1. 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

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

3. 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

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

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

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

7. 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.

8. 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)

9. Situational Specificity of Tolerance
Implications for drug-related deaths

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

11. 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

12. 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.

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

14. 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

15. 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.

16. 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

17. 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

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

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

20. 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

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

22. 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

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

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

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

26. 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

27. Do Cocaine and Amphetamine affect the nucleus accumbens?

28. 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

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

30. 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

31. 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

32. 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

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

34. Opiates and the VTA-NA Circuit
I.V. self-administration % 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