1. ¹Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA
2. ²Interdisciplinary Center for Neurosciences (IZN), University of Heidelberg, Heidelberg, Germany
3. ³Department of Neurology, Gallo Research Center, University of California, San Francisco, CA, USA
4. ⁴Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand

Correspondence: Dr KK Szumlinski, Department of Psychology, University of California at Santa Barbara, Santa Barbara, CA 91130-1996, USA. Tel: +1 805 893 6124; Fax: +1 805 893 4303; E-mail: szumlinski@psych.ucsb.edu

Received 7 June 2005; Accepted 21 July 2005; Published online 14 September 2005.

Abstract

Homer proteins modulate neuroplasticity in excitatory synapses and are dynamically regulated by cocaine. Whereas acute cocaine elevates immediate-early gene (short) isoforms of Homer1 in the nucleus accumbens, withdrawal from repeated cocaine administration downregulates the expression of constitutive Homer1 isoforms. The present study determined whether or not this downregulation in constitutive Homer expression in the accumbens is necessary for enduring alterations in cocaine-induced changes in the brain and behavior. The long vs short Homer isoforms were overexpressed in the rat nucleus accumbens during drug abstinence, and the adaptations elicited by repeated cocaine on glutamate transmission and motor behavior were measured. It was found that both chronic and acute overexpression of constitutive, but not short, Homer isoforms abolished cocaine-induced sensitization of locomotor hyperactivity and prevented the development of glutamate abnormalities in the accumbens, including the reduction in basal extracellular glutamate content and the sensitized glutamate response to a subsequent cocaine challenge injection. Together, these data indicate that the enduring reduction of long Homer isoforms in the nucleus accumbens of cocaine-withdrawn rats is necessary for the expression of cocaine-induced neuroplasticity.