Galloway M P
Department of Psychiatry, Wayne State University School of Medicine, Detroit, Michigan.
Synapse. 1990;6(1):63-72. doi: 10.1002/syn.890060108.
Because cocaine effectively increases extracellular levels of both dopamine (DA) and serotonin (5HT), it might be expected that this agent would inhibit transmitter biosynthesis in these monoamine neurons by activation of autoregulatory feedback pathways. This possibility was tested by measuring the effect of cocaine on 3,4-dihydroxyphenylalanine accumulation (DA synthesis) and 5-hydroxytryptophan accumulation (5HT synthesis) in vivo and in vitro after inhibition of aromatic amino acid decarboxylase with NSD-1015. In vivo, cocaine suppressed both DA and 5HT synthesis in a dose-dependent (10-60 mumols/kg, i.p.) and time-dependent fashion (maximum 60 min after administration, recovery by 120-150 min). Inhibition of DA and 5HT synthesis ranged from 35% to 60% depending on the brain region and was apparent in dopaminergic fields such as the medial prefrontal cortex, nucleus accumbens, piriform cortex, striatum, and in noradrenergic fields, such as the hippocampus and temporal cortex. Inhibition of DA, but not 5HT, synthesis was blocked by the D2 antagonist sulpiride in brain areas containing DA nerve terminals. Procaine (30 mumols/kg) did not inhibit DA or 5HT synthesis and prior treatment with reserpine diminished the effectiveness of cocaine in the medial prefrontal cortex, but not in the striatum. Cocaine did not reverse the gamma-butyrolactone-induced increase in striatal DA synthesis nor did cocaine block the ability of the D2 agonist quinpirole to reverse the increase. In vitro, cocaine inhibited DA synthesis in depolarized (K+ = 30 mM) striatal brain slices, an effect that was reversed by the D2 antagonist eticlopride. These results suggest that DA and 5HT neurons compensate in situ for cocaine-induced increases in synaptic transmitter levels by a transient inhibition of transmitter biosynthesis. Acute suppression of transmitter synthesis (and release) in mesoprefrontal DA neurons may represent the principal compensatory mechanism in this group of neurons.
由于可卡因能有效提高细胞外多巴胺（DA）和5-羟色胺（5HT）的水平，因此可以预期该药物会通过激活自身调节反馈途径来抑制这些单胺能神经元中的递质生物合成。在用NSD - 1015抑制芳香族氨基酸脱羧酶后，通过测量可卡因在体内和体外对3,4 - 二羟基苯丙氨酸积累（DA合成）和5 - 羟色氨酸积累（5HT合成）的影响来验证这种可能性。在体内，可卡因以剂量依赖性（10 - 60 μmol/kg，腹腔注射）和时间依赖性方式（给药后60分钟达到最大值，120 - 150分钟恢复）抑制DA和5HT的合成。DA和5HT合成的抑制率在35%至60%之间，具体取决于脑区，在多巴胺能区域如内侧前额叶皮质、伏隔核、梨状皮质、纹状体以及去甲肾上腺素能区域如海马体和颞叶皮质中均很明显。在含有DA神经末梢的脑区，D2拮抗剂舒必利可阻断DA合成的抑制，但不能阻断5HT合成的抑制。普鲁卡因（30 μmol/kg）不抑制DA或5HT的合成，利血平预处理会降低可卡因在内侧前额叶皮质中的有效性，但在纹状体中则不然。可卡因不会逆转γ-丁内酯诱导的纹状体DA合成增加，也不会阻断D2激动剂喹吡罗逆转该增加的能力。在体外，可卡因抑制去极化（K + = 30 mM）的纹状体脑片中的DA合成，D2拮抗剂依替必利可逆转这种作用。这些结果表明，DA和5HT神经元通过短暂抑制递质生物合成来原位补偿可卡因诱导的突触递质水平升高。中前额叶DA神经元中递质合成（和释放）的急性抑制可能代表了这组神经元中的主要补偿机制。
