Transcript Role of Dopamine

Drug Addiction
History: Opiate Effects
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Characteristics of drug addiction:
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Tolerance: decreased drug effect w/ repeated use
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Dependence: withdrawal syndrome
Initial hypothesis:
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Tolerance = down-regulation of opiate receptors
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Dependence = up-regulation of opiate receptors
Does addiction entail physical
dependence?
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Opiate addiction leads to physical
withdrawal symptoms.
BUT: Cocaine and amphetamine do not.
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All abused drugs increase DA in nucleus
accumbens (Nacc).
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Separate (opioid?) mechanism for physical
dependence
Role of Dopamine
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All abused drugs increase dopamine
release in nucleus accumbens (NAcc),
terminus of mesolimbic dopamine tract.
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Either directly or indirectly (by disinhibition:
inhibiting an inhibitor)
Mesolimbic dopamine system
Role of Dopamine
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Dopamine neurons in flies and worms
regulate responses to food and drugs.
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Abnormalities in humans may 
compulsive gambling, eating, sex,
depression.
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Decreased “liking” (tolerance)
Increased “wanting” (craving)
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Role of Dopamine
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How do you measure “liking” in a rat???
An analysis of facial expressions in the
rat. H. Davis, S. Simmons, 1979
Role of Dopamine
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Hyper-dopaminergic mice (bred to have fewer
dopamine transporters  increased dopamine in
synapse) showed fewer “liking” responses to
sucrose (fig. below).
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However, they ate more food, drank more water,
ran faster for food in a runway, & gained more
weight than wild-type.
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i.e., they showed more “wanting.”
Hyper-dopaminergic mice show
fewer “liking” responses to sucrose.
Role of Dopamine
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It’s not clear why some circuits show
tolerance and others show sensitization.
However, different regions of the NAcc are
important for “liking” (NAcc shell) vs
“wanting” (NAcc core).
Therefore, tolerance may occur in the shell
region, and craving may result from changes
in the core.
 Also, different types of receptors may be
important.
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How do drugs affect dopamine?
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Amphetamine makes dopamine vesicles in axon
terminals “leaky” & reverses the transporters 
flood of dopamine in synapses.
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Cocaine blocks the transporters  dopamine
can’t be removed from synapse after release 
more dopamine in synapses (similar to hyperdopaminergic mice above)
Role of Dopamine
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What does Ritalin do?
Role of Dopamine
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Is Ritalin addictive?
Role of Dopamine
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What does nicotine do?
Role of Dopamine
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Nicotinic receptors on dopamine terminals
in NAcc increase dopamine release.
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Nicotinic receptors on dopamine cell
bodies in ventral tegmental area (VTA) of
midbrain increase firing.
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Therefore, nicotine increases dopamine
activity in NAcc in 2 ways.
Role of Dopamine
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What do opiates do?
Role of Dopamine
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Inhibit inhibitory GABA neurons in VTA 
disinhibits dopamine neurons  increases
dopamine in Nacc.
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Benzodiazepine anti-anxiety drugs also
inhibit VTA GABA neurons and increase
dopamine in NAcc.
More permanent effects
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Cocaine  increased dendritic spine
density on NAcc neurons & increased cell
body size in VTA.
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Therefore, temporary biochemical
changes can  permanent morphology
changes
Role of Environment
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Home cage vs. novel cage administration
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Sensitization = increased motor activity in
response to previously ineffective dose
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Often used as measure of “wanting” or craving.
Intravenous catheter: no cues to onset of drug
 Low doses  sensitization only in novel cage
 High doses  sensitization in both cages
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Role of Environment
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Therefore, stress response to novel
environment may contribute to addiction.
Effects of Stress
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Cocaine can  anxiety via corticotropin
releasing hormone (CRH) release.
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(CRH activates ACTH from anterior pituitary; also
is used as a transmitter in the brain  stress)
May seem odd that CRH could mediate the
reward, as well as anxiety.
 But, self-administration is a CONTROLLABLE
stressor, which often has better effects than
no stress at all.
 Analogous to thrill-seeking
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15.17 Autonomic Activation during a Stress Situation (Part 1)
Effects of Stress
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Uncontrollable shock  increased
sensitivity to low doses of cocaine
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Inverted U curve for cocaine: low doses 
reinforcing; high doses  anxiety
All self-administered doses increased
corticosterone above a certain level.
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Further increase above that level  no further
effect.
Effects of Stress
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Inject corticosterone (no shock): mimicked
effects of uncontrollable stress 
increased self-administration of low doses
of cocaine.
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Adrenalectomy abolished acquisition of
self-administration of cocaine, but not of
food. (Therefore, they could still learn the
response.)
Effects of Stress
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Humans: ketoconazole, a glucocorticoid
(GC) synthesis antagonist, decreased
anxiety, depression, and craving.
3 of 5 continued to use cocaine and still
got high; 2 remained drug-free
Therefore, GCs do not affect “liking” of
drug, but do decrease “wanting” (craving).
Estrogen & Sex Differences
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Estrogen (E) rapidly increases DA release
in NAcc
Test ovariectomized (OVX) females, OVX
+ E, CAST males, intact males
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Unilateral lesion of dopamine neurons 
circling in response to increased dopamine
E or oil 30’ before cocaine for 4 da
Nothing for 3 da; continue pattern for 3 wks.
 Test for circling.
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No group differences on Day 1
OVX+E greater sensitization to
20 mg/kg cocaine
OVX+E greater sensitization to
5 mg/kg cocaine
Challenge R to 10 mg/kg cocaine,
w/o E (10 da after last doses)
E & Sex Differences Summary
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No group difference on first day
OVX+E sensitized more to each dose of
cocaine.
Even 10 da later, after no more E or
cocaine, OVX females previously treated
with E+cocaine showed greater remaining
sensitization to cocaine.
May explain why women are more easily
addicted to various substances.
Summary and Common Threads
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2 main elements of drug addiction:
tolerance to the rewarding effects (“liking”)
& sensitization to motivational effects
(“wanting”).
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Tolerance may result from down-regulation of
synapses in NAcc shell
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Cells that are over-stimulated try to normalize their
activity.
Craving may result from sensitization of
synapses in NAcc core.
Summary and Common Threads
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“Stress” hormones and novel
environmental cues contribute to craving.
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Stress or exposure to drug-related cues can
 relapse in people that had been “on the
wagon” (abstinent) for a long time.
Estrogen contributes to women’s greater
susceptibility to addiction.
Similar mechanisms underlie compulsive
gambling, eating, sex.