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Altered responsiveness to cocaine and increased immobility in the forced swim test associated with elevated cAMP response element-binding protein expression in nucleus accumbens.
J Neurosci. 2001 Sep 15; 21(18):7397-403.JN

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.

Authors+Show Affiliations

Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, Massachusetts 02478, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11549750

Citation

Pliakas, A M., et al. "Altered Responsiveness to Cocaine and Increased Immobility in the Forced Swim Test Associated With Elevated cAMP Response Element-binding Protein Expression in Nucleus Accumbens." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 21, no. 18, 2001, pp. 7397-403.
Pliakas AM, Carlson RR, Neve RL, et al. Altered responsiveness to cocaine and increased immobility in the forced swim test associated with elevated cAMP response element-binding protein expression in nucleus accumbens. J Neurosci. 2001;21(18):7397-403.
Pliakas, A. M., Carlson, R. R., Neve, R. L., Konradi, C., Nestler, E. J., & Carlezon, W. A. (2001). Altered responsiveness to cocaine and increased immobility in the forced swim test associated with elevated cAMP response element-binding protein expression in nucleus accumbens. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 21(18), 7397-403.
Pliakas AM, et al. Altered Responsiveness to Cocaine and Increased Immobility in the Forced Swim Test Associated With Elevated cAMP Response Element-binding Protein Expression in Nucleus Accumbens. J Neurosci. 2001 Sep 15;21(18):7397-403. PubMed PMID: 11549750.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Altered responsiveness to cocaine and increased immobility in the forced swim test associated with elevated cAMP response element-binding protein expression in nucleus accumbens. AU - Pliakas,A M, AU - Carlson,R R, AU - Neve,R L, AU - Konradi,C, AU - Nestler,E J, AU - Carlezon,W A,Jr PY - 2001/9/11/pubmed PY - 2001/10/5/medline PY - 2001/9/11/entrez SP - 7397 EP - 403 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 21 IS - 18 N2 - 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. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/11549750/Altered_responsiveness_to_cocaine_and_increased_immobility_in_the_forced_swim_test_associated_with_elevated_cAMP_response_element_binding_protein_expression_in_nucleus_accumbens_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=11549750 DB - PRIME DP - Unbound Medicine ER -