Drug Addiction

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Drug Addiction
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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

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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

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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)

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Mesolimbic dopamine system
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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)

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Role of Dopamine

• How do you measure liking in a rat???

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An analysis of facial expressions in the rat. H.
Davis, S. Simmons, 1979
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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.

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Hyper-dopaminergic mice show fewer liking
responses to sucrose.
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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.

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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)

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Role of Dopamine

• What does Ritalin do?

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Role of Dopamine

• Is Ritalin addictive?

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Role of Dopamine

• What does nicotine do?

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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.

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Role of Dopamine

• What do opiates do?

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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.

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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

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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

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Role of Environment

• Therefore, stress response to novel environment
  may contribute to addiction.

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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

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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.

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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.)

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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, GCs do not affect liking of drug,
  but do decrease wanting (craving).

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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.

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

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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.

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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.