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Drug Addiction

Drug Addiction. 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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Drug Addiction

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  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. 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.”

  10. Hyper-dopaminergic mice show fewer “liking” responses to sucrose.

  11. Role of Dopamine • 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.

  12. 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 can’t be removed from synapse after release  more dopamine in synapses (similar to hyper-dopaminergic mice above)

  13. Role of Dopamine • What does Ritalin do?

  14. Role of Dopamine • Is Ritalin addictive?

  15. Role of Dopamine • What does nicotine do?

  16. 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.

  17. Role of Dopamine • What do opiates do?

  18. 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.

  19. 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

  20. 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

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

  22. 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

  23. 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.

  24. 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.)

  25. 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).

  26. 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.

  27. No group differences on Day 1

  28. OVX+E greater sensitization to 20 mg/kg cocaine

  29. OVX+E greater sensitization to 5 mg/kg cocaine

  30. Challenge R to 10 mg/kg cocaine, w/o E (10 da after last doses)

  31. E & Sex Differences Summary • 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.

  32. 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.

  33. 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 women’s greater susceptibility to addiction. • Similar mechanisms underlie compulsive gambling, eating, sex.

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