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The Journal of Neuroscience, January 30, 2008, 28(5):1198-1207; doi:10.1523/JNEUROSCI.0988-07.2008

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Behavioral/Systems/Cognitive
Trk: A Neuromodulator of Age-Specific Behavioral and Neurochemical Responses to Cocaine in Mice

Michelle Niculescu,¹ Shane A. Perrine,¹ Jonathan S. Miller,¹ Michelle E. Ehrlich,² and Ellen M. Unterwald^1,3

¹Deparment of Pharmacology and Center for Substance Abuse Research, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, ²Farber Institute for Neurosciences and Department of Neurology, Thomas Jefferson University College of Medicine, Philadelphia, Pennsylvania 19107, and ³Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, New York 10021

Correspondence should be addressed to Dr. Ellen M. Unterwald, Department of Pharmacology, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, PA 19140. Email: ellen.unterwald{at}temple.edu

Responses to psychostimulants vary with age, but the molecular etiologies of these differences are largely unknown. The goal of the present research was to identify age-specific behavioral and molecular adaptations to cocaine and to elucidate the mechanisms involved therein. Postweanling, periadolescent, and adult male CD-1 mice were exposed to cocaine (20 mg/kg) for 7 d. The rewarding effects of cocaine were assessed, as were the response to a Trk antagonist and the regulation of dopamine and cAMP-regulated phosphoprotein, 32 kDa (DARPP-32). Cocaine was rewarding in both periadolescent and adult mice using a conditioned place preference procedure. In contrast, postweanling mice failed to demonstrate significant cocaine-induced place preference. Because components of the neurotrophin system including brain-derived neurotrophic factor and TrkB are developmentally regulated, their role in the age-specific effects of cocaine was determined using the Trk receptor antagonist K252a. Postweanling mice that received K252a before daily cocaine showed a significant place preference to the cocaine-paired environment that was not seen in the absence of K252a. DARPP-32 protein levels were significantly upregulated in the lateral region of the caudate–putamen exclusively in postweanling mice after chronic cocaine. Daily pretreatment with K252a attenuated the induction of DARPP-32 in the postweanling striatum. These data indicate that Trk neurotransmission plays a role in age-specific behavioral and molecular responses to cocaine and concurrently modulates DARPP-32 levels.

Key words: cocaine; DARPP-32; BDNF; TrkB; postweanling; striatum

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Received March 5, 2007; revised Dec. 13, 2007; accepted Dec. 13, 2007.

Correspondence should be addressed to Dr. Ellen M. Unterwald, Department of Pharmacology, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, PA 19140. Email: ellen.unterwald{at}temple.edu

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