Effects of high-frequency stimulation of the nucleus accumbens on the development and expression of ethanol sensitization in mice Christina N. Nona a,d , Meaghan C. Creed a,d , Clement Hamani d,e and Jose´ N. Nobrega a,b,c,d The behavioural effects of high-frequency electrical stimulation (HFS) are often similar to the effects of lesions, with the advantage of being reversible. The present study examined the effects of HFS of the nucleus accumbens (NAc), an area that has been shown to be important for sensitization to several psychostimulants, on the development and expression of EtOH sensitization. Male DBA/2 mice received five biweekly injections of EtOH (2.2 g/kg, intraperitoneally) or saline (SAL) immediately before assessments of locomotor activity (LMA). For some of the mice, each EtOH or SAL injection was preceded by 2 h of bilateral NAc HFS, whereas the remaining mice received no stimulation. Seven days after the last injection, LMA was again measured after the mice received a challenge dose of EtOH (1.8 g/kg, intraperitoneally) or SAL, either preceded or not preceded by 2 h of HFS. Mice receiving NAc HFS before EtOH injections during the sensitization period showed progressive increases in LMA that were not different from the LMA scores of EtOH-injected mice which had received no HFS. However, when the latter group was subsequently challenged after receiving HFS, a strong suppression of LMA was observed, in comparison with their own previous LMA scores (– 72%) and compared with EtOH-sensitized groups challenged in the absence of HFS (– 70%). A separate cohort of mice that were surgically implanted but not stimulated showed a robust EtOH sensitization response that did not differ from that of EtOH-treated mice without electrodes, demonstrating that HFS behavioural effects were not merely a result of the presence of electrodes in the NAc. These results suggest that NAc HFS may have different effects at different stages of the EtOH sensitization process, specifically suppressing expression, but not the development of EtOH sensitization. This pattern of distinct effects of NAc manipulations on different aspects of sensitization is similar to what has been reported for other drugs of abuse, suggesting a commonality of mechanisms. Our findings also suggest that the sensitization may provide a useful paradigm for the investigation of mechanisms of clinical effectiveness of HFS in humans. Behavioural Pharmacology 26:184–192 Copyright c 2015 Wolters Kluwer Health, Inc. All rights reserved. Behavioural Pharmacology 2015, 26:184–192 Keywords: alcohol, behavioural sensitization, DBA/2 mouse, deep brain stimulation, locomotor activity, nucleus accumbens Departments of a Pharmacology and Toxicology, b Psychiatry, c Psychology, University of Toronto, d Behavioural Neurobiology Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health and e Division of Neurosurgery, University Health Network, Toronto Western Hospital, Toronto, Ontario, Canada Correspondence to Jose´ N. Nobrega, PhD, Behavioural Neurobiology Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8 E-mail: jose.nobrega@camh.ca Received 27 October 2013 Accepted as revised 21 January 2014 Introduction In laboratory animals, repeated exposure to psychostimu- lants produces a long-lasting enhancement of locomotor activity (LMA) (Robinson and Berridge, 1993; Stewart and Badiani, 1993; Vanderschuren et al., 2001). This phenomenon, known as behavioural sensitization, is considered to produce various neurobiological changes that have also been implicated in addiction processes (Robinson and Berridge, 2000; Steketee and Kalivas, 2011). Sensitization has been shown to persist for weeks and months after the last drug treatment, and this has led to its classification as a form of pathological experience- dependent plasticity (Robinson and Berridge, 2000; Thomas et al., 2001; Nona et al., 2013). Indeed, sensitizing regimens of psychostimulant administration have been shown to induce changes in synaptic plasticity in brain regions involved in reward (Taepavarapruk et al., 2000; Thomas et al., 2001; Li and Kauer, 2004; Borgland et al., 2006; Abrahao et al., 2013). Brain processes underlying sensitization are often divided into two temporally distinct phases. The development phase refers to transient neuroadaptations induced by intermittent drug administration, which can then lead to more persistent changes in the subsequent expression phase (Jones and Bonci, 2005). The latter phase occurs after cessation of drug exposure and refers to the long-lasting changes in synaptic function of key neural circuits that mediate the persistent sensitivity to subsequent drug exposure (Vanderschuren and Kalivas, 2000; Jones and Bonci, 2005). Studies aimed at identifying key neuroanatomical regions involved in the maintenance of sensitization have 184 Research report 0955-8810 Copyright c 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/FBP.0000000000000033 Copyright © 2015 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.