for hallucinogenic eects receptor agonist

Salvinorin A is a potent and selective kappa opioid

Merrill Norton Pharm.D.,D.Ph.,ICCDP-D

studies in rats show depression-like eects

patient genetically predisposed to schizophrenia

Merrill Norton Pharm.D.,D.Ph.,ICCDP-D

watch over rst time users

Merrill Norton Pharm.D.,D.Ph.,ICCDP-D

tests or extended drug tests

It can be detected by liquid chromatography/mass

A Dangerous Legal High

Merrill Norton Pharm.D.,D.Ph.,ICCDP-D

Merrill Norton Pharm.D.,D.Ph.,ICCDP-D

(left) and HU-210, a synthetic cannabinoid (right)

Merrill Norton Pharm.D.,D.Ph.,ICCDP-D

Merrill Norton Pharm.D.,D.Ph.,ICCDP-D

Merrill Norton Pharm.D.,D.Ph.,ICCDP-D

relatively new (Spice rst appeared in 2004)

Toxicity and overdose:

DEFINITIONS OF PSYCHOACTIVE CHEMICAL USE, ABUSE, AND DEPENDENCE

Psychoactive Chemical Use

Merrill Norton Pharm.D.,D.Ph.,ICCDP-D

Endorphins/Dopamine Receptors 1 USE Cortex

Psychoactive Chemical Abuse

Psychoactive Chemical Dependence

Physical and Psychological Dependence

Factors Contribu.ng to Vulnerability to Develop a Specic Addic.on