Transcript DrugLecture2001

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:
Distinctive
Room
Colony
Room
Group 1
Alcohol
(tolerance devel.)
Saline
Group 2
Saline
Alcohol
(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
Room
No Tolerance
Tolerance
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
Left side
Right 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*
VTA
NA
DA release
Spiroperidol in NA
blockes dopamine
action on NA neurons
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
• Amphetamine
Blocks dopamine reuptake transport system
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. selfinto nucleus accumbens of rats
administration
• 6-OHDA lesions of the nucleus
attenuate i.v. selfaccumbens 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
Nicotine stimulates
ACh receptors
VTA
NA
DA release
Evidence for nicotine action on
VTA neurons
• Nicotine agonist into
rat VTA
• Nicotine antagonist into
rat VTA
• Nicotine antagonist into
rat VTA*
conditioned place
preference
reduces rewarding
effect of i.v. nicotine
blocks NA DA
release from i.v.
nicotine
CANNABIS
TETRAHYDROCANNABINOL
(THC)
• Inject rats with THC
systemically*
• Inject THC into NA
• Mechanism:
VTA
NA
NA DA release
DA release
NA neuron
DA
NA
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:
GABA neuron
GABA inhibits VTA
Neurons
G
Heroin, enkephalin
inhibit GABA neuron
VTA
NA