STRESS AND RELAPSE TO SUBSTANCE USE

1. STRESS AND RELAPSE TO SUBSTANCE USE Kathleen T. Brady, M.D., Ph.D. Director, Clinical Neuroscience Division Medical University South Carolina

2. Disclosures • Grant support or consultant: • Abbott Pharmaceuticals • Lilly Pharmaceuticals • Pfizer Pharmaceuticals • Cephalon Pharmaceuticals • Bristol-Myers Squibb Pharmaceuticals • Shire Pharmaceuticals

3. Acknowledgements • NIDA, NIAAA • MUSC colleagues: Aimee McRae, Susan Sonne, Sudie Back, Himanshu Upadhyaya, Carrie Randall, Hugh Myrick, Bob Malcolm, Ray Anton, Therese Killeen, Peter Kalivas, Ron See, Bruce Lydiard, etc.

4. OVERVIEW • Stress - definitions and neurobiology • Substance use disorders - theoretical models • Animal models of substance use disorders • Neurobiology of substance use disorders • Overlapping neurobiology - substance use/stress • Human Studies - stress/relapse • Treatment Implications • Conclusions

5. Definition Stress • Stress: a process involving perception, interpretation, response and adaptation to harmful, threatening or challenging events • Lazarus and Folkman, 1984

6. Neurochemical Response to Stress • Hypothalamic-Pituitary-Adrenal axis • Locus Coeruleus-Norepinephrine • Dopamine Systems • Serotonin Systems • GABA Systems • Glutamate Systems

8. Primary Stress Response Systems Hypothalamus CRF Locus Coeruleus Norepinephrine System Pituitary Gland ACTH Cortisol Brainstem Sympathetic Nervous System Adrenal Gland Gold PW et al. Biol Psychiatry. 2002;52:381-385.

9. Charney, Am.J.Psychiatry, 2002

10. Hypothalamus Paraventricular Nucleus Lateral Nucleus Autonomic Pathways Pituitary Adrenal Glands (Medial) Prefrontal Cortex Sensory Thalamus Basolateral Nucleus of the Amygdala Central Nucleus of the Amygdala Hippocampus Sensory Input Parabrachial Nucleus Dorsal Raphe Periacqueductal Gray Region Locus Coeruleus Adapted from Gorman, et al, Am J Psychiatry, 2000; 157:493

11. Facilitate Information Acquisition R J Dolan. Science 2002;298: 1191-4

16. Stress and Increased Vulnerability to Drug Abuse • Stress involved in major theoretical models • Tension-reduction • Self-medication models • Relapse prevention • Disease model • Alcoholics Anonymous • Preclinical models: Koob, Kreek, LeMoal • Stress - changes in brain reward systems that enhance reinforcing properties of drugs

17. STRESS AND ADDICTONS Sinha, 2001

18. Clinical Evidence for Stress-Relapse Connection • Intuitive appeal, but methodologic issues • Definition of stressor • Causal relationship difficult to establish • Relationship between PTSD, depression substance use disorders • Occupational stressors: high demand, low control

19. Animal Models of Relapse: Reinstatement • Resumption of previously drug-reinforced behavior by non-contingent exposure to drug or non-drug stimuli • Self-administration training • Extinction • Test for reinstatement under various conditions • deWit and Stewart, 1981; • Psychopharmacology (2003), Volume 168

20. Reinstatement Models • Drug-primed reinstatement: low dose drug administration • Cue-induced reinstatement: environmental cues associated with drug use • Stress-induced reinstatement: foot shock, forced swim, isolation, immobilization, etc.

21. Reinstatement Models: Drug-Primed and Stress-Induced Shaham et al., 2000

22. Stress-Induced Reinstatement:? Possible Mechanisms • Activation of HPA axis • Acute exposure to many drugs activates HPA • Stress augments drug response • Drug exposure augments stress response • CRF systems of the brain • NE-CRF interactions

23. Corticotrophin Releasing Factor and Stress-Induced Reinstatement Shaham et al., 1998

24. Stress-Induced Reinstatement:Pharmacologic and Surgical Manipulation • Blocked by intra-BNST CRF antagonists • Induced by intra-BNST CRF agonist • Blockade of B-receptors in amygdala and BNST blocks stress-induced reinstatement • Increased by amount of previous drug exposure • Cue-induced reinstatement increased by stress

25. Stress-Induced Reinstatement • Variety of stressors including footshock, isolation, forced swim, immobilization • Variety of substances including heroin, cocaine, ethanol and nicotine • Pharmacologic and surgical manipulation studies indicate distinct circuitry involved in different models of reinstatement

26. Effects of Pharmacologic/Surgical Manipulators on Reinstatement Shaham et al., 2003

27. Reinstatement Models: Summary • Cue-induced reinstatement: Basolateral amygdala and mesocorticolimbic dopaminergic projections • Drug-primed reinstatement: Dopamine/ glutamate interactions in ventral tegmental area • Stress-induced reinstatement: Brain CRF and NE systems in amygdala and BNST • Systems converge on anterior cingulate - final common output through nucleus accumbens • Systems separate, but intimately connected • Kalivas and McFarland, 2003

28. Neural Circuitry in Addiction

30. Effect of Stress on Glutamate Moghaddam et al., 1994

31. Saal et al., Neuron, 2003

32. Enhanced Cocaine Self-Administration in Adult Rats After Neonatal Stress • Neonatal isolation days 2-9 • Adult acquisition of cocaine self-administration lower doses, less training • No difference in acquisition of other tasks • Lower cortisol levels in isolated group Kosten et al., 2000

33. Neonatal Isolation and Cocaine-Induced Dopamine Release • Neonatal isolation days 2-9 • Increased dopamine release in ventral striatum after cocaine administration • Kosten et al., 2003 • Increased dopamine response to stress • Increased sensitivity to locomotor effects of cocaine • Meaney et al., 2002

34. Human Laboratory Studies • Study of stress response in substance dependent individuals • Impact of stress, cue presentation on craving (proxy for use) • Stress responding, cue reactivity in comorbid PTSD/substance dependence

35. Stress Response in Drug Dependent Individuals • Acute withdrawal from all drugs of abuse - activation of HPA axis • Dysregulation of HPA axis/abnormal stress response persists for weeks to months • ?? Role of dysregulation in drug craving/relapse • Kreek and Koob, 1998

36. Psychological Stress, Drug-Related Cues and Cocaine Craving • 20 cocaine-dependent subjects • Abstinent 2-4 weeks at time of testing • Stress Imagery Script based on recent personal stressful event • Drug-related Cues script • Measure subjective effect, physiologic, neuroendocrine response • Sinha et al., 2000

37. Psychological Stress, Drug-Related Cues and Cocaine Craving Sinha et al., 2000

38. Stress and Craving

39. HPA Response in Stress-induced and Drug Cue-Induced Craving • 54 cocaine-dependent subjects • Measure ACTH, prolactin, cortisol, norepinephrine, epinephrine, heart rate • Significant activation of CRF-HPA axis and noradrenergic/sympatho-adreno-medullary system with stress and drug-cue • Sinha et al., 2003

40. Cue Reactivity in Comorbid PTSD/Sub Dependence • Human laboratory paradigm • Exposure to trauma-related and/or substance-related cues • Measure subjective responses (craving), physiologic response (HR, GSR, EMG) Coffey et al., 2001

41. Cue Reactivity by Diagnostic Group-Alcohol Coffey et al., 2001

42. Cold Pressor Task • Submerge hand in 2° C water for up to 2 minutes • Dependent variables • HPA activity • Physiologic response • Subjective response

43. Cold Pressor Test Max Change ACTH

44. Alcohol Consumption in Follow-up Period after Cold Pressor Task * * * p ≤ 0.05 Trend towards lower post-task ACTH associated with greater post-task craving (p ≤ 0.09)

45. Naltrexone /Alcohol Self-Administration and HPA Axis • 18 alcohol-dependent subjects • 50 mg NTX or PBO for 6 days • Alcohol self-administration paradigm • NTX decreased alcohol craving /self-administration • NTX increased ACTH/cortisol • Cortisol negatively correlated with craving • O’Malley et al., 2002

47. Epidemiologic Data: PTSD/Substance Abuse Cottler et al (1992) Cocaine opiate use; female gender predict PTSD; > 10x risk Breslau et al (1997) Odds ratio 3.0 PTSD increased risk alcohol (3.0) Kessler et al (1995) Odds ratio 2-3 men 2-5 women Kilpatrick et al (1993) PTSD 5.2x more likely to be alcohol dependent

48. PTSD Integrated Treatment • Triffleman et al (1999) - manualized individual therapy: relapse prevention + stress inoculation + in vivo exposure • Najavits et al (1996) - “Seeking Safety” manualized group therapy: relapse prevention, education, affect management • Brady et al (1999) - manualized individual therapy: imaginal exposure + relapse prevention

49. Serotonin Reuptake Inhibitors Efficacious in treatment of PTSD Data in alcohol use inconsistent • Overall studies predominantly negative or show only modest improvement • Subtyping by psychiatric comorbidity or other features of illness shows promise

50. Drinking Outcomes for Sertraline vs. Placebo n=90 p=NS