Effects of cholinergic muscarinic receptor antagonists on the rewarding properties of methamphetamine and cocaine.

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Previous in vitro studies with COS cells expressing rat dopamine (DA) transporter have proposed a possibility that a muscarinic receptor antagonist trihexyphenidyl (THP) may attenuate rewarding properties of cocaine. To address this possibility, we studied effects of THP and other muscarinic receptor antagonists benztropine (BNZ) and scopolamine (SCP) on conditioned place preference (CPP) induced by cocaine and methamphetamine (MAP) in mice. This behavioral study unexpectedly revealed that THP suppressed CPP induced by MAP, but not by cocaine. Neither BNZ nor SCP affected the rewarding property of MAP and cocaine. Subsequent in vivo microdialysis study examined the effect of THP on extracellular DA levels in the nucleus accumbens after injection of MAP in mice. MAP increased the DA levels during an initial 3 hr after injection. Treatment with THP antagonized the increase in DA levels produced by MAP. Furthermore, we investigated the effect of THP on DA release from vesicles of PC 12 cells. THP suppressed the MAP-induced increase of DA release from the vesicles of PC 12 cells. Taken together, these results indicate that THP may attenuate rewarding properties of MAP via, at lease in part, suppression of DA release from vesicular monoamine transporter (VMAT) into the cytoplasm of the presynaptic terminals.