Transcript Cliff - USD Biology

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