Diazepam pretreatment prior to conditioning alters cue influences and tolerance to cocaine-stimulated NAcc DA responses

Manoranjan S. D’Souza, Ohio Northern University
A. Wongsa, University of Texas at Austin
Christine L. Duvauchelle, University of Texas at Austin


Uncertainty and errors in reward prediction influence mesolimbic dopaminergic neuronal activity. Previously, we found that in the presence of cues equally associated with cocaine and non-reward (“uncertainty cues”), cocaine-stimulated nucleus accumbens dopamine (NAcc DA) responses were significantly more than when in the presence of cues that accurately predicted cocaine (“certainty cues”). In addition, when cues associated with cocaine were presented prior to a non-reinforced operant response, NAcc DA levels were significantly depressed (e.g., a prediction error). Since diazepam, a GABAa receptor modulator, blocks cocaine-enhanced long-term potentiation (LTP), it was of interest to determine whether this effect would be relevant to cocaine conditioning effects in vivo. In the present study, animals were treated with low dose (0.25 mg/kg) diazepam or vehicle prior to conditioning trials. Conditioning trials consisted of cue pairings (olfactory and visual) during cocaine and non-reinforced self-administration sessions. Cue-induced expectations of cocaine or nonreward were achieved through consistent pairings of cues with either cocaine or saline. To produce cue-induced uncertainty, cues were equally paired with both cocaine and non-rewarded sessions. At the completion of conditioning trials (8 cocaine and 8 saline sessions), in vivo microdialysis was used to determine NAcc DA responses to cocaine and saline under various cue conditions. Findings revealed that animals receiving vehicle pretreatment prior to uncertainty training showed significantly greater cocaine-stimulated NAcc DA responses in the presence of uncertainty cues than diazepam pretreated animals. Also, in contrast to controls, diazepam pretreatment did not result in a significant decrease in NAcc DA when cocaine-associated cues were followed by non-reinforcement. These data indicate that diazepam interferes with NAcc DA responses to cocaine conditioning. Diazepam pretreated rats also showed significantly greater NAcc DA responses to cocaine under certainty conditions, which suggest that this treatment may attenuate indices of cocaine tolerance.