drug tolerance
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
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