Cocaine restricts nucleus accumbens feedforward drive through a monoamine-independent mechanism.

Parvalbumin-expressing fast-spiking interneurons (PV-INs) within feedforward microcircuits in the nucleus accumbens (NAc) coordinate goal-directed motivational behavior. Feedforward inhibition of medium spiny projection neurons (MSNs) is initiated by glutamatergic input from corticolimbic brain structures. While corticolimbic synapses onto MSNs are targeted by the psychostimulant, cocaine, it remains unknown whether cocaine also exerts acute neuromodulatory actions at collateralizing synapses onto PV-INs. Using whole-cell patch-clamp electrophysiology, optogenetics, and pharmacological tools in transgenic reporter mice, we found that cocaine decreases thalamocortical glutamatergic drive onto PV-INs by engaging a monoamine-independent mechanism. This mechanism relies on postsynaptic sigma-1 (σ1) activity, leading to the mobilization of intracellular Ca2+ stores that trigger retrograde endocannabinoid signaling at presynaptic type-1 cannabinoid receptors (CB1R). Cocaine-evoked CB1R activity occludes the expression of CB1R-dependent long-term depression (LTD) at this synaptic locus. These findings provide evidence that acute cocaine exposure targets feedforward microcircuits in the NAc and extend existing models of cocaine action on mesolimbic reward circuits.