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