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

以前在体外研究COS细胞表达大鼠多巴胺（DA）转运蛋白提出了一种可能性，毒蕈碱受体拮抗剂苯海索（THP）可能会减弱可卡因的奖励性质。为了探讨这种可能性，我们研究了THP和其他毒蕈碱受体拮抗剂苯扎托品（BNZ）和东莨菪碱（SCP）对可卡因和甲基苯丙胺（MAP）诱导的小鼠条件性位置偏爱（CPP）的影响。这项行为学研究意外地发现，THP抑制MAP诱导的CPP，但不抑制可卡因。BNZ和SCP均不影响MAP和可卡因的奖励性质。随后的体内微透析研究检查了THP对注射MAP后小鼠延髓核细胞外DA水平的影响。MAP在注射后最初3小时内增加DA水平。用THP处理拮抗MAP产生的DA水平的增加。此外，我们还研究了THP对PC 12细胞囊泡释放DA的影响。THP抑制MAP诱导的PC 12细胞囊泡DA释放的增加。两者合计，这些结果表明，THP可能会减弱奖励性质的MAP通过，至少部分地，抑制DA释放囊泡单胺转运体（VMAT）到突触前末梢的细胞质。

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.