1. Drug Addiction

2. History: Opiate Effects Characteristics of drug addiction: Characteristics of drug addiction: Tolerance: decreased drug effect w/ repeated use Tolerance: decreased drug effect w/ repeated use Dependence: withdrawal syndrome Dependence: withdrawal syndrome Initial hypothesis: Initial hypothesis: Tolerance = down-regulation of opiate receptors Tolerance = down-regulation of opiate receptors Dependence = up-regulation of opiate receptors Dependence = up-regulation of opiate receptors

3. Does addiction entail physical dependence? Opiate addiction leads to physical withdrawal symptoms. Opiate addiction leads to physical withdrawal symptoms. BUT: Cocaine and amphetamine do not. BUT: Cocaine and amphetamine do not. All abused drugs increase DA in nucleus accumbens (Nacc). All abused drugs increase DA in nucleus accumbens (Nacc). Separate (opioid?) mechanism for physical dependence 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. All abused drugs increase dopamine release in nucleus accumbens (NAcc), terminus of mesolimbic dopamine tract. Either directly or indirectly (by disinhibition: inhibiting an inhibitor) 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. Dopamine neurons in flies and worms regulate responses to food and drugs. Abnormalities in humans may  compulsive gambling, eating, sex, depression. Abnormalities in humans may  compulsive gambling, eating, sex, depression. Decreased “liking” (tolerance) Decreased “liking” (tolerance) Increased “wanting” (craving) Increased “wanting” (craving)

7. Role of Dopamine How do you measure “liking” in a rat??? How do you measure “liking” in a rat???

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

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). 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. 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.” i.e., they showed more “wanting.”

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

12. 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). 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. 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. Also, different types of receptors may be important.

14. How do drugs affect dopamine? Amphetamine makes dopamine vesicles in axon terminals “leaky” & reverses the transporters  flood of dopamine in synapses. 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) Cocaine blocks the transporters  dopamine can’t be removed from synapse after release  more dopamine in synapses (similar to hyper- dopaminergic mice above)

15. Role of Dopamine What does Ritalin do? What does Ritalin do?

16. Role of Dopamine Is Ritalin addictive? Is Ritalin addictive?

17. Role of Dopamine What does nicotine do? What does nicotine do?

18. Role of Dopamine Nicotinic receptors on dopamine terminals in NAcc increase dopamine release. 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. 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. Therefore, nicotine increases dopamine activity in NAcc in 2 ways.

19. Role of Dopamine What do opiates do? What do opiates do?

20. Role of Dopamine Inhibit inhibitory GABA neurons in VTA  disinhibits dopamine neurons  increases dopamine in Nacc. 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. 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. Cocaine  increased dendritic spine density on NAcc neurons & increased cell body size in VTA. Therefore, temporary biochemical changes can  permanent morphology changes Therefore, temporary biochemical changes can  permanent morphology changes

22. Role of Environment Home cage vs. novel cage administration Home cage vs. novel cage administration Sensitization = increased motor activity in response to previously ineffective dose Sensitization = increased motor activity in response to previously ineffective dose Often used as measure of “wanting” or craving. Often used as measure of “wanting” or craving. Intravenous catheter: no cues to onset of drug Intravenous catheter: no cues to onset of drug Low doses  sensitization only in novel cage Low doses  sensitization only in novel cage High doses  sensitization in both cages High doses  sensitization in both cages

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

24. Effects of Stress Cocaine can  anxiety via corticotropin releasing hormone (CRH) release. 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) (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. 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. But, self-administration is a CONTROLLABLE stressor, which often has better effects than no stress at all. Analogous to thrill-seeking Analogous to thrill-seeking

26. Effects of Stress Uncontrollable shock  increased sensitivity to low doses of cocaine Uncontrollable shock  increased sensitivity to low doses of cocaine Inverted U curve for cocaine: low doses  reinforcing; high doses  anxiety Inverted U curve for cocaine: low doses  reinforcing; high doses  anxiety All self-administered doses increased corticosterone above a certain level. All self-administered doses increased corticosterone above a certain level. Further increase above that level  no further effect. 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. 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.) 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. 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 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). Therefore, GCs do not affect “liking” of drug, but do decrease “wanting” (craving).

29. Estrogen & Sex Differences Estrogen (E) rapidly increases DA release in NAcc Estrogen (E) rapidly increases DA release in NAcc Test ovariectomized (OVX) females, OVX + E, CAST males, intact males Test ovariectomized (OVX) females, OVX + E, CAST males, intact males Unilateral lesion of dopamine neurons  circling in response to increased dopamine Unilateral lesion of dopamine neurons  circling in response to increased dopamine E or oil 30’ before cocaine for 4 da E or oil 30’ before cocaine for 4 da Nothing for 3 da; continue pattern for 3 wks. Nothing for 3 da; continue pattern for 3 wks. Test for circling. Test for circling.

30. No group differences on Day 1

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

32. OVX+E  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 No group difference on first day OVX+E sensitized more to each dose of cocaine. 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. 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. 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”). 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 Tolerance may result from down-regulation of synapses in NAcc shell Cells that are over-stimulated try to normalize their activity. Cells that are over-stimulated try to normalize their activity. Craving may result from sensitization of synapses in NAcc core. 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” 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. 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. Estrogen contributes to women’s greater susceptibility to addiction. Similar mechanisms underlie compulsive gambling, eating, sex. Similar mechanisms underlie compulsive gambling, eating, sex.