Drug Tolerance Cross Tolerance Metabolic Tolerance A shift in the dose-response curve to the right Cross Tolerance Exposure to one drug can produce tolerance to other similar acting drugs Metabolic Tolerance Reduction in amount of drug which reaches site of action Functional Tolerance Reduction in the reactivity of sites of drug action

Withdrawal Syndrome Sudden drug elimination Effects are opposite to initial drug effects Presence indicates physical dependence Relationship between drug tolerance and drug withdrawal effects

Withdrawal and Tolerance Long Term Drug Use Adaptive (compensatory) neural changes to counteract drug effects Tolerance Drug Withdrawal Unchecked adaptive neural changes opposite to drug effects = Withdrawal Symptoms

Conditioned (Learned) Tolerance Crowell, Hinson and Siegel, 1981 Alcohol Hypothermia Tolerance to alcohol-induced hypothermia Tolerance is learned

Crowell, Hinson and Siegel, 1981 2 groups of rats: - 20 injections of alcohol - 20 injections of saline (NaCl) Drug Exposure: Group 1 Group 2 Distinctive Alcohol Saline Room (tolerance devel.) Colony Saline Alcohol Room (tolerance devel.)

Crowell, Hinson and Siegel, 1981 Results Test for tolerance of hypothermia - one injection of alcohol in both rooms Group 1 Group 2 Distinctive Tolerance No Tolerance Room (no hypotherm.) (hypotherm.) Colony No Tolerance Tolerance Room hypotherm.) (no hypotherm.)

Seigel’s Theory After REPEATED pairings of the ROOM with ALCOHOL, the animals learn that the ROOM CUES predict the occurrence of the ALCOHOL effects and the ROOM CUES come to elicit a conditioned (learned)response (hyperthermic) that is opposite to the ALCOHOL hypothermic effects. This is conditioned (learned) tolerance.

Pavlovian Conditioning Conditioned Stimulus (CS): a NEUTRAL stimulus that predicts the occurrence of an Unconditioned Stimulus (US) - CS = ROOM CUES Unconditioned Stimulus (US): - US = the primary effects of the drug stimulus (e.g., HYPOthermia) Unconditioned Response (UR): - UR = the adaptive response to the drug, opposite to the drug effect (HYPERthermia) Conditioned Response (CR): - CR = the response elicited by the CS after repeated pairings of the CS with the US (e.g., HYPERthermia)

Situational Specificity of Tolerance Implications for drug-related deaths

Heroin in a Familiar Environment Tolerance Develops Increased dosing to achieve effect Increased dose in NEW Environment No learned tolerance exists Lethal consequences

Siegel et al., 1982 three groups of rats - Groups 1 and 2 made tolerant to heroin with repeated injections of increasing amounts - Group 3 (NAÏVE) received no heroin injections Tested effects of a HIGH dose of heroin on death rate Group 1: high dose in familiar environment Group 2: high dose in a new environment Group 3: high dose in familiar environment

Siegel et al., 1982-continued Results Group 1 (Familiar environment) - 32% died Group 2 (New Environment) - 64% died Group 3 (Naïve, Familiar environment) - 96% died An example of learned tolerance. Each incidence of drug administration is a Pavlovian conditioning trial. May account for drug-related deaths attributed to overdose.

Biopsychological Theories of Addiction Physical-Dependence Theory Positive-Incentive Theory

Physical Dependence Theory Drug addicts take drugs to alleviate withdrawal symptoms Problems: Detoxified addicts return to drug-taking habits Some highly addicting drugs (e.g., cocaine) have minimal withdrawal symptoms

Positive-Incentive Theory The craving for the positive-incentive (i.e., pleasure-producing) properties of the drug is the primary factor in addiction. The anticipated pleasure of drug-taking is the basis of addiction, not so much the pleasurable effects of the drug per se.

Major Questions Is addiction to a drug due to its pleasurable or rewarding properties? What is the brain mechanism(s) by which the drug exerts its pleasurable or rewarding effects

Intracranial Self-Stimulation (ICSS) Olds and Milner (1954)* Animals work at high rates to obtain ICSS ICSS enhances the rewarding properties of food, water, sex Animals prefer ICSS over food, water, sex Areas of the brain that best support ICSS are those of the natural reward circuits

The Mesotelencephalic Dopamine System* The substantia nigra - the nigrostriatal pathway The ventral tegmental area (VTA) - mesocorticolimbic pathway

What is the evidence for dopamine involvement in ICSS? Dopamine receptor antagonists and ICSS -Pimozide reduces ICSS* Destruction of dopamine VTA neurons reduces ICSS*

Fibiger et al., 1987- The VTA, ICSS and Dopamine Right side Left side Forebrain Forebrain Dopamine axons Inject 6-OHDA into left VTA VTA VTA Bilateral stimulation electrodes

Where in the brain does the release of dopamine from VTA neurons contribute to rewarding ICSS? The Nucleus Accumbens (NA)*

The Nucleus Accumbens, Dopamine and ICSS Spiroperidol = dopamine receptor antagonist Inject Spiroperidol into markedly reduce nucleus accumbens VTA ICSS ICSS increases dopamine release in nucleus accumbens* NA VTA Spiroperidol in NA blockes dopamine action on NA neurons DA release

Do Natural Rewards (e.g., food, sex) increase Dopamine Release in the Nucleus Accumbens?

The Nucleus Accumbens, Dopamine and Natural Rewards* Rat lever presses for food or engages in reproductive behavior increase in dopamine release in nucleus accumbens

Neural Mechanisms of Addiction: Behavioral Paradigms* Drug Self-administration Paradigm Conditioned place preference

Cocaine and Amphetamine What are the brain mechanisms by which they exert their addictive effects? Cocaine Blocks dopamine reuptake transport system Amphetamine Stimulates the release of dopamine Blocks dopamine reuptake

Do Cocaine and Amphetamine affect the nucleus accumbens?

Cocaine, Amphetamine and the Nucleus Accumbens I.V. Self administration of DA release cocaine or amphetamine in nucleus accumbens in rats* Rats self-administer cocaine or amphetamine into the nucleus accumbens DA receptor antagonists injected attenuate i.v. self- into nucleus accumbens of rats administration 6-OHDA lesions of the nucleus attenuate i.v. self- accumbens of rats* administration

Do other addictive drugs affect the nucleus accumbens? Nicotine? Cannabis? Opiates?

Nicotine Rats self-administer nicotine i.v. Systemic nicotine DA release in injections in rats* nucleus accumbens Mechanism: ACh receptors NA VTA Nicotine stimulates ACh receptors DA release

Evidence for nicotine action on VTA neurons Nicotine agonist into conditioned place rat VTA preference Nicotine antagonist into reduces rewarding rat VTA effect of i.v. nicotine Nicotine antagonist into blocks NA DA rat VTA* release from i.v. nicotine

CANNABIS TETRAHYDROCANNABINOL (THC) Inject rats with THC NA DA release systemically* Inject THC into NA DA release Mechanism: NA neuron NA VTA NA DA THC affects receptors on DA boutons

OPIATES Heroin – - the sap of opium poppy seeds - active ingredients = morphine, codeine Endogenous opiates - Endorphins enkephalins - brain opiate receptors

Opiates and the VTA-NA Circuit I.V. self-administration 300% DA increase of heroin in rats in NA Rats self administer heroin or enkephalin into VTA Mechanism for VTA effect: Heroin, enkephalin inhibit GABA neuron GABA neuron GABA inhibits VTA Neurons G VTA NA