Ventral Tegmental Area M5 Muscarinic Receptors Mediate Effort-Choice Responding and Nucleus Accumbens Dopamine in a Sex-Specific Manner

Optimization of effort-related choices is impaired in depressive dis-orders. Acetylcholine (ACh) and dopamine (DA) are linked to de-pressive disorders, and modulation of ACh tone in the ventral tegmental area (VTA) affects mood-related behavioral responses in rats. However, it is unknown if VTA ACh mediates effort-choice be-haviors. Using a task of effort-choice, rats can choose to lever press on a fixed-ratio 5 (FR5) schedule for a more-preferred food or con-sume freely available, less-preferred food. VTA administration of physostigmine (1 mu g and 2 mu g/side), a cholinesterase inhibitor, re-duced FR5 responding for the more-preferred food while leaving consumption of the less-preferred food intact. VTA infusion of the M5 muscarinic receptor negative allosteric modulator VU6000181 (3 mu M, 10 mu M, 30 mu M/side) did not affect lever pressing or chow consumption. However, VU6000181 (30 mu M/side) coadministration with physostigmine (2 mu g/side) attenuated physostigmine-induced decrease in lever pressing in female and male rats and significantly elevated lever pressing above vehicle baseline levels in male rats. In in vivo voltammetry experiments, VTA infusion of combined physo-stigmine and VU6000181 did not significantly alter evoked phasic DA release in the nucleus accumbens core (NAc) in female rats. In male rats, combined VTA infusion of physostigmine and VU6000181 increased phasic evoked DA release in the NAc compared with vehicle, physostigmine, or VU6000181 infusion alone. These data indicate a critical role and potential sex differ-ences of VTA M5 receptors in mediating VTA cholinergic effects on effort choice behavior and regulation of DA release.