1. Stress and Drugs of Abuse An Introduction

3. I. Drugs of Abuse and Addiction A. Reward, Reinforcement and Motivation 1. addiction: an overwhelming dependence on a compound or activity a. drugs (including alcohol, nicotine, caffeine, psychostimulants - amphetamine, meth, cocaine, ecstasy, opiates - heroine, morphine, codeine) b. compulsion to partake but also food, social attachment, sexual partners, aggression, stress

4. 2. reward/motivation brain centers activated a. Mesolimbic dopamine (DA) system i. Ventral Tegmental Area produces DA ii. projects to cortex and nucleus accumbens b. incentive-motivated behavior c. addictive and reinforcing properties

5. Mesolimbic DA pathway

6. Dopamine Model of Drug Addiction

10. 3. Limbic System adds emotional context a.Glu (glutamate) interacts with mesolimbic DA for emotive-motor integration i. Glu is also in MSG b. input from hippocampus and amygdala

11. The Limbic System: Motivation and Addiction Pathways

12. The Human Limbic System: Motivation and Addiction Pathways Nucleus accumbens Hippocampus Amygdala

13. Conditioned Stimuli also Increase Accumbal Dopamine Release! Day 7 Day 9 Stress

14. II. Stress  enhances drug seeking and relapse A.Stress is a Neuroendocrine response B.Neuroendocrine responses integrate neural and hormonal messages

15. III. Stress stimulates an integrated Neuroendocrine response A. Regulating endocrine axis function 1.Specific brain regions input a. to Hypothalamus 2. Hypothalamic Neurohormone Regulation 3. Hypothalamic control of homeostasis

16. Hypothalamus

17. Hypothalamic Nuclei PVN

18. B. steroid neuromodulation 1. peripheral hormone influences on CNS 2. de novo CNS steroid production C. neuroactive peptides 1. peptide hormones made in the brain = neuromodulators D. Feedback 1. environmental 2. behavioral 3. endocrine

19. E. Examples from Mental Health 1. Addiction and Stress Hormones, but also Depression, Anorexia, OCD, Schizophrenia IV.Endocrine Axes = Cascade: A. Brain  Hypothalamus  Pituitary  Gland 1. Neurotransmitter(s) Neurohormone Tropic Hormone Hormone

20. hippocampusamygdala BNST adrenal PVN Pituitary GABA -+ Glu GABA- AVPCRF ++ + ACTH F Limbic Brain Hypothalamus Hypophysis Peripheral

21. B. STRESS hormone Axis: LHPA (limbic-hypothalmo-pituitary-adrenal) Axis 1. Limbic input: a. Amygdala stimulates HPA i. indirectly by inhibiting bed nucleus of the stria terminalis (BNST) (1) Amygdala - GABA (inhibitory) BNST – GABA PVN - CRH

22. 2. Paraventricular Nucleus makes CRH (corticotropin releasing hormone) 3. CRH + AVP stimulate pituitary ACTH (adrenocorticotropic hormone) 4. ACTH stimulates adrenal cortex steroids: Cortisol (F) 5. limbic  PVN - CRH  Pit - ACTH Adrenal - F

23. C. Brainstem monoamine input 1. serotonin from raphé 2. dopamine from ventral tegmental area 3. norepinephrine from locus ceruleus

24. Raphé

25. raphe Serotonergic innervation of Limbic Brain

26. amygdala GABA - BNST GABA- PVN AVPCRF ++ Pituitary ACTH + adrenal F Stimulate HPA Stress hormone release Red = stop = inhibitory Green = go = stimulatory Inhibit Inhibitor =disinhibition + LC NE SN VTA DA raphé 5-HT brainstem

27. b. Hippocampus inhibits HPA i. indirectly by stimulating BNST (1) Hippocampus - Glu (stimulatory) BNST - GABA (inhibitory) PVN – CRH c. BNST common to both pathways

29. BNST GABA- Pituitary ACTH adrenal F Inhibit HPA Stress hormone release Stimulate Inhibitor = Inhibition Inhibition hippocampus + Glu - PVN AVPCRF

30. Hippocampus is also important for spatial and temporal memory

31. amygdala BNST adrenal PVN Pituitary GABA - hippocampus + Glu GABA- AVPCRF ++ + ACTH F Balanced System

32. D. Steroids act in the Brain (Feedback) 1. negative = F binds to glucocorticoid (GR) and mineralocorticoid (MR) receptors in hippocampus and PVN and limit CRF output 2. positive = F activates CRF expression a. F stimulation of CRF gene in central amygdala (CeA) BNST and PVN b. next stress gets a stronger neuroendocrine response than the first

33. hippocampusamygdala BNST adrenal PVN Pituitary GABA -+ Glu GABA- AVPCRF ++ + ACTH Negative Feedback GR MR F F F Positive Feedback: chronic chronic stress stress

34. II. Stress  F enhances drug seeking and relapse A.rewarding stimuli (drugs, food, sexual partner) increase plasma cortisol (F) B.F alone has positive reinforcing effects on drug use 1.stress levels of F 2.also facilitates rewarding effects of drugs C.Effects of F are context dependent

35. Conditioned Stimuli also Increase Accumbal Dopamine Release! Day 7 Day 9 StressLHPA

36. D. Cortisol (F) enhances mesolimbic DA 1. especially in Nucleus Accumbens 2. mediates reward-related behavior 3. mesolimbic DA neurons express GR & MR 4. F stimulates the enzyme for DA synthesis and inhibits breakdown (MAO) and inhibits DA reuptake (like cocaine) therefore more DA

37. E. Glu induces burst firing of VTA 1. context dependent increase in Nucleus Accumbens DA 2. F enhances Glu stimulated firing rate a. acting at VTA b. acting at hippocampus i.Acting at amygdala

38. The Limbic System: Motivation and Addiction Pathways F

39. F. Glutamate and Cortisol are necessary for development of behavioral sensitization 1. Events, Places and People associated with addiction… promote addiction 2. enhances relapse G. Stress, stress circuitry and hormones 1.Promote Addiction 2.Also the Social Reinforcing Mechanisms

40. H. Behavioral sensitization is greater during puberty 1. Stress sensitization is greater during puberty 2. Addiction rates are greatest before age 20 a. Addiction is more likely before age 20 b. Social Stress Reinforcing Mechanisms i. via Glu and F Puberty and Addiction