M5 Muscarinic Receptor Knockout Mice Show Reduced Morphine-Induced Locomotion but Increased Locomotion after Cholinergic Antagonism in the Ventral Tegmental Area

M-5 muscarinic receptors are the only muscarinic receptor subtype expressed by mesencephalic dopamine neurons and provide an important excitatory input to mesolimbic and nigrostriatal dopamine systems. Here, we studied locomotion induced by systemic morphine (3, 10, and 30 mg/kg i.p.) in M-5 knockout mice of the C57BL/6 (B6) and CD1 x 129SvJ background strains. M 5 knockout mice of both strains showed reduced locomotion in response to 30 mg/kg morphine. B6 M-5 knockout mice were less sensitive to naltrexone in either the antagonism of morphine-induced locomotion or in the reduction of locomotion by naltrexone alone. This suggests that M-5 knockout mice are less sensitive to the effects of either exogenous or endogenous opiates on locomotion and that spontaneous locomotion in B6 mice is sustained by endogenous opiates. In B6 wild-type mice, ventral tegmental area (VTA) pretreatment with the muscarinic receptor antagonist atropine (3 mu g bilateral), but not the nicotinic receptor antagonist mecamylamine (5 mu g bilateral), reduced locomotion in response to 30 mg/ kg morphine to a similar extent as systemic M-5 knockout, suggesting that reduced morphine-induced locomotion in M-5 knockout mice is due to the loss of M-5 receptors on VTA dopamine neurons. In contrast, in M-5 knockout mice, but not in wild-type mice, either intra-VTA atropine or mecamylamine alone increased locomotion by almost 3 times relative to saline and potentiated morphine-induced locomotion. Therefore, in M-5 knockout mice, blockade of either VTA muscarinic or nicotinic receptors increased locomotion, suggesting that in the absence of VTA M-5 receptors, VTA cholinergic inputs inhibit locomotion.