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The Reward Pathway The Bottom Up System vs. The Top Down SystemNicotine, Alcohol, Opiates, Stimulants, Hallucinogens Psychopharmacology of Feeding, Hunger and Sex

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 A natural high or drug induced high is mediated by the mesolimbic dopamine pathway which is sometimes referred to as the pleasure center of the brain, with dopamine as the pleasure neurotransmitter.

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1. Ventral tegmentalarea(VTA), (dopamine cellbodies)2. Nucleusaccumbens, (dopaminergic axons project)3. Amygdala, connectswith both the VTA andthe nucleus accumbens

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Projections from :1. orbitofrontal cortex(OFC) involved in regulating impulses,2. ventromedial prefrontal cortex(VMPFC) involved in regulating emotions,3. dorsolateral prefrontal cortex(DLPFC) involved in analyzing situations and regulating whether an action takes place.

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The brain makes its own drugs: Endorphines and Enkephalins = Morphine/Heroin Anandamide = Cannabis/marijuana Acetylcholine = Nicotine Dopamine = Cocaine/amphetamine

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 The numerous psychotropic drugs of abuse that occur in nature mimic the brain’s own neurotransmitters. Directly stimulate the brain’s receptors in the reward system, causing dopamine release and a consequent “artificial high”.

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Impulsive Cycle *Occasional substance use is an impulsive choice driven by positive reinforcement of the drug’s expected effect (pleasure and reward). *This “teaches” the brain to anticipate reward on subsequent exposure to the drug. *When the substance is taken, pleasure will be experienced again, usually followed by regretCompulsive Cycle*With repeated exposure to drugneurobiological changes occur inthe brain, leading tocraving, reduced reward on drugexposure and withdrawal duringabstinence(negative reinforcement).*This leads to craving which isreleased by drug ingestion.

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 The rate of dopamine release in the nucleus accumbens determines how addictive a substance is. Two ways of dopamine release: Regular (Tonic) and Irregular (Phasic) Constant (tonic) dopamine release is not addictive. Bursts of dopamine (Phasic) release is addictive.

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 Three mechanisms of action: Directly causes dopamine release in the nucleus accumbens by binding to α4β2 nicotinic postsynaptic receptors on dopamine neurons in the VTA Indirectly causes dopamine release by binding to the alpha 7 nicotinic receptors on the glutamatergic neurons. Disinhibits mesolimbic dopamine neurons by desensitizing α4β2 on GABA interneurons in the VTA.

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 Varenicline is a nicotinic partial agonist (NPA) selective for the α4β2 nicotinic receptors located on dopamine neurons and GABA interneurons in the VTA

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CHANTIX tablets contain varenicline (as the tartrate salt), which is apartial agonist selective for α4β2 nicotinic acetylcholine receptorsubtypes. The recommended dose of CHANTIX is 1 mg twice daily following a 1week titration as follows:Days 1 – 3: 0.5 mg once dailyDays 4 – 7: 0.5 mg twice dailyDay 8 - 1 mg twice dailyPatients should be treated with CHANTIX for 12 weeks.Box Warning: Serious neuropsychiatric events including, but notlimited to, depression, suicidal ideation, suicide attempt, andcompleted suicide have been reported in patients taking CHANTIX.

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 In addition to enhancing GABA inhibition and reducing glutamate excitation, alcohol also enhances euphoric effects by releasing opiates and endocannabinoids, thereby mediating its “high”.

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 Naltrexone is a mu opiate receptor antagonist Available in oral formulation and a once-monthly intramuscular injection (extended-release 380 mg every 4 weeks). Extended-release form requires less will power to refrain from drinking. With oral naltrexone, one must decide daily whether or not to continue the treatment.

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 Acamprosate is a derivative of the amino acid taurine . It can be thought of as “artificial alcohol” because : -Reduces excitatory glutamate neurotransmission - Enhances GABA neurotransmission.Acamprosate: dosage for alcohol dependence: The recommended dose of acamprosate for most people is 666 mg TID It is not approved for use in people who have not yet stopped drinking. Acamprosate should be used with an appropriate treatment program, including counseling and group sessions as necessary.Adverse effects: Acamprosate is renally excreted, thus for people with moderate kidney problems, the recommended dose is acamprosate 333 mg TID. For people with severe kidney problems, the drug is not recommended.

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 Opiate Neurons originate in the arcuate nucleus and project to both the ventral tegmental area(VTA), and to the nucleus accumbens. Opiate neurons release endogenous opiates such as enkephalin. Enkephalin increases dopamine in nucleus accumbens.

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 Opiate drugs act on opiate receptors such as mu, delta, and kappa. Endogenous opiate- are peptides derived from precursor proteins called POMC (pro-opio-melano-cortin). They are proenkephalin and prodynorphin. Endorphins, enkephalins or dynorphin, which are then stored in opiate neurons. Sigma receptors are no longer considered opiate receptors.

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Methadone is a full agonist at allopioid receptors.Buprenorphine is a partial agonistµ-opioid receptors, partialagonist at δ-opioidreceptors, and antagonist at theκ-opioid receptors.

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 Buprenorphine is much harder to abuse (partial agonist) so patients are allowed to take it home. Methadone can be abused, so patients need to travel to a clinic each day to take their medication. Withdrawal from Buprenorphine is generally less severe than Methadone. The risk of a fatal overdose on Buprenorphine is less than with Methadone. For people with heavy opiate habits and serious addiction, Buprenorphine cannot provide effective relief from withdrawal symptoms. Methadone works better for such individuals.

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Buprenorphine is used for:1. Treatment of opioid addiction in higher dosages (>2 mg),2. Control moderate chronic pain in dosages ranging from 20–70 µg/hour.Formulations:

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 The abuse properties of stimulants stem from their ability to enhance dopamine release in the nucleus accumbens.

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 The main mechanism of action of cocaine is to block reuptake of monoamines, principally dopamine(DA) but also norepinephrine(NE) and serotonin(5HT). There is also a local anesthetic action.

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 Amphetamine and methamphetamine are both pseudosubstrates reverse transporters of dopamine (DAT) act as inhibitors of the vesicular monoamine transporter(VMAT).

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Changes in dopamine neurons, include:-long lasting depletions of dopamine levels-axonal degeneration,-a state that clinically and pathologically is called “burn-out”

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Decrease in the release ofGABA from GABA-ergicneurons causes DA neuronsto be disinhibited and theirfiring rate increases (seeexample single-unitrecording in red).This results in more DA beingreleased in the nucleusaccumbens.

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 Marijuana delivers its active ingredients, the cannabinoids to the brain’s own cannabinoid receptors, triggering dopamine release in the nucleus accumbens.

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Receptors:*CB1 receptor is foundprimarily in thebrain, and mediatesthe psychologicaleffects of THC.*CB2 receptor isassociated with theimmune system

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 Nonpsychotropic cannabinoids act as N-methyl-D- aspartate receptor blockers. Cannabidiol is a component of marijuana that does not activate cannabinoid receptors, but moderately inhibits the degradation of the endocannabinoid anandamide. Elevation of anandamide levels in cerebrospinal fluid is inversely correlated to psychotic symptoms. Enhanced anandamide signaling leads to a lower transition rate from initial prodromal states of schizophrenia into frank psychosis. Currently in Phase 2 clinical trials.

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Club drugs such asphencyclidine(PCP) and ketamineare antagonists at N-methyl-D-aspartate(NMDA) receptors andthus cause NMDAhypoactivity, which in turn leadsto disinhibition of dopaminerelease.Gamma hydroxybutirate(GHB) isan agonist at GHB and GABA-Breceptors.GHB is used in the treatment offibromyalgia.

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The circuitry of hunger isinterconnected with thecircuitry of reward, howeverfood consumption is alsoregulated by peripheralsignaling systems (leptin andinsulin).Dopamine projections extendto the mamilary nucleus(MAM) of thehypothalamus, an areaimportant for regulatorycontrol of eatingProjections from the MAMnucleus extend to the nucleusaccumbens.

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Dopamine activity in rewardcircuitry is thought to play acentral role in sexual desireand arousal.Dopaminergic neurons alsoproject to thehypothalamus, where theymay have input to theregulation of sexual desireand arousal via neurons inthe medial preoptic area(MPOA) and the projection ofthose neurons to the nucleusaccumbens.