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Stress and Drugs of Abuse An Introduction 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) but also food, social attachment, sexual partners, aggression, stress b. compulsion to partake 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 Mesolimbic DA pathway Dopamine Model of Drug Addiction 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 The Limbic System: Motivation and Addiction Pathways The Human Limbic System: Motivation and Addiction Pathways Nucleus accumbens Hippocampus Amygdala Conditioned Stimuli also Increase Accumbal Dopamine Release! Stress Day 7 Day 9 II. Stress enhances drug seeking and relapse A. Stress is a Neuroendocrine response B. Neuroendocrine responses integrate neural and hormonal messages 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 Hypothalamus Hypothalamic Nuclei PVN 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 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 hippocampus Limbic Brain amygdala + - Glu GABA BNST - GABA Hypothalamus Hypophysis PVN CRF+ +AVP Pituitary +ACTH F adrenal Peripheral 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 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 C. Brainstem monoamine input 1. serotonin from raphé 2. dopamine from ventral tegmental area 3. norepinephrine from locus ceruleus Raphé Serotonergic innervation of Limbic Brain raphe Stimulate HPA Stress hormone release amygdala Inhibit Red = stop Green = go==inhibitory stimulatory GABA Inhibitor = BNST brainstem - GABA NE disinhibition LC DA PVN SN VTA CRF+ +AVP 5-HT raphé Pituitary + +ACTH F adrenal b. Hippocampus inhibits HPA i. indirectly by stimulating BNST (1) Hippocampus - Glu (stimulatory) BNST - GABA (inhibitory) PVN – CRH c. BNST common to both pathways Inhibit HPA Stress hormone release hippocampus Stimulate + Inhibitor = Glu Inhibition BNST - - GABA PVN CRF AVP Pituitary ACTH F adrenal Hippocampus is also important for spatial and temporal memory hippocampus amygdala + - Glu GABA BNST Balanced - GABA System PVN CRF+ +AVP Pituitary +ACTH F adrenal 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 Negative Feedback Positive Feedback: chronic amygdala stress MR hippocampus GR F + Glu GABA BNST - GABA F PVN F CRF+ +AVP Pituitary +ACTH adrenal 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 Conditioned Stimuli also Increase Accumbal Dopamine Release! LHPA Stress Day 7 Day 9 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 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 The Limbic System: Motivation and Addiction Pathways F 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 Puberty and Addiction 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