Previous studies have examined the behavioral and cognitive effects (Land and Riccio, 1999
; Myers and Davis, 2002
; Ho et al., 2005
) of DCS and have reported that DCS may be involved in the facilitation of new memory formation that oppresses or overrides previously conditioned memories. In addition, it has been reported that as an NMDA partial agonist, DCS plays an important role in the consolidation of memories (Richardson, 2004
), long-term potentiation or LTP (Yaka et al., 2007
), and cocaine potentiated synaptic strength in the VTA (Borgland et al., 2004
Evidence of the therapeutic effects of DCS, on extinction, has been widely described with respect to the extinction of conditioned fear and anxiety (Richardson, 2004
; Hofmann et al., 2006
; Norberg et al., 2008
). Most recently, DCS has been examined for its properties of extinction of drug-seeking behavior after repeated drug exposures. The present findings, along with those of recent studies (Botreau et al., 2006
; Paolone et al. 2009
; Thanos et al., 2009
), further support the notion that DCS may have therapeutic value for the extinction of cocaine seeking and abuse. Progressing from the original study on DCS-facilitated cocaine CPP extinction in rats (Botreau et al., 2006
) and mice (Thanos et al., 2009
); this study, utilizing a self-administration paradigm and two doses (15 mg/kg or 30 mg/kg i.p. DCS), revealed the dose effect and efficacy of DCS on the extinction of cocaine self-administration in rats.
Rats displayed similar cocaine self-administration behavior during the maintenance portion of the study as previously reported (Mark et al., 1999
). When the cocaine dose was decreased in week 2 of self-administration, rats showed a corresponding increase in active lever responding for cocaine. Extinction of cocaine self-administration behavior in the rats indicated a progressive, daily, decrease in active lever responses; and slight increases in inactive lever responses. There were no significant differences in extinction between the vehicle (control) and the 15 mg/kg DCS rats. These results challenged those previously found in the extinction of a cocaine CPP (Botreau et al., 2006
); study in which 15 mg/kg DCS were found effective in the facilitation of a cocaine CPP extinction. This is likely to reflect the differences in the neuronal processes that are involved in CPP, which does not require behavioral output other than choice of space verus those involved in drug self-administration, which require lever pressing to get the expected cocaine. This could be interpreted to indicate that whereas the lower DCS (15 mg/kg) dose may be sufficient to inhibit the place conditioning association it is insufficient to inhibit the motivational drive to lever press for cocaine.
The results from this study also indicated that there were differences in the rate at which the extinction took place between the vehicle (control) and the 30 mg/kg DCS treated rats. This higher DCS dose (30 mg/kg) showed a sharper decline in active lever responding and produced this effect rapidly (within the first treatment sessions). In addition, this effect was maintained throughout the first week extinction period (days 21–26). This facilitated cocaine extinction observed in the rats treated with 30 mg/kg DCS is consistent with findings for this dose of DCS on the extinction of fear and anxiety (Anthony and Nevins, 1993
) and with findings of extinction on cocaine self-administration (Nic Dhonnchadha et al. 2010
However, analysis of the inactive lever presses for all three treatment groups; during the extinction session indicate a somewhat erratic behavior. Although an increased number of inactive lever presses during the first few days of extinction is expected due to the initial cocaine-seeking response that rats show; this response typically lasts a few sessions. Indeed, the vehicle treated rats in this study within two extinction sessions showed a similar number of inactive lever responses in the extinction phase as in the cocaine self-administration phase. However, the DCS treated rats did show a greater number of inactive lever responses compared with the vehicle treated rats overall during extinction; although no significant difference was found on a day to day analysis. This increase in inactive lever responses during extinction of cocaine self-administration following DCS treatment has not been previously examined and further research is needed into its significance and mechanism. Thus, although DCS seems to facilitate the extinction of lever responding for cocaine; probably by enhancing learning of new contextual relationships during extinction sessions; this new learning of contextual relationships needs to be further examined in terms of responses to other cues.
Finally, there was no significant effect of DCS on locomotor activity throughout the extinction phase. This was in part consistent with the locomotor activity during CPP observed with 15 mg/kg DCS (Thanos et al. 2009
). In addition, although previous data in CPP had shown inhibition of locomotor activity at 30 mg/kg, this was not observed here during the self-administration extinction paradigm. This may be due to the differences in the methods used (40 min per session, eight sessions of DCS treatment in the CPP study (Thanos et al., 2009
); 90 min per session, 15 sessions of DCS treatment in this study. Although rats treated with DCS compared with control rats did not show significant locomotor side effects, further studies need to examine long-term effects following DCS treatment beyond 2 weeks.