Dolphin A C, Jenner P, Marsden C D
Pharmacol Biochem Behav. 1976 Jun;4(6):661-70. doi: 10.1016/0091-3057(76)90217-3.
Two animal models of Parkinsonism have been employed to investigate the role of noradrenaline in the motor effects of levodopa. Pretreatment with reserpine or alpha-methyl-p-tyrosine (AMPT) causes cerebral amine depletion and reduction of motor activity, which can be reversed by levodopa. The effect of inhibitors of noradrenaline (NA) synthesis and antagonists of NA and dopamine (DA) receptors on the action of levodopa have been studied. For comparison, the effects of such treatments on apomorphine action has been investigated. Reversal of reserpine (10 mg/kg) induced akinesia in mice by levodopa (200 mg/kg) plus the peripheral decarboxylase inhibitor MK 486 (L-alpha-methyl-dopahydrazine; 25 mg/kg) was inhibited by prior administration of phenoxybenzamine (20 mg/kg), haloperidol (1 mg/kg), pimozide (1 mg/kg) or the dopamine-beta-hydroxylase inhibitor FLA-63 (bis [4-methyl-l-homopiperazinylthiocarbonyl] disulphide; 15 or 25 mg/kg). Apomorphine (2 mg/kg) reversal of reserpine akinesia was similarly inhibited by haloperidol (1 mg/kg) and pimozide (2 mg/kg) but not by phenoxybenzamine (20 mg/kg) or FLA-63 (25 mg/kg). Apomorphine (5 mg/kg) reversal of reserpine akinesia was enhanced by simultaneous administration of the noradrenergic agonist clonidine (1 mg/kg) and this effect was not significantly altered by prior administration of FLA-63. Clonidine, however, reversed the FLA-63 induced inhibition of the levodopa effect on reserpine akinesia. Levodopa reversal of akinesia induced by AMPT (200 mg/kg) was also inhibited by FLA-63, pimozide and haloperidol. Phenoxybenzamine, however, was without effect, but produced a different pattern of behaviour. Similarly, pimozide and haloperidol blocked apomorphine reversal of AMPT induced akinesia; FLA-63 was without effect but phenoxybenzamine produced marked inhibition. The results suggest that full restoration of motor activity in reserpine or AMPT pretreated animals requires stimulation of both DA and NA receptors.
已采用两种帕金森病动物模型来研究去甲肾上腺素在左旋多巴运动效应中的作用。用利血平或α-甲基对酪氨酸（AMPT）预处理会导致脑内胺类物质耗竭并降低运动活性，而左旋多巴可使其逆转。已研究了去甲肾上腺素（NA）合成抑制剂以及NA和多巴胺（DA）受体拮抗剂对左旋多巴作用的影响。为作比较，还研究了此类处理对阿扑吗啡作用的影响。预先给予苯氧苄胺（20 mg/kg）、氟哌啶醇（1 mg/kg）、匹莫齐特（1 mg/kg）或多巴胺-β-羟化酶抑制剂FLA-63（双[4-甲基-1-高哌嗪基硫代羰基]二硫化物；15或25 mg/kg）可抑制左旋多巴（200 mg/kg）加外周脱羧酶抑制剂MK 486（L-α-甲基多巴肼；25 mg/kg）对利血平（10 mg/kg）诱导的小鼠运动不能的逆转作用。氟哌啶醇（1 mg/kg）和匹莫齐特（2 mg/kg）同样可抑制阿扑吗啡（2 mg/kg）对利血平诱导的运动不能的逆转作用，但苯氧苄胺（20 mg/kg）或FLA-63（25 mg/kg）则无此作用。同时给予去甲肾上腺素能激动剂可乐定（1 mg/kg）可增强阿扑吗啡（5 mg/kg）对利血平诱导的运动不能的逆转作用，且预先给予FLA-63不会显著改变这种作用。然而，可乐定可逆转FLA-63诱导的对左旋多巴治疗利血平诱导的运动不能作用的抑制。FLA-63、匹莫齐特和氟哌啶醇也可抑制左旋多巴对AMPT（200 mg/kg）诱导的运动不能的逆转作用。然而，苯氧苄胺无此作用，但会产生不同的行为模式。同样，匹莫齐特和氟哌啶醇可阻断阿扑吗啡对AMPT诱导的运动不能的逆转作用；FLA-63无此作用，但苯氧苄胺会产生明显抑制作用。结果表明，在利血平或AMPT预处理的动物中，运动活性的完全恢复需要同时刺激DA和NA受体。
