Effects of excitotoxic lesions of the rat prefrontal cortex on CREB regulation and presynaptic markers of dopamine and amino acid function in the nucleus accumbens

The present study investigated the effects of excitotoxic lesions of the pr efrontal cortex (PFC) on dopamine (DA) and excitatory amino acid (EAA) func tion in the nucleus accumbens core using in vivo microdialysis in freely mo ving rats. As a postsynaptic marker of neuronal function, the nuclear level s of the transcriptional factor CREB and its active phosphorylated form, CR EB-P, were measured in the ventral tegmental area (VTA), and in the core an d shell subregions of the nucleus accumbens of sham and lesioned animals. P FC-lesioned animals exhibited a greater locomotor response to novelty and a mphetamine administration (125-500 mu g/kg i.v.). No change was observed in extracellular levels of glutamate or saturable D-aspartate binding (a mark er for the high-affinity EAA transporter) in the nucleus accumbens of PFC-l esioned animals. Extracellular levels of DA were comparable in sham and les ioned animals under tonic conditions, however, following amphetamine admini stration, DA efflux was significantly attenuated in lesioned animals. No co rrelation was observed between microdialysate levels of amino acids and the attenuated dopaminergic response to amphetamine in lesioned animals. Furth er, no effect of the lesion was found on nuclear CREB protein in saline- an d amphetamine-treated rats. The density of CREB-P immunoreactive nuclei, wh ile remaining unchanged in the VTA, increased in the nucleus accumbens shel l following amphetamine treatment in lesioned animals. The results show tha t an important modulatory role of the PFC on the behavioural response to no velty and amphetamine is associated with the level of immediate-early gene regulation rather than levels of extracellular DA and amino acids in the ve ntral striatum.