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) b. compulsion to partake but also food, social attachment, sexual partners, aggression, stress

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! Day 7 Day 9 Stress

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

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

raphe Serotonergic innervation of Limbic Brain

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

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

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

Hippocampus is also important for spatial and temporal memory

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

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

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

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! Day 7 Day 9 StressLHPA

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

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