Reward - Drug Abuse Anatomy Physiology Pathophysiology

Rational Approach to CNS Pharmacotherapy Behaviors - Symptoms  Circuits  Neurotransmitter Systems  Neuropharmacological TARGETS SGO tf

Pharmacologic Principles Underlying Drug Abuse Acute Intoxication [OPI - GABA - NMDA - DA NE - 5HT - ACh - CB] Reinforcing Properties Euphoria [DA / 5HT / OPI /CB] Anxiolysis [GABA] CNS Stimulation [DA / NE / ACh] Altered Perception [5HT] Pharmacodynamics Pharmacokinetics ER Chronic Use Prescribing Controlled Substances Medical Medical / Social Consequences Relapse Craving [DA / NMDA] Tolerance / Dependence Pharmacodynamic & Pharmacokinetic Psychiatry ER Abstinence Withdrawal Rebound Hypersensitivity

1. Brain pathway central to the reinforcing actions of dopaminergic drugs. Substantia nigra  striatum Striatum  globus pallidus Ventral tegmental area  nucleus accumbens Ventral tegmental area  prefrontal cortex Locus ceruleus  prefrontal cortex

for survival and reproduction Brain Reward Pathways Hypothalamus as “Master Effector” for survival and reproduction

1. Brain pathway central to the reinforcing actions of dopaminergic drugs. Substantia nigra  striatum Striatum  globus pallidus Ventral tegmental area  nucleus accumbens Ventral tegmental area  prefrontal cortex Locus ceruleus  prefrontal cortex

Physiologic Role of Reward Pathway Normal function: Mediate pleasure perception (reward) and strengthen behaviors (reinforcement) associated with natural reinforcers Produces motivational states that modulate physiological-behavioral responses ensuring survival and reproduction Complementary pathway to networks for learning about dangerous stimuli (fear)

Amygdala  Fear-Related Information Flow

Physiologic Role of Reward Pathway Reward: Stimulus interpreted as intrinsically positive – something to be approached Drug-induced pleasurable states are strong motivators of initial drug use Reinforcing stimulus: Increases probability that behaviors paired with it will be repeated

Brain Reward Pathways Ventral Tegmental Area [VTA]  Nucleus Accumbens [NA] Major components of reward and reinforcement circuitry Function as interface between limbic emotional-motivational information and extrapyramidal regulation of motor behavior

Brain Reward Pathways Hippocampus Amygdala Memory circuit that mediates associations between biologic stimuli (or drugs) and environmental cues Amygdala Integrative structure that is critical to formation of stimulus-reward associations

Brain Reward Pathways Prefrontal Cortex Critical for executive function in providing control over impulses from destructive behavior - impairment important mediator of loss of control

Rational Approach to CNS Pharmacotherapy Behaviors - Symptoms  Circuits  Neurotransmitter Systems  Neuropharmacological TARGETS

2. Neurotransmitter central to pathologic learning in reward pathway. Acetylcholine Dopamine Endocannabinoids Enkephalins GABA Glutamate Serotonin

Common Pathway - Reward-Reinforcement NTs Natural reinforcers produce sensory cues that activate reward pathway VTA activation releases DA onto NA neurons  pleasure perceived and identifies stimulating activity as one to be repeated Drugs of abuse - acting via multiple NT systems - share final common pathway and also increase DA release in the nucleus accumbens The more intense and more direct this effect on DA release  greater the addiction potential of the drug Dopamine Terminal Natural Reinforcers Dopamine Neuron

Reactive Reward System - VTA  NA [1] Amygdala to VTA functions to signal prospect of pleasure-reward (relevance detection) from natural reinforcers and provides motivational state to achieve it [2] Drug-induced DA release (VTA to NA) is more explosive (pleasurable) than with natural reinforcers The more intense and more direct this effect on DA release  greater the addiction potential of the drug Natural Reinforcers Drugs of Abuse [2] [1] [1] Drugs of Abuse

Reactive Reward System - VTA  NA [3] Repeated drug exposures result in pathologic learning (VTA to amygdala) to trigger drug-seeking behavior when presented with drug cues [4] Amygdala to NA and VTA signals triggering of emotional memories by drug cues that then initiates behavior to seek and take drugs Drug Addiction thus “hijacks” the normal reward circuitry Natural Reinforcers [4] Drugs of Abuse [2] [1] [1] [3] [4] Drugs of Abuse

2. Neurotransmitter central to pathologic learning in reward pathway. Acetylcholine Dopamine Endocannabinoids Enkephalins GABA Glutamate Serotonin

Reflective Reward System - PFC  NA Prefrontal cortex to nucleus accumbens Orbitofrontal  regulating impulses Dorsolateral  analysis of situation Ventromedial  integration with emotions Complementary and competitive component of reactive reward system System built over time with influences from: Genetics Neurodevelopment Experience Peer pressure Learning social rules

Balance between reflective and reactive systems determines output of reward circuitry Natural rewards vs Drug-seeking

Compulsive Drug Use - Addiction Reflective Reward Reactive Reward [1,2] Amygdala learns drug and cues cause pleasure – may signal relief from craving [3] Drug cues lead to DA release in NA  triggers output to thalamus and cortex [4] [4] In absence of activity from reflective reward system  drug-seeking initiated

Drug Addiction Progressive behavioral syndrome  compulsive drug-seeking and drug-taking despite serious consequences Loss of ability to make choices promoting happiness and survival Weakening of executive function  PFC-NA pathways Realization of destructive nature of addiction - unable to alter behavior Strengthening of working memory-habit  striatal-cortical pathways Pathologic effects of drugs mediated in large part via actions – acute and chronic – on the brain Reward Pathway

Proposed Sites of Drug Action in Alcohol Reinforcement Pathways Neurotransmitter Systems

Reward - Drug Abuse Pharmacology

Pharmacologic Principles Underlying Drug Abuse Acute Intoxication [OPI - GABA - NMDA - DA NE - 5HT - ACh - CB] Reinforcing Properties Euphoria [DA / 5HT / OPI /CB] Anxiolysis [GABA] CNS Stimulation [DA / NE / ACh] Altered Perception [5HT] Pharmacodynamics Pharmacokinetics ER Chronic Use Prescribing Controlled Substances Medical Medical / Social Consequences Relapse Craving [DA / NMDA] Tolerance / Dependence Pharmacodynamic & Pharmacokinetic Psychiatry ER Abstinence Withdrawal Rebound Hypersensitivity

Variables Influencing Drug Abuse Pharmacodynamics Reinforcing Properties Drugs that reliably produce intense feelings of pleasure are more likely to be abused All drugs with abuse liability share property of enhancing dopamine activity in nucleus accumbens

Common Pathway - Reward and Reinforcement Natural reinforcers produce sensory cues that activate reward pathway VTA activation releases DA onto NA neurons  pleasure perceived and identifies stimulating activity as one to be repeated Drugs of abuse - acting via multiple NT systems - share final common pathway and also increase DA release in the nucleus accumbens The more intense and more direct this effect on DA release  greater the addiction potential of the drug Dopamine Terminal Natural Reinforcers Dopamine Neuron

3. Which mechanism of drug action is associated with the greatest risk for development of addictive behaviors? Increased release of norepinephrine Increased release of dopamine Activation of mu-opioid receptors Block of NDMA-glutamate receptors Activation of CB-1 receptors Block of dopamine transporter (DAT) Partial agonist at 5-HT2A receptors Block of D2 receptors

Variables: Pharmacodynamics of Drug Abuse [4] [4] [3] [3] [4] [3] [5] [1] Benzodiazepines [4] [2] Relative Risk of Addiction: 1 = nonaddictive, 5 = highly addictive

Initial Pharmacodynamic Actions - Addictive Drugs Relative Risk Drug Molecular Target Mode of Action Effect on DA Neurons of Addiction Stimulants Cocaine DAT (+ SERT-NET) Inhibitor Blocks DA Uptake 5 Methamphetamine DAT (+ SERT-NET, VMAT) Reverses transporter DA releaser 5 Nicotine Nicotinic receptor Agonist Excitation 4 MDMA (Ecstasy) SERT > DAT, NET Reverses transporter (5HT releaser) ?   Opioids  opioid receptor [Gi/o] Agonist Disinhibition 4 CNS Depressants Alcohol GABA-A channel Complex-facilitate Excitation, disinhibition 3 NMDA receptor Complex-antagonize Benzodiazepines GABA-A channel Positive modulator Disinhibition 3 Cannabinoids CB1 receptor [Gi/o] Agonist Disinhibition 2 Marijuana Hallucinogens 5-HT2A receptor [Gq] Partial agonist (- - -) 1 LSD, psilocybin, MDMA Dissociative Anesthetics NMDA receptor Antagonist (- - -) 1 Phencyclidine, Ketamine ___________________________________________________________________________________________________

3. Which mechanism of drug action is associated with the greatest risk for development of addictive behaviors? Increased release of norepinephrine Increased release of dopamine Activation of mu-opioid receptors Block of NDMA-glutamate receptors Activation of CB-1 receptors Block of dopamine transporter (DAT) Partial agonist at 5-HT2A receptors Block of D2 receptors

4. A drug of abuse that blocks the reuptake of dopamine and norepinephrine into presynaptic catecholamine neurons and also blocks sodium channels in neuronal membranes is: Methamphetamine Nicotine MDMA Lysergic acid diethylamide (LSD) Cocaine Mescaline

4. A drug of abuse that blocks the reuptake of dopamine and norepinephrine into presynaptic catecholamine neurons and also blocks sodium channels in neuronal membranes is: Methamphetamine Nicotine MDMA Lysergic acid diethylamide (LSD) Cocaine Mescaline

Dopamine, Pharmacokinetics, and Reinforcing Effects Reinforcing Effects of Drugs Rate at which DA increases in brain Abrupt and large increase in striatal DA mimics phasic DA firing associate with reward and saliency

Variables Influencing Drug Abuse Pharmacokinetics Rate of Onset of Action Abuse liability increased with faster of onset of action Route of Administration – correlated with onset of effect Inhalation – highly addictive Onset of effects within 7 sec User can titrate blood levels precisely Preferred by users of cocaine, nicotine, methamphetamine, cannabis

Variables Influencing Drug Abuse Pharmacokinetics Route of Administration – correlated with onset of effect Intravenous – highly addictive Onset of effects within 15-30 sec (IM-SC within 3-5 min) Large amount of drug enters blood rapidly  most intense rush-like feelings Most dangerous route  exaggerated reactions, infections, overdose toxicities

Variables Influencing Drug Abuse Pharmacokinetics Route of administration – correlated with onset of effect Mucous membrane absorption Most commonly via insufflation – effects within 3-5 minutes More rapid and intense than oral (bypasses liver) Oral Easiest route of administration – onset of effects delayed 20-30 minutes Difficult to obtain rush feelings via this route BUT will prevent withdrawal symptoms – useful route in treatment programs

Rate of Onset of Action Nicotine Cp Resulting from 5 Different Delivery Systems

5. Which route of administration for psychoactive drugs will provide the most rapid onset of effects in the brain? Insufflation (nasal) Inhalation (smoking) Subcutaneous Oral Suppository Intramuscular Intravenous

5. Which route of administration for psychoactive drugs will provide the most rapid onset of effects in the brain? Insufflation (nasal) Inhalation (smoking) Subcutaneous Oral Suppository Intramuscular Intravenous

Variables: Pharmacokinetics of Drug Abuse Termination of Effects Within a class of abused drugs  drugs with shorter half-lives have higher abuse potential Acute considerations Quick offset  frequent administrations  increased likelihood for loss of control Inhalation of cocaine (free base) more addicting than insufflation (flakes)

Termination of Effects Differences in Responses to Heroin and Methadone t1/2 = 30 min t1/2 = 8-59 h

Variables: Pharmacokinetics of Drug Abuse Termination of Effects Chronic considerations Withdrawal effects more severe for drugs with short half-lives Leads to continued drug administration simply to prevent withdrawal Heroin (short t1/2) more addicting than methadone (long t1/2)

Termination of Effects For a drug-dependent individual, the more rapidly the target-receptor becomes unoccupied by drug, the more severe the withdrawal effects

Pharmacologic Principles Underlying Drug Abuse French Acute Intoxication [OPI - GABA - NMDA - DA NE - 5HT - ACh - CB] Reinforcing Properties Euphoria [DA / 5HT / OPI /CB] Anxiolysis [GABA] CNS Stimulation [DA / NE / ACh] Altered Perception [5HT] Pharmacodynamics Pharmacokinetics ER Chronic Use Sakai Prescribing Controlled Substances Medical Medical / Social Consequences Relapse Craving [DA / NMDA] Tolerance / Dependence Pharmacodynamic & Pharmacokinetic Psychiatry ER Abstinence Friday 9-30-16 Withdrawal Rebound Hypersensitivity