CRF in VTA: Escalation of Alcohol and Cocaine Intake After Social Stress

1. CRF in VTA: Escalation of Alcohol and Cocaine Intake After Social Stress Klaus A. Miczek, Lara S. Hwa, Emily Newman, Michael Leonard, Herbert Covington III, and Joseph F. DeBold Chemistry and Pharmacology of Drug Abuse (CPDA) Conference Northeastern University Boston, MA August 2017

2. 86% of homicide offenders, 37% of assault offenders, 60% of sexual offenders, up to 57% of men and 27% of women involved in marital violence, and 13% of child abusers were drinking at the time of the offense. National Institute on Alcohol Abuse and Alcoholism, 1997 • Ca. 40% of violent crimes involve alcohol, according to the crime victim. Ca. 40% of criminal offenders report that they were using alcohol at the time of their offense. Bureau of Justice Statistics, US Department of Justice, 1998 • Among spousal abuse victims, 75% of the incidents were reported to have involved an offender who had been drinking. Bureau of Justice Statistics, US Department of Justice, 2006 • Almost one in four victims of violent crime report that the perpetrator had been drinking prior to committing the violence. Approximately 3 million crimes occur every year in which the offenders are perceived to have been under the influence of alcohol. Greenfeld, L. (1998) Alcohol and Crime: An analysis of national data on the prevalence of alcohol involvement in crime

3. Stress and Cocaine Use • Initiate drug use earlier • Transition more rapidly to high dose/binge patterns of drug use • Experience stronger cocaine cravings during stress imagery

4. Submissive supine posture and USV in response to aggressive posture

5. Social Stress, Cocaine, and Alcohol Male L-E Rats,4 defeats/10d(Boyson et al. 2014)

6. Social Stress, Cocaine, and Alcohol Male L-E Rats,4 defeats/10d(Boyson et al. 2014) Adolescent M rats, 4 defeats/10d(Burke & Miczek 2015)

7. Social Stress, Cocaine, and Alcohol Male L-E Rats,4 defeats/10d(Boyson et al. 2014) Adolescent M rats, 4 defeats/10d(Burke & Miczek 2015) Female rats, 4 defeats/10d(Holly et al. 2012)

8. Social Stress, Cocaine, and Alcohol Male L-E Rats,4 defeats/10d(Boyson et al. 2014) Adolescent M rats, 4 defeats/10d(Burke & Miczek 2015) Female rats, 21 d chronic stress(Shimamoto et al. 2015) Female rats, 4 defeats/10d(Holly et al. 2012)

9. Social defeat posture by intruder mouse: retracted ears, limp forelimbs, failure to orient to attacking resident Miczek, Thompson & Shuster 1982

10. Social Stress, Cocaine, and Alcohol Male L-E Rats,4 defeats/10d(Boyson et al. 2014) Adolescent M rats, 4 defeats/10d(Burke & Miczek 2015) Male B6 mice, 10 daily defeats(Han et al. 2015) Female rats, 21 d chronic stress(Shimamoto et al. 2015) Female rats, 4 defeats/10d(Holly et al. 2012)

11. Social Stress, Cocaine, and Alcohol Male L-E Rats,4 defeats/10d(Boyson et al. 2014) Adolescent M rats, 4 defeats/10d(Burke & Miczek 2015) Male L-E Rats,4 defeats/10d(Holly et al. 2016) Male B6 mice, 10 daily defeats(Han et al. 2015) Female rats, 21 d chronic stress(Shimamoto et al. 2015) Female rats, 4 defeats/10d(Holly et al. 2012)

12. Social Stress, Cocaine, and Alcohol Male L-E Rats,4 defeats/10d(Boyson et al. 2014) Adolescent M rats, 4 defeats/10d(Burke & Miczek 2015) Male CFW mice, 10 daily defeats(Norman et al. 2015) Male B6 mice, 10 daily defeats(Han et al. 2015) Male L-E Rats, 4 defeats/10d(Holly et al. 2016) Female rats, 21 d chronic stress(Shimamoto et al. 2015) Female rats, 4 defeats/10d(Holly et al. 2012)

13. Social Stress, Cocaine, and Alcohol Male L-E Rats,4 defeats/10d(Boyson et al. 2014) Adolescent M rats, 4 defeats/10d(Burke & Miczek 2015) Male CFW mice, 10 daily defeats(Norman et al. 2015) Male B6 mice, 10 daily defeats(Hwa et al. 2015) Male B6 mice, 10 daily defeats(Han et al. 2015) Male L-E Rats, 4 defeats/10d(Holly et al. 2016) Female rats, 21 d chronic stress(Shimamoto et al. 2015) Female rats, 4 defeats/10d(Holly et al. 2012)

14. Social Stress, Cocaine, and Alcohol Male L-E Rats,4 defeats/10d(Boyson et al. 2014) Adolescent M rats, 4 defeats/10d(Burke & Miczek 2015) Male CFW mice, 10 daily defeats(Norman et al. 2015) Male B6 mice, 10 daily defeats(Han et al. 2015) Male L-E Rats, 4 defeats/10d(Holly et al. 2016) Male B6 mice, 10 daily defeats(Hwa et al. 2015) Female rats, 21 d chronic stress(Shimamoto et al. 2015) Female rats, 4 defeats/10d(Holly et al. 2012)

15. Social Stress: Rise in Corticolimbic Dopamine Tidey and Miczek 1996

17. Intermittent Stress: Accumbal DA response to cocaine challenge in females is long-lasting, regardless of estrous cycle Holly et al. 2012 ** p<0.01, *** p<0.001 vs baseline ## p<0.01, ### p<0.001 vs non-stressed

18. Instigation Threat Fight Defeat Dopamine Transients (“Bursts”) In N. Accumbens while being Threatened Anstrom et al. 2009

19. Mesocorticolimbic dopamine during repeated stress Increased Dopamine in mPFC and NAcSh persists with repeated stress

20. ventromedial vs. ventrolateral Ikemoto 2007

21. A closer look at stress, dopamine, and the VTA more careful approach to characterizing dopamine neurons closer examination of VTA along dorsal-ventral axis (Brischoux et al 2009)

23. Interim Summary Intermittent Episodes of Social Stress • Induce Escalated Dopamine in NAC and mPFC • Concurrent with Escalated Alcohol and Cocaine “Binge” • Stress-induced DA is persistent • In Males and Females • In Adults and Adolescents • In Rats and Mice

24. PVN CRF → HPA axis → glucocorticoid response to stress VTA CRF → NAccSh, mPFC → (1) anticipatory excitement (2) Neuroadaptation to social stress CRF Cleck and Blendy 2008

25. CRF actions in reward-associated neurocircuitry Increases in CRF levels during withdrawal (Olive et al. 2002; Merlo-Pich et al. 1995) Red: DA Blue: Glutamate Yellow: GABA CRF antagonist in CeA decreases ethanol-withdrawal anxiety (Rassnick et al. 1993) CRFR1 antagonism in VTA during stress reduces later drug self-administration (Boyson et al. 2011) Lüthi & Lüscher 2014

26. Corticotropin Releasing Factor Bale and Vale 2004

27. Corticotropin Releasing Factor (CRF) governs stress response Van Pett et al. 2000

28. Eugène Grasset La Morphinomane 1897

29. CRF-R1 antagonist protects against social stress-induced escalated cocaine intake in male CFW mice Han et al. 2017

30. VTA cellular heterogeneity along anterior to posterior axis Chieng et al. 2011

31. CRF-R1 antagonist protects against social stress-induced escalated cocaine intake in a 24 h binge, when injected into Ventral Tegmental Area prior to each stress episode. Boyson et al. 2014

32. Intra-VTA CRF-R2 antagonist is also effective in protecting against social stress-induced escalated cocaine intake Boyson et al. 2014

33. Role of VTA CRF-Rs after stress on context-induced reinstatement Intra-VTA CRFR1 and CRFR2 antagonism prevents reinstatement

34. Intra-VTA CRF-R1 and R2 antagonists are effective in attenuating stress-induced escalated DA increase in NAC shell

35. Mesocorticolimbic CRF modulation of DA during repeatedstress? CRF actions on CRFR2, but not CRFR1, mediate DA increases in the mPFC

36. Behavioral Economics Analysis of Stress-Escalated Cocaine Self-Administration

37. Behavioral Economics Analysis of Stress-Escalated Cocaine Self-Administration

39. Distribution of DA neuron cell groups in the rat brain Cortex A16 Striatum A11 A13 A9 A15 A10 A8 A14 A12 A. Björklund & S.B. Dunnett TRENDS in Neurosciences, 2007

40. Distribution of DA neuron cell groups in the rat brain Cortex A16 Striatum A11 A13 A9 A15 A10 A8 A14 A12 mPFC NAcc DRN SN VTA AnteriorPosteriorCRF-modulated a p PVN

41. Conclusions CRF modulation of DA in the VTA plays a fundamental role in the link between stress and escalated psychostimulant and alcohol use CRF is released into the VTA during stress, and tonic CRF is increased with repeated stress, modulating DA CRF actions in the VTA during stress, abstinence, and reinstatement contribute to escalated alcohol and cocaine taking and seeking.