Behavioural Brain Research 131 (2002) 9 – 16 Research report The dorsomedial shell of the nucleus accumbens facilitates cocaine-induced locomotor activity during the induction of behavioral sensitization M.S. Todtenkopf *, T. Carreiras, R.H. Melloni Jr, J.R. Stellar Department of Psychology, Northeastern Uniersity, 360 Huntington Ae (125 NI) Boston, MA 02115 USA Received 11 May 2001; received in revised form 6 July 2001; accepted 30 July 2001 Abstract The mesolimbic dopamine system has been intensely studied as the neural circuit mediating the locomotor response to psychostimulants and behavioral sensitization. In particular, the dopaminergic innervation of the nucleus accumbens has been implicated as a site responsible for the manifestations of behavioral sensitization. Previous studies have demonstrated an augmented release of dopamine in the nucleus accumbens upon a systemic injection of a psychostimulant. In addition, alterations in the dopaminergic innervation patterns in this brain region have been demonstrated in animals that received repeated injections of cocaine. Furthermore, lesions of projection sites that have terminations in the nucleus accumbens have demonstrated alterations in psychostimulant induced locomotion, both acutely, as well as in sensitization paradigms. Since dopamine in the nucleus accumbens is believed to regulate several excitatory amino acid inputs, the present study examined the effects of a localized electrolytic lesion in the dorsomedial shell of the nucleus accumbens in order to better understand the functional role this brain region has in behavioral sensitization. All animals received bi-daily injections of 15 mg/kg i.p. cocaine. Only those demonstrating behavioral sensitization after a subsequent challenge dose were included in the analysis. Following acute exposure to cocaine, lesioned animals did not show any difference in their locomotor response when compared with sham controls. However, after repeated exposure to cocaine, sensitized animals demonstrated a significant attenuation in locomotor behavior when compared with sensitized sham controls. This decrease in horizontal locomotion persisted 2 days into withdrawal, yet dissipated in the sensitized animals that were challenged 2 weeks following their last injection. The data presented here demonstrate that the dorsomedial shell of the nucleus accumbens plays an important role in the initial stages of behavioral sensitization to cocaine. © 2002 Elsevier Science B.V. All rights reserved. Keywords: Lesion; Cocaine; Dopamine; Sensitization; Accumbens shell; Glutamate www.elsevier.com/locate/bbr 1. Introduction Repeated exposure to cocaine and other psychostim- ulants can lead to a development of an enhanced locomotor response to a subsequent exposure to these drugs. This phenomenon, termed behavioral sensitiza- tion, or ‘reverse-tolerance’, is believed to be mediated by activity of the mesocorticolimbic system [31,34]. Indeed, psychostimulants have been shown to have their primary reinforcing and behavioral activating ef- fects on the dopamine (DA) containing neurons origi- nating in the ventral tegmental area (VTA) [32,39], which has primary termination sites in the nucleus accumbens (NAc, [3,20], i.e. the site believed to be responsible for the manifestations of behavioral sensi- tization [32,35]. Several reports have demonstrated that the NAc is not a homogeneous structure. Based on histological and topographical data describing the NAc afferent and efferent projections, the caudal two thirds of this * Corresponding author. Tel.: +1-617-373-3078; fax: +1-617-373- 8714. E-mail address: todtenkopf@neu.edu (M.S. Todtenkopf). 0166-4328/02/$ - see front matter © 2002 Elsevier Science B.V. All rights reserved. PII:S0166-4328(01)00352-7