Relationship between the role of muscarinic M3 receptors in morphine-induced conditioned place preference and the mesolimbic dopamine system

Abstract

Opioid use disorder mainly results from functional defects in the brain reward loop, which includs the ventral tegmental area (VTA) and nucleus accumbens (NAc; consisting of shell and core, NAcS and NAcC). Reward effects contribute to opioid use disorder. RMTg M₃ receptors play a role in opioid reward by regulating the γ-aminobutyric acid (GABA) neuron activity. Dopamine D₁ receptors expressed on GABA neurons regulate opioid reward by mediating the dopamine neuron activity in the VTA. Therefore, we investigated the effect of activating M₃ receptors by microinjecting pilocarpine into the RMTg along with activating D₁ receptors by microinjecting SKF38393 into the VTA on morphine-induced reward effect, using the conditioned place preference (CPP) paradigm (locomotion was also recorded). We also investigated whether the activation of M₃ receptors in the RMTg influenced dopamine release in the NAcS. The results showed that the inhibitory role of RMTg pilocarpine (60 μg/rat) infusions in morphine-induced CPP was reversed by VTA SKF38393 (4 μg/rat) infusions. Moreover, morphine (5 mg/kg, i.p.) increased dopamine release in the NAcS, which was blunted by microinjecting pilocarpine (60 μg/rat) into the RMTg. These results indicate that RMTg M₃ receptors mediate morphine-induced reward effect, which is probably related to the dopamine activity within the VTA and NAcS. The relationship between RMTg M₃ receptors and the mesolimbic dopamine system could be a potential direction for the treatment of opioid use disorder, but further verification through more comprehensive techniques is needed.

Keywords: Mesolimbic dopamine system; Morphine reward; Muscarinic M(3) receptor; Nucleus accumbens shell; Rostromedial tegmental nucleus; Ventral tegmental area.