Altered Responsiveness to Cocaine and Increased Immobility in the Forced Swim Test Associated with Elevated cAMP Response Element-Binding Protein Expression in Nucleus Accumbens
Andrea M. Pliakas, Richard R. Carlson, Rachael L. Neve, Christine Konradi, Eric J. Nestler et al.
Objective: Assessment of cocaine reward and aversion by measuring time spent in drug-paired environments following HSV-CREB or HSV-mCREB treatment in the nucleus accumbens
Materials & Equipment Checklist
6 items2 from ConductScience
Gather these items before starting the experiment. Check off items as you prepare.
Equipment2
Not specified • Not specified • Not specified • Not specified
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Protocol Steps
View Abstract
Drugs of abuse regulate the transcription factor cAMP response element-binding protein (CREB) in striatal regions, including the nucleus accumbens (NAc). To explore how regulation of CREB in the NAc affects behavior, we used herpes simplex virus (HSV) vectors to elevate CREB expression in this region or to overexpress a dominant-negative mutant CREB (mCREB) that blocks CREB function. Rats treated with HSV-mCREB in place conditioning studies spent more time in environments associated with cocaine, indicating increased cocaine reward. Conversely, rats treated with HSV-CREB spent less time in cocaine-associated environments, indicating increased cocaine aversion. Studies in which drug-environment pairings were varied to coincide with either the early or late effects of cocaine suggest that CREB-associated place aversions reflect increased cocaine withdrawal. Because cocaine withdrawal can be accompanied by symptoms of depression, we examined how altered CREB function in the NAc affects behavior in the forced swim test (FST). Elevated CREB expression increased immobility in the FST, an effect that is opposite to that caused by standard antidepressants and is consistent with a link between CREB and dysphoria. Conversely, overexpression of mCREB decreased immobility, an effect similar to that caused by antidepressants. Moreover, the kappa opioid receptor antagonist nor-Binaltorphimine decreased immobility in HSV-CREB- and HSV-mCREB-treated rats, suggesting that CREB-mediated induction of dynorphin (an endogenous kappa receptor ligand) contributes to immobility behavior in the FST. Exposure to the FST itself dramatically increased CREB function in the NAc. These findings raise the possibility that CREB-mediated transcription within the NAc regulates dysphoric states.
1
Viral vector administration
Administer HSV-CREB or HSV-mCREB vectors to elevate or block CREB expression in nucleus accumbens
Not specifiedNot specified
Note: Two treatment groups: HSV-CREB (elevated CREB expression) and HSV-mCREB (blocked CREB function)
View evidence from paper
“we used herpes simplex virus (HSV) vectors to elevate CREB expression in this region or to overexpress a dominant-negative mutant CREB (mCREB)”
2
Place conditioning with cocaine
Conduct place conditioning studies where rats are exposed to environments paired with cocaine administration
Not specifiedNot specified
Note: Drug-environment pairings were varied to coincide with either early or late effects of cocaine
View evidence from paper
“Rats treated with HSV-mCREB in place conditioning studies spent more time in environments associated with cocaine”
3
Measure time in drug-paired environment
Measure and record time spent in cocaine-associated environments as indicator of reward or aversion
Not specifiedNot specified
Note: Increased time indicates increased cocaine reward; decreased time indicates increased cocaine aversion
View evidence from paper
“Rats treated with HSV-mCREB in place conditioning studies spent more time in environments associated with cocaine, indicating increased cocaine reward”
4
Forced swim test
Place rats in forced swim test to measure immobility as indicator of depression-like behavior