[NS 09-27-16 10am - French]

Pharmacology of Reward

I.Brain Reward Pathways

A.Neural Substrates: A set of interconnected forebrain structures that underlie the perception of reward and the phenomenon of positive reinforcement. These structures include the nucleus accumbens (the major component of the ventral striatum), the amygdala, hippocampus, lateral hypothalamus, and prefrontal cortex, all receiving dopaminergic innervation from cell bodies in midbrain ventral tegmental area.

  • Ventral Tegmental Area (VTA) and nucleus accumbens: Function in reward and reinforcement as part of a neural circuit that interfaces between limbic emotional-motivational information and extrapyramidal regulation of motor behavior.
  • Amygdala: Critical integrative structureprojecting to the VTA and the nucleus accumbens. Thought to be important to the formation of stimulus-reward associations (i.e., remembering the pairing of stimulus with reward).
  • Hippocampus: Memory circuit involved in mediating associations between biologic stimuli [or drugs of abuse] and environmental cues.
  • Prefrontal cortex: Certain regions arecritical for executive function in providing control over impulses from destructive behavior. Their impairment in humans following chronic drug abuse appears to be an important mediator in the loss of control over drug intake (addiction).

B.Physiologic Role: The normal function of the reward pathway is to mediate pleasure (reward) and the strengthening of behaviors (reinforcement) associated with natural reinforcers such as food, water, and sexual contact. The pathway produces motivational states, shaped by natural selection, that allow modulation of physiological and behavioral responses ensuring survival and reproduction. This system can be thought of as complementary to survival networks in the brain that mediate learning about dangerous and harmful stimuli (fear-related information).

  • A reward is a stimulus that the brain interprets as intrinsically positive or something to be approached. Drug-induced pleasurable states are important motivators of initial drug use.
  • A reinforcing stimulusis one thatincreases the probability that behaviors paired with it will be repeated. Note that not all reinforcers are rewarding. For example, a negative or punishing stimulus might reinforce avoidance behaviors. Or a positive reinforcement might involve the alleviation of unpleasant symptoms, resulting from preexisting states or from drug withdrawal.

C.Central Role of Dopamine Release from VTA into NA: Final common pathway of reinforcement and reward is hypothesized to be the mesolimbic dopamine pathway – ventral tegmental area to nucleus accumbens. Once thought of as the “pleasure center” of the brain with dopamine as the “pleasure neurotransmitter”, it is now thought that dopamine may affect motivation and attention to salient stimuli, including rewarding stimuli. Multiple neurotransmitter inputs to this mesolimbic dopamine pathway can modulate these natural highs.

  • Sensory cues produced by the presence of natural reinforcers such as food, water, or a sexual partner activate the reward pathways, identifying these activities as those that should be repeated (reinforced)
  • Stimulation of VTA neurons by these natural reinforcers results in dopamine release in the nucleus accumbens
  • The majority of drugs of abuse also share thisfinal common pathway of increasing synaptic dopamine levels in the nucleus accumbens via interactions either directly with dopamine neurons or indirectly with other neurotransmitter systems shown in figure below and described in table (p. 6)
  • The more intense and more direct the effect of the drug on dopamine neurons, the greater the addiction potential (e.g., cocaine, methamphetamine, nicotine)

D.Reactive Reward System: Consists of the VTA (dopamine cell bodies), the nucleus accumbens (where DA neurons project) and the amygdala (which connects to both the VTA and NA). This system functions to signal the immediate prospect of either pleasure (positive) or pain (negative) and provides the motivational and behavioral drive to achieve that pleasure or avoid that pain.

  • Drug-induced increase in dopamine activity is often more explosive and pleasurable than that occurring with natural reinforcers. Repeated exposures to drugs of abuse results in pathologic “learning” to trigger drug-seeking behaviors when presented with internal (craving, withdrawal) or external (environmental associations with past drug use) cues.
  • Once learning has been conditioned in the amygdala, connections back to the VTA act as a detector for anything relevant to previous drug abuse experience. Projections from amygdala to nucleus accumbenssignal that emotional memories have been triggered by internal or external cues and initiate impulsive-automatic-obligatory actions to find and take more drugs (almost as a reflex action).
  • NET RESULT: Development of drug addiction produces changes whereby the “reactive reward system hijacks the normal reward circuitry”.

E.Reflective reward system: Acomplementary and potentially competitive component of the reactive reward system with connections from the prefrontal cortex to the nucleus accumbens:

  • Orbitofrontal projections (OFC) may be involved in regulating impulses
  • Dorsolateral prefrontal projections (DLPFC) in analysis of situation
  • Ventromedial prefrontal (VMPFC) may be involved in integration of impulsiveness and cognitive flexibility with its regulation of emotions

  • This system is built over time with influences from genetics, neurodevelopment, experience, peer pressure, and learning social rules and can focus the final output of the reward system into beneficial long-term goal-directed behavior.
  • The balance betweenreactive reward drives and reflective reward decisionsdetermines whether the output of the reward circuitry will be converted into short-term rewards (drug-seeking) orlong-

F.Compulsive Drug Use – Addiction

  • Repetitive drug-induced rewarding experiences alter the reward circuits so that not only will drug ingestion itself cause mesolimbic dopamine release, but also cues that merely predict pleasure
  • The amygdala has learned that a drug causes pleasure and has associated drug cues with pleasure and may also signal relief from craving ([1, 2] in figure above)
  • Drug cues then lead to dopamine release in the nucleus accumbens ([3]) that triggers GABA-ergic output from NAc  thalamus  prefrontal cortex
  • In the absence of activity in the reflective reward system (shown as dashed lines to amygdala and nucleus accumbens) actions such as drug seeking behavior will be initiated ([4])

II.Drug Variables Influencing Likelihood of Drug Abuse

A.Pharmacodynamics of Drug Abuse

  • Reinforcing properties: Drugs that reliably produce intense feelings of pleasure (euphoria) orrelief of a negative effectare more likely to be abused due to these reinforcing properties.
  • All drugs with significant dependence liability share the pharmacologic property ofenhancing dopamine activity in the nucleus accumbens: directly or indirectly through several different neurotransmitter systems and via several different mechanisms.

Initial Pharmacodynamic Actions of Addictive Drugs

Relative Risk

DrugMolecular Target Mode of ActionEffect on DA Neuronsof Addiction1

Stimulants

CocaineDAT (+ SERT-NET) InhibitorBlocks DA Uptake 5

MethamphetamineDAT (+ SERT-NET, VMAT) Reverses transporterDA releaser 5

NicotineNicotinic receptor AgonistExcitation 4

MDMA (Ecstasy)SERT > DAT, NET Reverses transporter(5HT releaser) ?

Opioids opioid receptor [Gi/o] AgonistDisinhibition 4

CNS Depressants

AlcoholGABA-A channel Complex-facilitateExcitation, disinhibition 3

NMDA receptor Complex-antagonize

BenzodiazepinesGABA-A channel Positive modulatorDisinhibition 3

CannabinoidsCB1 receptor [Gi/o] AgonistDisinhibition 2

(Marijuana)

Hallucinogens5-HT2A receptor [Gq] Partial agonist(- - -) 1

LSD, psilocybin

Dissociative AnestheticsNMDA receptor Antagonist(- - -) 1

Phencyclidine, Ketamine

______

1Relative Risk of Addiction: ranges from 1 = non-addictive to 5 = highly addictive

B.Pharmacokinetics of Drug Abuse

  • Rate of onset of action. The abuse liability of a drug is increased with an increase in the rapidity of the onset of effect. The sooner the drug effects occur, the more likely it is that the chain of events leading to loss of control over drug taking will be initiated.
  • Modes of administration [routes in order of most rapid onset of CNS action to slowest].
  • Inhalation

•Drug in vapor state reaches the large absorptive surface of the pulmonary circulation, enters the left side of the heart and reaches the cerebral circulation with dilution in systemic circulation

•Delivery of drug by this route is preferred by users of cocaine, nicotine, and cannabis. Because discernible CNS effects can be obtained within as few as 7 seconds, the user is able to titrate blood levels more precisely than via other routes

•Aerosol and nasal routes of administration are being developed to deliver medical dronabinol [synthetic THC], thus avoiding the hazards of smoking

  • Intravenous

•Effects achieved within 15-30 seconds (intramuscular/subcutaneous effects in 3-5 minutes) and because a large amount of drug enters plasma in a short time psychoactive drugs are most likely to produce an intense rush or flash of euphoria similar to a sexual orgasm

•Most dangerous route with greatest potential for exaggerated reactions, introduction of infectious agents or contaminants, and overdose toxicity.

  • Mucous membrane absorption

•Most commonly via insufflation (snorting via the nose) with effects occurring more rapidly (within 3-5 minutes) and more intensely because of bypass of liver metabolism (first-pass effect)than after oral ingestion

  • Oral

•Easiest route for administration of drugs but CNS effects are delayed (up to 20-30 minutes)

•Difficult to obtain intense rush feelings via this route, but it can prevent drug withdrawal symptoms and this route is useful in treatment programs.

  • SUMMARY: The intravenous and inhalational routes are associated with the most rapid rise in brain levels of the drug and a greater likelihood to produce addiction.
  • Termination of effects. For any particular class of abused drugs, those drugs with the shortest half-lives tend to have higher abuse liabilities.
  • Acutely, quick offset of drug action is more likely to lead user to frequent administrations that increase likelihood of loss of control over drug consumption.

Example: Routes of cocaine administration can influence addictive potential as seen with smoking crack-free base cocaine (inhalation) versus snorting (insufflation) cocaine flakes. Inhalation route is much more addictive than insufflation.

  • Chronically, withdrawal effects are generally more severe for drugs with short half-lives leading users to continue drug administration simply to avoid these withdrawal symptoms.

•Opioids (heroin [B]shorter half-life than methadone [A]) or benzodiazepines (lorazepam [B] shorter half-life than diazepam [A])

•Antagonist naloxone given to opioid dependent patient [C]

C.Pharmacogenetics of Drug Abuse - Heredity. Drug effects vary among individuals, possibly due to polymorphisms in the genes that code for enzymes involved in absorption, metabolism, and excretion, or in receptor-mediated responses. This can influence propensity for a drug to be abused through effects on innate tolerance, rate of acquired tolerance development, or the likelihood of experiencing intoxication as pleasurable feeling.

  • Metabolism of alcohol. Asians that are deficient in the enzyme that metabolizes acetaldehyde (oxidative metabolite of alcohol that produces unpleasant flushing reaction) have a much lower incidence of alcoholism than the general population. (Increased protection against addiction)
  • Metabolism of nicotine. Individuals with a gene for impaired nicotine metabolism have a lower probability of becoming addicted to nicotine as they are more likely to experience unpleasant effects when beginning to smoke. (Increased protection against addiction)

REFERENCES USED

1.Molecular Pharmacology, 3rdEd. (2015), Nestler, Hyman, Holtzman and Malenka, McGraw-Hill, N.Y., Chapter 15.

2.Basic and Clinical Pharmacology, 13th Ed. (2014), Katzung, ed.; McGraw-Hill, New York, NY , Chapter 32.

3.Stahl’s Essential Psychopharmacology, 4rd Ed. (2013), Stahl, Cambridge University Press, New York, N.Y., Chapters 9-13.

Tom French, Ph.D.

Fall 2016

Study Guide - Learning Objectives

Pharmacology of Reward

1.Identify the major brain structures and systems that are thought to comprise the brain reward pathway.

2.Describe the central role of brain dopamine systems in learning physiologically relevant behaviors and possible contributions of other neurotransmitter systems.

3.Describe the interaction of drugs of abuse with brain reward pathways in the development of addictive behaviors.

4.Describe the contribution of pharmacodynamics, pharmacokinetics (rapidity of onset-route of administration and half-life) and pharmacogenetics to the abuse liability of an individual drug.

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