Reynolds D S, O'Meara G F, Newman R J, Bromidge F A, Atack J R, Whiting P J, Rosahl T W, Dawson G R
Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex CM20 2QR, UK.
Neuropharmacology. 2003 Feb;44(2):190-8. doi: 10.1016/s0028-3908(02)00370-2.
The GABA(A) receptor system provides the major inhibitory control in the CNS, with the alpha 1 beta 2 gamma 2 subunit combination being the most abundant and widely distributed form of the receptor. The alpha1 subunit knock-out (alpha1 KO) mice had a surprisingly mild overt phenotype, despite having lost approximately 60% of all GABA(A) receptors. The alpha1 KO mice had normal spontaneous locomotor activity, but were more sensitive to the sedating/ataxic effects of diazepam than wildtype (WT) mice. Pharmacological modulation of dopamine and N-methyl-D-aspartate (NMDA) receptors also produced altered responses in alpha1 KO mice compared with WT mice. As expected, the NMDA receptor antagonist MK801, amphetamine and cocaine increased locomotor activity in WT mice. Although MK801 increased locomotor activity in alpha1 KO mice, amphetamine and cocaine induced stereotypy not hyperlocomotion. Binding studies showed no gross changes in the total number of D1, D2 or NMDA receptors. Furthermore, pre-pulse inhibition of acoustic startle and the effects of cocaine in conditioned place preference were similar in both alpha1 KO and WT mice, indicating selective rather that global changes in response to dopaminergic agents. These data demonstrate subtle changes in behaviours mediated by neurotransmitters other than GABA in alpha1 KO mice and suggest that compensation may have occurred beyond the GABAergic system.
GABA(A)受体系统在中枢神经系统中发挥着主要的抑制性控制作用，其中α1β2γ2亚基组合是该受体最丰富且分布最广泛的形式。尽管α1亚基敲除（α1 KO）小鼠失去了约60%的所有GABA(A)受体，但其明显的表型却出人意料地轻微。α1 KO小鼠具有正常的自发运动活性，但与野生型（WT）小鼠相比，它们对安定的镇静/共济失调作用更为敏感。与WT小鼠相比，多巴胺和N-甲基-D-天冬氨酸（NMDA）受体的药理学调节在α1 KO小鼠中也产生了改变的反应。正如预期的那样，NMDA受体拮抗剂MK801、苯丙胺和可卡因增加了WT小鼠的运动活性。虽然MK801增加了α1 KO小鼠的运动活性，但苯丙胺和可卡因诱导的是刻板行为而非运动亢进。结合研究表明，D1、D2或NMDA受体的总数没有明显变化。此外，α1 KO小鼠和WT小鼠在听觉惊吓的预脉冲抑制以及可卡因在条件性位置偏好中的作用方面相似，这表明对多巴胺能药物的反应是选择性的而非全局性的变化。这些数据证明了α1 KO小鼠中除GABA外由神经递质介导的行为存在细微变化，并表明可能在GABA能系统之外发生了补偿作用。
