Stress and Stress and Drugs of AbuseDrugs of Abuse

An IntroductionAn 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 pathwayMesolimbic 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: The Human Limbic System: Motivation and Addiction Motivation and Addiction PathwaysPathways

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 NucleiHypothalamic 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 amygdala

BNST

adrenal

PVN

Pituitary

GABAGABA-+

GluGlu

GABAGABA-

AVPAVPCRFCRF+ +

+ACTHACTH

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

RaphéRaphé

raphe

Serotonergic innervation of Serotonergic innervation of Limbic BrainLimbic Brain

amygdala

GABA-

BNST

GABA-

PVN

AVPCRF+ +Pituitary

ACTH+

adrenalF

Stimulate HPA Stress hormone release

Red = stop = inhibitoryGreen = go = stimulatory Inhibit

Inhibitor =

disinhibitiondisinhibition+ LC

NE

SN VTADA

raphé5-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

adrenalF

Inhibit HPA Stress hormone releaseStimulate

Inhibitor =

InhibitionInhibition

hippocampus

+Glu

-PVN

AVPCRF

Hippocampus is also Hippocampus is also important for spatial and important for spatial and temporal memorytemporal 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

hippocampus amygdala

BNST

adrenal

PVN

Pituitary

GABA-+

Glu

GABA-

AVPCRF+ +

+ACTH

Negative FeedbackNegative Feedback

GR

MR

F

F

F

Positive Feedback:Positive Feedback: chronicchronic stressstress

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 AddictionPuberty and Addiction