Drug 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 2Distinctive Alcohol Saline Room (tolerance devel.)

Colony Saline Alcohol Room (tolerance devel.)

Crowell, Hinson and Siegel, 1981Results

• 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 theROOM 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 isconditioned (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

ResultsGroup 1 (Familiar environment) - 32% diedGroup 2 (New Environment) - 64% diedGroup 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

VTA VTA

Bilateral stimulation electrodes

Inject 6-OHDAinto left VTA

Left side Right side

Dopamine axons

Forebrain Forebrain

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*

VTA NA Spiroperidol in NAblockes dopamineaction 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:

VTA NA

ACh receptors

Nicotine stimulatesACh 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

CANNABISTETRAHYDROCANNABINOL

(THC)

• Inject rats with THC NA DA release

systemically*

• Inject THC into NA DA release

• Mechanism:

VTA NA NA

THC affects receptors on DA boutons

DA

NA neuron

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 neuronVTA NA

G

GABA neuron GABA inhibits VTA Neurons