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					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 McRae, 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
                           ACTH
          Gland                                    Brainstem

         Adrenal                                          Sympathetic
                                                          Nervous
         Gland                                            System
Gold PW et al. Biol Psychiatry. 2002;52:381-385.
Charney, Am.J.Psychiatry, 2002
                      (Medial) Prefrontal Cortex
                                                                            Sensory Thalamus


                      Basolateral           Central
                       Nucleus             Nucleus
Hippocampus             of the              of the
                      Amygdala             Amygdala



                                                             Parabrachial     Sensory Input
                     Hypothalamus                              Nucleus
 Dorsal
 Raphe        Paraventricular       Lateral
                 Nucleus            Nucleus
                                                          Periacqueductal
                                                           Gray Region
                  Pituitary       Autonomic
                                  Pathways
               Adrenal Glands                      Locus
                                                  Coeruleus

               Adapted from Gorman, et al, Am J Psychiatry, 2000; 157:493
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, LeMoal
        • 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
           » deWit 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

CB1 antagonist                                          
Corticosterone synthesis                                   
inhibitor                       

Adrenalectomy                                             
CRF antagonist                                            
D1 antagonist                                 
D1 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 McFarland, 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 self-
  administration 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, epinephrine, 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
             Craving After Alcohol Cue
20
18                             Alcohol/PTSD (n=44)
16
                               Alcohol Only (n=48)
14
12                             PTSD Only (n=39)
10                             Control (n=42)
 8
 6
 4
 2                                          Craving After Trauma Cue
 0
         F=38.93, p< 0.01      20
                               18                             Alcohol/PTSD (n=44)
                               16
                                                              Alcohol Only (n=48)
                               14
                               12                             PTSD Only (n=39)
                               10                             Control (n=42)
                                8
                                6
                                4
 Coffey et al., 2001            2
                                0
                                         F=17.59, p < 0.001
      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
30

25    23.9

20
                     15.1
15
                               10.9
10
                                          6.4
 5

 0
      Control        ETOH    ETOH/PTSD    PTSD

     (N=12)          (N=9)    (N=11)     (N=12)

                   Diagnostic Group
        Alcohol Consumption in Follow-up
          Period after Cold Pressor Task
  120

  100                                                 High craving/Low
                                                      mood
                                                      Low craving/High
   80                                                 mood

   60

   40
                      *
   20                                      *
    0
             Total Drinks       % Days Drinking

* 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 /self-
    administration
  – 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; > 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
     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

   4           3.69
        3.47                        Sertraline (n=47)
  3.5
                                    Placebo (n=43)
   3
  2.5
   2                                1.85
                                           1.5
  1.5
   1
  0.5                 0.21   0.19
   0
         Adj DDD       Adj PDD      Adj ADD


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

4.5                                4.07
 4
3.5
 3
2.5                                       2.35
                                                       Sertraline
 2                                                     Placebo
1.5                   1.1 1.13
               1.02
 1
0.5     0.36
 0
        Cluster 1     Cluster 2     Cluster 3

                                  Cluster x group p=0.068
    Adjusted Mean Drinks per Drinking Day Over
                Treatment Period

8
                                   7
7
6
5            4.74
                                                      Sertraline
4                                       3.57
                    3.23                              Placebo
3                          2.75

2
1
      0.19
0
      Cluster 1     Cluster 2     Cluster 3

                                       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

				
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