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Drug Addiction

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Title: Drug Addiction


1
Drug Addiction
2
History 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

3
Does 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

4
Role 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)

5
Mesolimbic dopamine system
6
Role 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)

7
Role of Dopamine
  • How do you measure liking in a rat???

8
An analysis of facial expressions in the rat. H.
Davis, S. Simmons, 1979
9
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10
Role 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.

11
Hyper-dopaminergic mice show fewer liking
responses to sucrose.
12
Role 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.

13
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14
How 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)

15
Role of Dopamine
  • What does Ritalin do?

16
Role of Dopamine
  • Is Ritalin addictive?

17
Role of Dopamine
  • What does nicotine do?

18
Role 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.

19
Role of Dopamine
  • What do opiates do?

20
Role 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.

21
More permanent effects
  • Cocaine ? increased dendritic spine density on
    NAcc neurons increased cell body size in VTA.
  • Therefore, temporary biochemical changes can ?
    permanent morphology changes

22
Role 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

23
Role of Environment
  • Therefore, stress response to novel environment
    may contribute to addiction.

24
Effects 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

25
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26
Effects 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.

27
Effects 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.)

28
Effects 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).

29
Estrogen 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.

30
No group differences on Day 1
31
OVXE? greater sensitization to 20 mg/kg cocaine
32
OVXE? greater sensitization to 5 mg/kg cocaine
33
Challenge R to 10 mg/kg cocaine, w/o E (10 da
after last doses)
34
E 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.

35
Summary 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.

36
Summary 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.
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