Limbic-Cortical-Ventral Striatal Activation during Retrieval of a Discrete Cocaine-Associated Stimulus: A Cellular Imaging Study with γ Protein Kinase C Expression

Abstract

We investigated the neuronal activation associated with reexposure to a discrete cocaine-associated stimulus using in situ hybridization to quantify the expression of the plasticityregulated gene, ␥ protein kinase C (␥ PKC), in the limbiccortical-ventral striatal system. Groups of rats were trained to self-administer cocaine paired with a light stimulus (Paired) or paired with an auditory stimulus but also receiving light presentations yoked to those in the Paired group (Unpaired). Additional groups received noncontingent cocaine-light pairings (Pavlovian) or saline-light pairings (Saline) that were yoked to the Paired group. After acquisition of self-administration by the Paired and Unpaired groups, all groups had a 3 d drug-and training-free period before being reexposed to noncontingent presentations of the light conditioning stimulus during a 5 min test session in the training context. There were four major patterns of results for regional ␥ PKC expression 2 hr later. (1) Changes occurred only in groups in which the light was predictive of cocaine. (2) Increases were seen in the amygdala, but decreases were seen in the medial prefrontal cortex. (3) No changes were seen in the hippocampus. (4) Although changes were observed in the basal and central nuclei of the amygdala and the prelimbic cortex in both the Paired and Pavlovian groups, additional changes were observed in the nucleus accumbens core, lateral amygdala, and anterior cingulate cortex in the Pavlovian group. These results suggest not only that regionally selective alterations in ␥ PKC expression are an index of the retrieval of Pavlovian associations formed between a drug and a discrete stimulus, but also that a distinct neural circuitry may underlie Pavlovian stimulus-reward associations in cocaine-experienced rats.

Altered Prelimbic Cortex Output during Cue-Elicited Drug Seeking

“…The decreased IEG expression in PrL output neurons of animals expressing cocaine CPP accords with the finding of Thomas and Everitt (2001) of decreased PrL expression of ␥ protein kinase C during retrieval of a cocaine-associated light stimulus; however, these results appear to contrast with conclusions from several recent studies suggesting that activation of the mPFC is necessary for cocaine-, stress-, and cue-primed reinstatement of cocaine seeking. Using a self-administration paradigm followed by extinction, the reinstatement of lever pressing normally induced by either cocaine priming or footshock was abolished when testing was immediately preceded by inactivation of either the dorsal PFC (anterior cingulate and dorsal PrL) or PrL (Capriles et al, 2003;McFarland et al, 2003McFarland et al, , 2004.…”

Opposing Regulation of Pair Bond Formation by cAMP Signaling within the Nucleus Accumbens Shell

“…However, appreciation for independent pathways continues to grow (Gainetdinov et al, 2004). These systems, as well as other intracellular signaling systems involved in motivated behavior (Thomas and Everitt, 2001), must be examined before a comprehensive understanding of the intracellular regulation of pair bond formation is reached. …”

Regulation of 5-HT2A/C receptors and DOI-induced behaviors by protein kinase Cγ

“…This suggests a possible selective role of PKCγ in 5-HT 2 receptor regulation. Further support for this association is indicated by the shared brain regional localization of PKCγ and 5-HT 2 receptors, including prefrontal cortex, as well as their post-synaptic localizations (Backstrom et al, 2001;Naik et al, 2000;Pazos et al, 1985;Thomas and Everitt, 2001). …”