Astrocyte Ca²⁺ 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 Ca²⁺. However, the manner in which Ca²⁺ in dorsal striatum astrocytes impacts neuronal signaling after exposure to self-administered cocaine remains unclear. We addressed this question following over-expression of the Ca²⁺ extrusion pump, hPMCA2w/b, in dorsal striatum astrocytes and the Ca²⁺ 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 Ca²⁺ increased the amplitude of neuronal Ca²⁺ transients in brain slices, but only after cocaine self-administration. This was accompanied by decreased duration of neuronal Ca²⁺ events in the cocaine group and no changes in Ca²⁺ event frequency. Acute administration of cocaine to brain slices decreased amplitude of neuronal Ca²⁺ in both the control and cocaine self-administration groups regardless of hPMCA2w/b expression. These results indicated that astrocyte Ca²⁺ control over neuronal Ca²⁺ 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 Ca²⁺ events by NPS-2143, a Ca²⁺ sensing receptor (CaSR) antagonist, suggesting that plasticity of neuronal signaling after hPMCA2w/b over-expression was unlikely to result from elevated extracellular Ca²⁺. We conclude that astrocyte Ca²⁺ 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 Ca²⁺ influences neuronal output in the dorsal striatum to promote resistance to cue-induced reinstatement of cocaine seeking.