STRESS AND RELAPSE TO SUBSTANCE USE Kathleen T

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

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

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

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

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

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

Primary Stress Response Systems Hypothalamus CRF Locus Coeruleus Norepinephrine System Pituitary Gland ACTH l so i t r o C Adrenal Gland Gold PW et al. Biol Psychiatry. 2002; 52: 381 -385. Brainstem Sympathetic Nervous System

Charney, Am. J. Psychiatry, 2002

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

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

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, Le. Moal • Stress - changes in brain reward systems that enhance reinforcing properties of drugs

STRESS AND ADDICTONS Sinha, 2001

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

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 » de. Wit and Stewart, 1981; » Psychopharmacology (2003), Volume 168

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.

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

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

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

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

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

Effects of Pharmacologic/Surgical Manipulators on Reinstatement Agent Cocaine Prime Cocaine Cue Stress CB 1 antagonist Corticosterone synthesis inhibitor Adrenalectomy CRF antagonist D 1 agonist NMDA antagonist GABA B Agonist Opioid agonist Opioid antagonist Shaham et al. , 2003

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 Mc. Farland, 2003

Neural Circuitry in Addiction

Effect of Stress on Glutamate Moghaddam et al. , 1994

Saal et al. , Neuron, 2003

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

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

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

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

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

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

Stress and Craving

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

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

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

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

Cold Pressor Test Max Change ACTH

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)

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 /selfadministration – NTX increased ACTH/cortisol – Cortisol negatively correlated with craving » O’Malley et al. , 2002

Epidemiologic Data: PTSD/Substance Abuse Cottler et al (1992) Cocaine opiate use; female gender predict PTSD; > 10 x 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. 2 x more likely to be alcohol dependent

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

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

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

Cluster Analysis Sertraline Three distinct clusters – Cluster one: Early onset PTSD; later onset, less severe alcoholism (N=14) – Cluster two: Onset PTSD/alcohol relatively close; less severe alcohol dependence (N=53) – Cluster three: Early onset, severe alcoholism; later onset PTSD (N=27)

Adjusted Mean Average Days Drinking Over Treatment Period Cluster x group p=0. 068

Adjusted Mean Drinks per Drinking Day Over Treatment Period Cluster x group p=0. 001

Conclusions: Sertraline PTSD/Alcohol Trial • Sertraline efficacious in treating PTSD in alcohol-dependent individuals • In the sub-group of patients with early onset PTSD, sertraline significantly improved alcohol-related outcomes

Controlled Evaluation of Stress Management on Cortisol Responses to Acute Stress • 48 healthy college students • Group-based cognitive-behavioral stress management therapy • Standardized psychosocial stress task (Trier Social Stress Test) » Gaab et al. , 2003

Effects of Stress Management Therapy on Cortisol Response to Stress

Social Support and Oxytocin Interact to Suppress Cortisol and Subjective Responses to Psychosocial Stress • 37 healthy males • Trier Social Stress Test • Social support from friend during preparation • Intranasal oxytocin (24 IU) before task • Measure cortisol, subjective effects » Heinrichs et al. , 2003

Social Support and Oxytocin in Psychosocial Stress Task Heinrichs et al. , 2003

Stress and Relapse: Clinical Considerations • Careful assessment/aggressive treatment of co-occurring stress sensitive disorders • Importance of social support in mediating effects of stress • Stress management techniques routine part of treatment of addictions

CONCLUSIONS • Relationship between stress and substance use/relapse, development of dependence • Mechanistic studies important • Identification of new avenues for treatment development