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

先前对表达大鼠多巴胺（DA）转运体的COS细胞进行的体外研究表明，毒蕈碱受体拮抗剂三己苯基（THP）可能会减弱可卡因的有益特性。为了探讨这种可能性，我们研究了THP和其他毒碱受体拮抗剂苯托品（BNZ）和东莨菪碱（SCP）对小鼠可卡因和甲基苯丙胺（MAP）诱导的条件位置偏好（CPP）的影响。该行为研究意外地发现THP抑制MAP诱导的CPP，而不抑制可卡因诱导的CPP。BNZ和SCP均不影响MAP和可卡因的奖励特性。随后的体内微透析研究检测了THP对小鼠注射MAP后伏隔核细胞外DA水平的影响。在注射后最初的3小时内，MAP增加了DA水平。THP可拮抗MAP引起的DA水平升高。此外，我们还研究了THP对pc12细胞囊泡释放DA的影响。THP抑制map诱导的pc12细胞囊泡DA释放增加。综上所述，这些结果表明THP可能通过抑制DA从囊泡单胺转运体（VMAT）释放到突触前末端的细胞质，至少部分地减弱MAP的奖励特性。

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.