Stress and Drugs of Abuse An Introduction Mesolimbic DA

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Stress and Drugs of Abuse

• An Introduction

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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
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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
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Mesolimbic DA pathway
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Dopamine Model of Drug Addiction
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• 3. Limbic System adds emotional context
• Glu (glutamate) interacts with mesolimbic
• DA for emotive-motor integration
• i. Glu is also in MSG
• b. input from hippocampus and amygdala

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The Limbic System Motivation and Addiction
Pathways
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The Human Limbic System Motivation and
Addiction Pathways
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Conditioned Stimuli also Increase Accumbal
Dopamine Release!
Day 7
Day 9
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• II. Stress enhances drug seeking and relapse
• Stress is a Neuroendocrine response
• Neuroendocrine responses integrate neural and
  hormonal messages

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• III. Stress stimulates an integrated
  Neuroendocrine response
• A. Regulating endocrine axis function
• Specific brain regions input
• a. to Hypothalamus
• 2. Hypothalamic Neurohormone Regulation
• 3. Hypothalamic control of homeostasis

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Hypothalamus
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Hypothalamic Nuclei
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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
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• E. Examples from Mental Health
• 1. Addiction and Stress Hormones, but also
  Depression, Anorexia, OCD, Schizophrenia
• Endocrine Axes Cascade
• A. Brain Hypothalamus Pituitary Gland
• 1. Neurotransmitter(s)
• Neurohormone
• Tropic
  Hormone
• 
  Hormone

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hippocampus
amygdala
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GABA
Glu
BNST
GABA
-
Hypothalamus
PVN
AVP
CRF


Hypophysis
Pituitary
ACTH

Peripheral
F
adrenal
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• 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

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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
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C. Brainstem monoamine input 1. serotonin from
raphé 2. dopamine from ventral tegmental area 3.
norepinephrine from locus ceruleus
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Raphé
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Serotonergic innervation of Limbic Brain
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Stimulate HPA Stress hormone release
Red stop inhibitory
Green go stimulatory
brainstem
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b. Hippocampus inhibits HPA i. indirectly by
stimulating BNST (1) Hippocampus - Glu
(stimulatory) BNST - GABA
(inhibitory) PVN CRH c. BNST common
to both pathways
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Inhibit HPA Stress hormone release
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Hippocampus is also important for spatial and
temporal memory
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amygdala
-
GABA
BNST
Balanced System
GABA
-
PVN
AVP
CRF


Pituitary
ACTH

F
adrenal
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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
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Negative Feedback
Positive Feedback chronic
stress
MR
hippocampus
amygdala
GR
-

GABA
Glu
BNST
GABA
-
PVN
AVP
CRF


Pituitary
ACTH

adrenal
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• II. Stress F enhances drug seeking and relapse
• rewarding stimuli (drugs, food, sexual partner)
  increase plasma cortisol (F)
• F alone has positive reinforcing effects on drug
  use
• stress levels of F
• also facilitates rewarding effects of drugs
• Effects of F are context dependent

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Conditioned Stimuli also Increase Accumbal
Dopamine Release!
Day 7
Day 9
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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
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• 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
• Acting at amygdala

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The Limbic System Motivation and Addiction
Pathways
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• 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
• Promote Addiction
• Also the Social Reinforcing Mechanisms

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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