Astrocyte Ca in the dorsal striatum suppresses neuronal activity to oppose cue-induced reinstatement of cocaine seeking.

Recent literature supports a prominent role for astrocytes in regulation of drug-seeking behaviors. The dorsal striatum, specifically, is known to play a role in reward processing with neuronal activity that can be influenced by astrocyte Ca. However, the manner in which Ca in dorsal striatum astrocytes impacts neuronal signaling after exposure to self-administered cocaine remains unclear. We addressed this question following over-expression of the Ca extrusion pump, hPMCA2w/b, in dorsal striatum astrocytes and the Ca indicator, GCaMP6f, in dorsal striatum neurons of rats that were trained to self-administer cocaine. Following extinction of cocaine-seeking behavior, the rats over-expressing hMPCA2w/b showed a significant increase in cue-induced reinstatement of cocaine seeking. Suppression of astrocyte Ca increased the amplitude of neuronal Ca transients in brain slices, but only after cocaine self-administration. This was accompanied by decreased duration of neuronal Ca events in the cocaine group and no changes in Ca event frequency. Acute administration of cocaine to brain slices decreased amplitude of neuronal Ca in both the control and cocaine self-administration groups regardless of hPMCA2w/b expression. These results indicated that astrocyte Ca control over neuronal Ca transients was enhanced by cocaine self-administration experience, although sensitivity to acutely applied cocaine remained comparable across all groups. To explore this further, we found that neither the hMPCA2w/b expression nor the cocaine self-administration experience altered regulation of neuronal Ca events by NPS-2143, a Ca sensing receptor (CaSR) antagonist, suggesting that plasticity of neuronal signaling after hPMCA2w/b over-expression was unlikely to result from elevated extracellular Ca. We conclude that astrocyte Ca in the dorsal striatum impacts neurons via cell-intrinsic mechanisms (e.g., gliotransmission, metabolic coupling, etc.) and impacts long-term neuronal plasticity after cocaine self-administration differently from neuronal response to acute cocaine. Overall, astrocyte Ca influences neuronal output in the dorsal striatum to promote resistance to cue-induced reinstatement of cocaine seeking.