¹Department of Cellular and Molecular Pharmacology, Rosalind Franklin University of Medicine and Science/The Chicago Medical School, North Chicago, IL, USA

Correspondence: Dr H Steiner, Department of Cellular and Molecular Pharmacology, Rosalind Franklin University of Medicine and Science/The Chicago Medical School, 3333 Green Bay Road, North Chicago, IL 60064, USA. Tel: +1 847 578 8679; Fax: +1 847 578 3268; E-mail: Heinz.Steiner@rosalindfranklin.edu

Received 29 June 2005; Revised 21 October 2005; Accepted 21 October 2005; Published online 4 January 2006.

Abstract

Psychostimulant-induced molecular changes in cortico-basal ganglia-cortical circuits play a critical role in addiction and dependence. These changes include alterations in gene regulation particularly in projection neurons of the sensorimotor striatum. We previously showed that cocaine-induced gene regulation in such neurons is dependent on the behavior performed during drug action. Rats trained on a running wheel under the influence of cocaine for 4 days subsequently displayed greater c-fos induction by cocaine than untrained controls. This effect was selective for the sensorimotor striatum, which is known to mediate forms of motor learning. In the present study, we investigated whether this enhanced cellular responsiveness was associated with learning of wheel running or with prolonged running (exercising), by assessing c-fos inducibility after 1, 2, or 8 days of training. Wheel training was performed after injection of cocaine (25 mg/kg) or vehicle, and c-fos induction by a cocaine challenge was measured 24 h later. Rats that trained under cocaine (but not vehicle) showed a greater c-fos response in the striatum compared to locked-wheel controls. This effect was present after the 1-day training, peaked after 2 days, and dissipated by 8 days of training. Similar effects were found for substance P, but not enkephalin, expression. These changes in striatal gene regulation paralleled improvement in wheel running, which was facilitated by cocaine. Thus, these training-induced molecular changes do not appear to represent exercising effects, but may reflect motor learning-associated neuronal changes altered by cocaine. Such cocaine effects may contribute to aberrant motor learning implicated in psychostimulant addiction.