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Stress and Drug Abuse
• Primary interaction of stress and drug abuse is relapse.
• Can stress cause initiation of drug use/abuse?
Reinstatement Mediated relapse
• following extinction of drug use, introduce a small dose of drug or drug context.• results in addictive relapse
Stress can cause drug relapse in human and animals.
Footshock following extinction causes relapse (as measured by drug seeking behavior) in rats.
Humans report an increase in relapse when confronted with stressful situations.
In animal studies stress induced relapse has limitations.
It is context dependent.• Footshock must be applied in the lever box
The stress must be negative• Sexual stimulation (stress response equal to FS) does not induce relapse
Stress Mediated relapse
Salient actions other than abuse drugs. (food, sex and just plain old brain stimulation)
Are Primed and Stress mediated relapse influenced by similar neurochemical phenomenology?
DA antagonists
DA1 (SCH-23390), DA2 (raclopride), and DA1+2 (flupenthixol decanoate) receptor antagonists all block primed relapse
Foot Shock mediated relapse is only blocked by DA1+2 antagonist
Are Primed and Stress mediated relapse influenced by similar neurochemical phenomenology?
Systemic administration of a -opiate receptor antagonist (naltrexone) inhibits heroin primed relapse, but not FS mediated relapse.
CRF antagonist (-H-CRF) decrease FS mediated relapse, but not heroin primed relapse
Cocaine Experience establishes control of midbrain Glu and DA by
CRF: A role in stress-induced relapse to drug seeking.
Wang et al. 2005
CRF injections into the BNST reinstate drug seeking behavior.
CRF injections into the VTA induce increases in locomotion as well as mesocorticolimbic DA activity.
Increased mesocorticolimbic DA activity is also observed with drug use and stress exposure.
• AMPH• Cocaine• Morphine• Nicotine• Ethanol
http://learn.genetics.utah.edu/units/addiction/drugs/mouse.cfm
Rat Surgery and Manipulation
Rats were fitted with a jugular catheter for cocaine/saline injection.
Rats were fitted with guide cannulae directed towards the VTA or Substantia nigra for recording neurotransmitter activity or injection of pharmaceuticals.
All cannulae were connected to a micropump, to allow infusion of drugs, and collection of ECF for analysis.
SNNAcc
VTA
CPu
DA
DA
Getting them addicted (Self-administration training).
Rats pressed a lever for IV cocaine administration in an operant chamber over a 10 day period (4 hours of training each day).
Controls were injected with saline via IV catheter of similar placement for a similar time period.
Le
ver
Pre
sse
s/S
ess
ion
(4
ho
urs
)
0
10
20
30
40
50
Active
Inactive
0
10
20
30
40
50
Cocaine-Trained
Cocaine-Naive
Active Lever injected only saline.
Continued until fewer than 16 lever presses/session.
This took 14-25 sessions.
Extinction Session
Withdrawal
Three groups of animals did not experience extinction.
They were assessed following self administration training:
• either 1,7,or 21 days later.
(these animals will come later)
Footshock ParadigmA test was performed the night before the footshock administration to determine individual threshold levels of current necessary to induce freezing.
20 minute series of inescapable and unpredictable 0.5 second 0.3-0.6mA shock (depending on individual threshold level for freezing) every 40+30s.
Following footshock, levers were returned to the box, and a light was illuminated above the lever.
Footshock ParadigmA test was performed the night before the footshock administration to determine individual threshold levels of current necessary to induce freezing.
20 minute series of inescapable and unpredictable 0.5 second 0.3-0.6mA shock (depending on individual threshold level for freezing) every 40+30s.
Following footshock, levers were returned to the box, and a light was illuminated above the lever.
Footshock ParadigmA test was performed the night before the footshock administration to determine individual threshold levels of current necessary to induce freezing.
20 minute series of inescapable and unpredictable 0.5 second 0.3-0.6mA shock (depending on individual threshold level for freezing) every 40+30s.
Following footshock, levers were returned to the box, and a light was illuminated above the lever.
Foot Shock effect on Reinstatement and VTA CRF release
Over two hours following footshock and lever introduction, microdialysis samples were taken to measure VTA CRF releaseTTX (Na+ channel blocker) was given to one group to ensure that CRF increase was due to AP induced synaptic neurotransmission.
VTA
CeA
BNST
CRF
? ?
?
Foot Shock effect on Reinstatement and VTA DA and Glu release
Same methods as used previously, except that VTA DA and Glu were measured.
VTA
mPFC
LDT/PPT
Glu
Glu
CeA
BNST
CRF
? ?
?
Effect of Foot Shock + -H-CRF infusion into the VTA on Reinstatement and VTA DA and Glu release
Effect of Foot Shock + -H-CRF infusion into the VTA on Reinstatement and VTA DA and Glu release
Effect of Foot Shock + -H-CRF infusion into the SN on reinstatement and SN DA and Glu release.
1M -H-CRF 10M -H-CRF
Effect of Foot Shock + -H-CRF infusion into the SN on reinstatement and SN DA and Glu release
1M -H-CRF 10M -H-CRF
No effect of CRF in the SN!!!
Effect of Foot Shock + Glu antagonist (Kynurenic Acid) infusion into the VTA on reinstatement
and DA and Glu release.
Effect of Foot Shock + Glu antagonist (Kynurenic Acid) infusion into the VTA on reinstatement
and DA and Glu release.
Effect of CRF infusion into the VTA reinstatement behavior.
with -H-CRF and Kyn
Effect of withdrawal on CRF mediated VTA Glu release.Effects of -H-CRF and TTX on CRF mediated VTA Glu release.
Takehome Messages
Stress induced relapse is:• mediated via CRF release into the VTA • onto Glutamate axon terminals• which potentiates DA release at the NAcc and mPFC.
Additionally, relapse is blocked by injection of DA antagonists into the NAcc or mPFC.
CeA
BNST
CRF
Stress
CeA
BNST
CRF
Stress
CeA
BNST
CRF
mPFC
LDT/PPT
Glu
Glu
Stress
CeA
BNST
CRF
mPFC
LDT/PPT
Glu
GluDA VTA
Stress
CeA
BNST
CRF
mPFC
LDT/PPT
Glu
Glu
NAcc
DA VTA
