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The Journal of Neuroscience, August 9, 2006, 26(32):8235-8242; doi:10.1523/JNEUROSCI.0880-06.2006

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Neurobiology of Disease
Induction of Inducible cAMP Early Repressor Expression in Nucleus Accumbens by Stress or Amphetamine Increases Behavioral Responses to Emotional Stimuli

Thomas A. Green,¹ Imran N. Alibhai,¹ Jonathan D. Hommel,¹ Ralph J. DiLeone,¹  Arvind Kumar,¹ David E. Theobald,¹ Rachael L. Neve,² and Eric J. Nestler¹

¹Department of Psychiatry and Center for Basic Neuroscience, The University of Texas Southwestern Medical Center, Dallas, Texas 75390, and ²Department of Psychiatry, McLean Hospital, Harvard University School of Medicine, Boston, Massachusetts 02479

Correspondence should be addressed to Dr. Eric J. Nestler at the above address. Email: eric.nestler{at}utsouthwestern.edu

Previous research has shown that cAMP response element (CRE)-mediated transcription is activated in the nucleus accumbens, a major brain reward region, by a variety of environmental stimuli and contributes to neuroadaptations to these stimuli. CRE-binding protein (CREB) is the most studied activator of CRE transcription and has been implicated in this brain region as a gating mechanism for behavioral responses to emotional stimuli. Little attention, however, has been given to naturally occurring inhibitors of CRE-mediated transcription, such as the inducible cAMP early repressor (ICER), an inhibitory product of the CRE modulator gene. In the present study, we investigated the extent to which ICER is induced in the nucleus accumbens by two types of environmental stimuli, stress and amphetamine, and characterized how induction of ICER in this region affects complex behavior. We show that stress and amphetamine each induces ICER expression and that overexpression of ICER in the nucleus accumbens, using viral-mediated gene transfer, increases behavioral responses to both rewarding and aversive emotional stimuli. For example, ICER overexpression increases sensitivity to amphetamine-stimulated locomotor activity as well as to natural rewards such as sucrose and social grooming. However, ICER overexpression also increases measures of anxiety in the elevated plus maze and neophobia to novel tastes. Finally, ICER produces an antidepressant-like effect in the forced swim test, further indication of an enhanced active response to stress. These results suggest that ICER is an important mechanism for modulating CRE-mediated transcription in the nucleus accumbens.

Key words: depression; addiction; anxiety; drugs of abuse; stimulants; CREB; CREM; striatum; cocaine; sucrose preference

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Received Oct. 18, 2006; revised June 29, 2006; accepted July 1, 2006.

Correspondence should be addressed to Dr. Eric J. Nestler at the above address. Email: eric.nestler{at}utsouthwestern.edu

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