Effects of high-frequency stimulation of the nucleus accumbens on the development and expression of ethanol sensitization in mice

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.