Knockdown of the M5 acetylcholine muscarinic receptor in the ventral tegmental area (VTA) reduces brain-stimulation reward sensitivity in rats. Knockout (KO) of the M5 receptor in mice reduces morphine-induced dopamine efflux, locomotion, conditionedplace- preference, and mating-induced 30-110 kHz ultrasonic vocalizations (USVs). The GFP-labeled M5 receptor gene was transfected using a Herpes simplex virus either into the VTA or 0.2-0.7 mm posterior in the medial tegmentum (MT) of male M5 KO mice. HSV-M5-GFP transfection in VTA fully restored mating-induced USVs and augmented morphine-induced locomotion and stereotypy consistent with activation of DA neurons by M5 receptors. HSV-M5-GFP transfection sites in the MT inhibited USVs and morphine-induced locomotion presumably through inhibition of DA neurons. Putative transfection of M5 in GABA neurons of the rostromedial tegmental nucleus (RMTg) or 5HT neurons of the median raphe (mR) may explain this inhibition. Therefore, HSV-M5- GFP transfection in the VTA enhances DA-mediated behaviours while MT transfections inhibits these behaviours.

Knockdown of the M5 acetylcholine muscarinic receptor in the ventral tegmental area (VTA) reduces brain-stimulation reward sensitivity in rats. Knockout (KO) of the M5 receptor in mice reduces morphine-induced dopamine efflux, locomotion, conditionedplace- preference, and mating-induced 30-110 kHz ultrasonic vocalizations (USVs). The GFP-labeled M5 receptor gene was transfected using a Herpes simplex virus either into the VTA or 0.2-0.7 mm posterior in the medial tegmentum (MT) of male M5 KO mice. HSV-M5-GFP transfection in VTA fully restored mating-induced USVs and augmented morphine-induced locomotion and stereotypy consistent with activation of DA neurons by M5 receptors. HSV-M5-GFP transfection sites in the MT inhibited USVs and morphine-induced locomotion presumably through inhibition of DA neurons. Putative transfection of M5 in GABA neurons of the rostromedial tegmental nucleus (RMTg) or 5HT neurons of the median raphe (mR) may explain this inhibition. Therefore, HSV-M5- GFP transfection in the VTA enhances DA-mediated behaviours while MT transfections inhibits these behaviours.

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