Rastogi S K, Rastogi R B, Singhal R L, Lapierre Y D
Prog Neuropsychopharmacol Biol Psychiatry. 1983;7(2-3):153-64. doi: 10.1016/0278-5846(83)90102-1.
Behavioural and biochemical studies were carried out in rats given a single daily dose (1 mg/kg, i.p.) of haloperidol for 30 days and subsequently withdrawn for 7 days. Long-term administration of haloperidol resulted in supersensitivity of dopamine receptors. This was manifested by enhanced stereotypic biting, rearing, locomotor and floor activity of haloperidol withdrawn rats when challenged to a low dose of apomorphine (0.5 mg/kg, s.c.) on the 8th day. Chronic haloperidol treatment significantly decreased dopamine synthesis and release as evidenced by low activity of tyrosine hydroxylase and low level of homovanillic acid in striatum. Dopamine levels did not change in the frontal cortex, striatum and midbrain. Haloperidol treatment significantly increased striatal gamma-aminobutyric acid content and glutamic acid decarboxylase activity by 17% and 16% respectively. The decreased tyrosine hydroxylase activity and homovanillic acid level in corpus striatum might, in part, be due to an inhibitory effect of GABAergic neurons on dopaminergic system. Rats withdrawn from chronic haloperidol treatment showed significant increases in GABA level and glutamic acid decarboxylase activity. This probably resulted in further inhibition of dopamine release as evidenced by marked accumulation of dopamine in the corpus striatum and midbrain. No significant alterations in the endogenous levels of norepinephrine, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid were observed in haloperidol-treated and subsequently withdrawn rats. These data suggest that chronic haloperidol treatment and subsequent withdrawal results in the development of behavioural dopamine supersensitivity as well as biochemical alterations in dopaminergic and GABAergic system. The changes in these two neuronal systems seem to be interrelated.
对大鼠进行行为学和生物化学研究，这些大鼠每天腹腔注射一次氟哌啶醇（1毫克/千克），持续30天，随后停药7天。长期给予氟哌啶醇导致多巴胺受体超敏。这表现为在第8天对撤药后的大鼠注射低剂量阿扑吗啡（0.5毫克/千克，皮下注射）时，刻板咬、竖尾、运动和在地面活动增强。慢性氟哌啶醇治疗显著降低了多巴胺的合成和释放，纹状体中酪氨酸羟化酶活性低和高香草酸水平低证明了这一点。额叶皮质、纹状体和中脑的多巴胺水平没有变化。氟哌啶醇治疗使纹状体γ-氨基丁酸含量和谷氨酸脱羧酶活性分别显著增加17%和16%。纹状体中酪氨酸羟化酶活性降低和高香草酸水平降低可能部分是由于GABA能神经元对多巴胺能系统的抑制作用。撤药的慢性氟哌啶醇治疗大鼠的GABA水平和谷氨酸脱羧酶活性显著增加。这可能导致多巴胺释放进一步受到抑制，纹状体和中脑中多巴胺明显蓄积证明了这一点。在氟哌啶醇治疗及随后撤药的大鼠中，去甲肾上腺素、5-羟色胺和5-羟吲哚乙酸的内源性水平没有显著变化。这些数据表明，慢性氟哌啶醇治疗及随后撤药导致行为性多巴胺超敏以及多巴胺能和GABA能系统的生化改变。这两个神经元系统的变化似乎相互关联。
