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Neurobiology of Addiction

Dept of Psychiatry, University of Virginia

Mandrill Taylor

on 21 February 2013

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Transcript of Neurobiology of Addiction

Club Drugs Mesolimbic Dopamine Circuit Neural Circuits Nicotine & Alcohol Nicotine Marijuana, Stimulants & Opiates Dionysus, Bacchus and other related matters
Drugs Sex, Food Sexual Disorders Eating Disorders - Mandrill Taylor Dionysus, Bacchus Michelangelo's Bacchus [1497] - Cornerstone of any Cocktail Conversation - God of Wine, Merry Making and Ecstasy - Worshiped since 1500 BC - Power to subvert oppressive restraints of the powerful - Supposedly killed during infancy yet was reborn - Namesake of Bacchanalia - Drunken Festivals of Ancient Rome - Inputs: Natural Neurotransmitters [e.g., Endorphins, Endocannaboids, Acetylcholine, Dopamine, etc.]
Substance-induced Activation - Components: Dopaminergic Neurons in the Ventral Tegmental Area [VTA, ATV] of Midbrain
- Fast Transmission due to Electrical Synapses; Gap Junctions in GABAergic interneurons Medial Forebrain Bundle [MFB]
- Ascending and Descending Fibers KRISHNAN-SARIN et al, NIAAA Study with Dept of Psychiatry at Yale Nucleus Accumbens [NA] in Subcortical Forebrain
- Composed of Spiny Neurons
- Also receives input from Glutamergic Neurons of the
Hippocampus, Amygdala & Medial Prefrontal Cortex - Direct Agonist of Nicotinic Acetylcholine Receptors [nAChRs] in VTA
- Major Receptor Subtypes in Reward System - Alpha-4 Beta-2 & Alpha-7 - Alpha-4 Beta-2: Post-Synaptic Activation of DA Neuronal Dendrite in VTA
Desensitization of inhibitory GABAergic interneurons in VTA
- less GABA, less inhibition of DA neurons, more Dopamine in NA - Alpha-7: Pre-Synaptic Activation of Glutaminergic Neuronal Axon in VTA
- Glutamate activates DA neurons, releasing more Dopamine in NA
Post-Synaptic Activation of Glutaminergic Neuronal Dendrite in Prefrontal Cortex
- Stimulates Cognitive Attentiveness Stahl's Essential Psychopharmacology Centrally-Acting Treatments Alcohol - Prevents release of Glutamate and enhances release of GABA in VTA
- Major Receptors in Reward System - mGluR, GABA, Opiates & possibly NMDA - mGluR: Pre-Synaptic Activation of Glutaminergic Negative Feedback Axons in VTA
- Decreases release of Glutamate - GABA-A: Positively Modulates Post-Synaptic Activation of DA Neuronal Dendrites in VTA
- Increased Affinity, Increased Uptake of GABA - GABA-B: Pre-Synaptic Inhibition of GABAergic Negative Feedback Axons in VTA
- Both Interneurons (within VTA) and outer neurons (from NA)
- Increases release of GABA - Mu-Opioid: Pre-Synaptic Inhibition of Glutaminergic and GABAergic Neuronal Axons in VTA
- Increased Production of Dopamine in NA - NMDA: Negatively Modulates Post-Synaptic Activation of DA Neuronal Dendrites in VTA Alcohol Withdrawal and Treatment - Shortage of GABA, Surplus of Glutamate - Prolonged Consumption and/or Genetic Predisposition may lead to Protracted Withdrawal Syndrome
- Persistently Raised Glutamate Levels
- Glutamate Receptor Sensitivity
- Excitotoxin-Induced Neuronal Death
Marijuana - Produces Euphoria, Relaxation, Loss of Temporal Awareness and ST Memory Loss
- May Induce Delirium, Panic Attacks & possibly Psychosis in High Doses
- Interacts with CB1 Pre-Synaptic Receptors on GABAergic and/or Glutamatergic Neurons
- Reducing either or both GABA and Glutamate in VPA and NA
- Natural Endocannabinoids; e.g., Anandamide
- Controversy in Diagnosis of Cannabis Dependence, Lack of Evidence re: Physical Dependence
- CB1 Antagonist [Rimonabant]produced withdrawal symptoms in chronically exposed mice
- Research in Treatment of Craving, associated with SI in long-term use Opioids Cocaine, Amphetamines and Ritalin - Cocaine [Powder, Crack]
- NOT Orally Activated
- Blocks DA Transporters [DATs], Serotonin (5HT) Transporters [SERTs] & NE Transporters [NETs]
- Prevents Re-uptake; Increases Amount of Available DA, 5HT & NE
- Methylphenidate [Ritalin]
- Blocks DA Transporters [DATs] (via Allosteric Inhibition) on Pre-Synaptic DA Neuronal Axons in NA
- Slower DA Onset than Cocaine
- Prevents Re-uptake; Increases Amount of Available DA & NE
- Amphetamine [Crystal Meth, Adderall]
- Block Both DATs & Vesicular Monoamine Transporters [VMATs] (via Competitive Inhibition)
- Prevents Re-uptake and Storage; Increases Amount of Available DA PCP, Ketamine & GHB - PCP & Ketamine
- Binds to Calcium Channel Site on NDMA Receptor (via non-competitive inhibition)
- Current Ketamine research focused on rapid-onset anti-depressant effect
- Inhibits Calcium influx non-competitively; prevents Glutamate release
- GHB [sodium oxybate, Xyrem]
- Trademarked for treatment of cataplexy and daytime sedation
- Misused for the purpose of
- elevating HGH in athletes
- obtaining feelings of euphoria in recreational settings
- assaulting unknowing victims due to its odorless and colorless properties. Erectile Dysfunction - Loss of Available Nitric Oxide [NO] with Age
- Low NO, Low cGMP, Decreased Smooth Muscle Relaxation, Decreased Erection
- NO Production requires Substrate [Arginine], Enzyme [NO Synthase] &
Five Co-Factors, including Heme and Oxygen - Treatment: PDE-5 Inhibitors [Viagra, Cialis, Leviterra]
- Less cGMP Breakdown, Longer Smooth Muscle Relaxation - Research: PnTx2-6, Spider Venom Toxin [Nunes et al, 2012, J. of Sexual Medicine]
- Increase in NO Synthase Activation
- Increase in NO Release, Increase in cGMP, Prolongation of Erection Sexual Response Cycle - Originally coined by Masters and Johnson in 1966
- Excitement (Arousal), Plateau, Orgasm, Resolution
- Inclusion of Libido/Desire in DSM Criteria
- Desire - Hypoactive Sexual Desire Disorder, Sexual Aversion Disorder
- Arousal - Female Sexual Arousal Disorder, Male Erectile Disorder [ED]
- Orgasm - Female Orgasmic Disorder, Male Orgasmic Disorder,
Premature Ejaculation [PE]
- Resolution - Postcoital Dysphoria, Postcoital Headache Eating, Hunger and Reward Circuits - Hypothalamus
- Main Regulator of Appetite
- Inputs from VTA & Arcuate, Outputs to NA
- Appetite Supressants
- Rimonabant - CB1 Antagonist - Discontinued due to associated SI
- Fluoxetine - Inhibits 5HT Re-uptake on Post-Synaptic GABAergic Dendrites
- Less GABA, More Activation of DA & NE Neurons; More DA & NE in PFC
- Symlin - Analogue of Amlin [Pancreatic Peptide Hormone] Any Questions? - Alternatives: Exercise, Low Fat Diet, Arginine (Substrate for NO Synthase, Mixed Results) Francis and Corbin, 2011, Dept of Psychiatry at Vanderbilt Males -
One complete response cycle with subsequent excitement after refractory period.

Females -
(A) - Similar to the male cycle, with the added possibility of multiple orgasms
(B) - Lengthy plateau phase with no orgasm
(C) - Rapid cycle with several fluctuations of excitment before reaching orgasm Hypoactive Sexual Desire Disorder - Controversial to Self-Identified Asexuals
- 1% of population, based on 18,000 person study in Britain
- No Approved Treatment, Several Areas of Research
- Contact Dr Anita Clayton, if further interested Stahl's Essential Psychopharmacology ALCOHOL decreases glutamate activity CAFFEINE inhibits GABA release PCP
"angel dust" increases glutamate activity CAFFEINE increases glutamate activity HYPNOTICS increase GABA activity ALCOHOL increases GABA activity Genetic Science Learning Center, Univ. of Utah Nicoll and Algers, 2004, Dept of Pharmacology at UCSF The Neurobiology of Pleasure - Bupropion [Zyban]
- NE/Dopamine Re-uptake Inhibitor [NDRI]
- Increases available DA without use of Nicotine

- Varenicline [Chantix]
- Nicotinic Partial Agonist [NPA] for the Alpha-4 Beta-2 receptors - Current Commonly used Pharmacotherapies
- Dilsulfiram, Naltrexone and Acamprosate
- Advancing Pharmacotherapeutic Research
- Topiramate [Topamax]
- Gabapentin [Neurontin]
- SSRIs & Ondansetron [Zofran] - Three Receptor Subtypes - mu, delta & kappa; mainly mu
- Natural Endogenous Opiates - Endorphins & Enkephalins
- Produced in Opiate Neurons from Arcuate Nucleus

- Treatment
- Methadone
- Full Opioid Agonist
- Slow Metabolism, Highly Lipid Soluble
- Controversial due to Associated Physical Dependence
- Buprenorphine
- Partial Opioid Agonist
- Often combined with Naloxone [Opioid Antagonist]
- Prevents Abusive Behaviors, IV use
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