Title: Drug Addiction
1Drug Addiction
2History Opiate Effects
- Characteristics of drug addiction
- Tolerance decreased drug effect w/ repeated use
- Dependence withdrawal syndrome
- Initial hypothesis
- Tolerance down-regulation of opiate receptors
- Dependence up-regulation of opiate receptors
3Does addiction entail physical dependence?
- Opiate addiction leads to physical withdrawal
symptoms. - BUT Cocaine and amphetamine do not.
- All abused drugs increase DA in nucleus accumbens
(Nacc). - Separate (opioid?) mechanism for physical
dependence
4Role of Dopamine
- All abused drugs increase dopamine release in
nucleus accumbens (NAcc), terminus of mesolimbic
dopamine tract. - Either directly or indirectly (by disinhibition
inhibiting an inhibitor)
5Mesolimbic dopamine system
6Role of Dopamine
- Dopamine neurons in flies and worms regulate
responses to food and drugs. - Abnormalities in humans may ? compulsive
gambling, eating, sex, depression. - Decreased liking (tolerance)
- Increased wanting (craving)
7Role of Dopamine
- How do you measure liking in a rat???
8An analysis of facial expressions in the rat. H.
Davis, S. Simmons, 1979
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10Role of Dopamine
- Hyper-dopaminergic mice (bred to have fewer
dopamine transporters ? increased dopamine in
synapse) showed fewer liking responses to
sucrose (fig. below). - However, they ate more food, drank more water,
ran faster for food in a runway, gained more
weight than wild-type. - i.e., they showed more wanting.
11Hyper-dopaminergic mice show fewer liking
responses to sucrose.
12Role of Dopamine
- Its 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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14How do drugs affect dopamine?
- Amphetamine makes dopamine vesicles in axon
terminals leaky reverses the transporters ?
flood of dopamine in synapses. - Cocaine blocks the transporters ? dopamine cant
be removed from synapse after release ? more
dopamine in synapses (similar to
hyper-dopaminergic mice above)
15Role of Dopamine
16Role of Dopamine
17Role of Dopamine
18Role of Dopamine
- Nicotinic receptors on dopamine terminals in NAcc
increase dopamine release. - Nicotinic receptors on dopamine cell bodies in
ventral tegmental area (VTA) of midbrain increase
firing. -
- Therefore, nicotine increases dopamine activity
in NAcc in 2 ways.
19Role of Dopamine
20Role of Dopamine
- Inhibit inhibitory GABA neurons in VTA ?
disinhibits dopamine neurons ? increases dopamine
in Nacc. - Benzodiazepine anti-anxiety drugs also inhibit
VTA GABA neurons and increase dopamine in NAcc.
21More permanent effects
- Cocaine ? increased dendritic spine density on
NAcc neurons increased cell body size in VTA. - Therefore, temporary biochemical changes can ?
permanent morphology changes
22Role of Environment
- Home cage vs. novel cage administration
- Sensitization increased motor activity in
response to previously ineffective dose - 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
23Role of Environment
- Therefore, stress response to novel environment
may contribute to addiction.
24Effects of Stress
- Cocaine can ? anxiety via corticotropin releasing
hormone (CRH) release. - (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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26Effects of Stress
- Uncontrollable shock ? increased sensitivity to
low doses of cocaine - Inverted U curve for cocaine low doses ?
reinforcing high doses ? anxiety - All self-administered doses increased
corticosterone above a certain level. - Further increase above that level ? no further
effect.
27Effects of Stress
- Inject corticosterone (no shock) mimicked
effects of uncontrollable stress ? increased
self-administration of low doses of cocaine. - Adrenalectomy abolished acquisition of
self-administration of cocaine, but not of food.
(Therefore, they could still learn the response.)
28Effects of Stress
- 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, GC antagonists do not affect liking
of drug, but do decrease wanting (craving).
29Estrogen Sex Differences
- Estrogen (E) rapidly increases DA release in NAcc
- Test ovariectomized (OVX) females, OVX E, CAST
males, intact males - 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.
30No group differences on Day 1
31OVXE? greater sensitization to 20 mg/kg cocaine
32OVXE? greater sensitization to 5 mg/kg cocaine
33Challenge R to 10 mg/kg cocaine, w/o E (10 da
after last doses)
34E Sex Differences Summary
- No group difference on first day
- OVXE sensitized more to each dose of cocaine.
- Even 10 da later, after no more E or cocaine, OVX
females previously treated with Ecocaine showed
greater remaining sensitization to cocaine. - May explain why women are more easily addicted to
various substances.
35Summary and Common Threads
- 2 main elements of drug addiction tolerance to
the rewarding effects (liking) sensitization
to motivational effects (wanting). - Tolerance may result from down-regulation of
synapses in NAcc shell - Cells that are over-stimulated try to normalize
their activity. - Craving may result from sensitization of synapses
in NAcc core.
36Summary and Common Threads
- Stress hormones and novel environmental cues
contribute to craving. - 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 womens greater
susceptibility to addiction. - Similar mechanisms underlie compulsive gambling,
eating, sex.