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

Abstract

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.

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Fig. 1: Ex vivo cocaine decreases glutamatergic drive onto PV-INs through a presynaptic mechanism of action.
Fig. 2: Cocaine decreases glutamatergic drive onto PV-INs through a monoamine-independent mechanism.
Fig. 3: Cocaine decreases glutamatergic transmission by recruiting σ1 signaling to mobilize intracellular Ca2+ stores.
Fig. 4: Cocaine-induced σ1 activity triggers 2-AG-independent eCB signaling at presynaptic CB1Rs.
Fig. 5: Acute cocaine exposure occludes synaptically-evoked CB1R-dependent long-term depression at synapses onto PV-INs.

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Funding

This study was supported by National Institute on Drug Abuse (NIDA) grant R01DA040630 (to B.A.G). KMM is supported by National Institute of General Studies T32 GM108554.

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Conceptualization, KMM and BAG; Methodology, KMM, BCC, ANJ, DG, and BAG; Investigation, KMM, BCC, ANJ and DG; Resources, BAG, SP; Writing – original draft, KMM; Writing – Reviewing & Editing, KMM and BAG; Supervision, BAG; Funding Acquisition, BAG.

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Correspondence to Brad A. Grueter.

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Manz, K.M., Coleman, B.C., Jameson, A.N. et al. Cocaine restricts nucleus accumbens feedforward drive through a monoamine-independent mechanism. Neuropsychopharmacol. (2021). https://doi.org/10.1038/s41386-021-01167-3

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