stress and drug abuse primary interaction of stress and drug abuse is relapse. can stress cause...

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