Graeff F G, Brandão M L, Audi E A, Schütz M T
Behav Brain Res. 1986 Nov;22(2):173-80. doi: 10.1016/0166-4328(86)90038-0.
Experiments performed in our laboratory, using electrical stimulation combined with microinjection of drugs in the dorsal midbrain central grey (CG) of the rat, evidenced that direct stimulation of GABA receptors with locally administered gamma-aminobutyric acid (GABA) or the GABAA receptor agonists 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol, isoguvacine and muscimol raised the aversive threshold, defined as the lowest electrical current intensity inducing flight or escape behaviour when applied to the dorsal CG. The GABAB receptor agonist baclofen was ineffective. Also, enhancement of endogenous GABA action through local injection of the benzodiazepines chlordiazepoxide and midazolam or of pentobarbital resulted in anti-aversive effects. Ro 15-1788 antagonized both chlordiazepoxide and midazolam, suggesting benzodiazepine receptor mediation. In contrast to pro-GABAergic drugs, microinjection of the GABA antagonists bicuculline and picrotoxin into the CG elicited flight behaviour, like the electrical stimulation. Similar experiments with drugs influencing serotonergic neurotransmission evidenced that intra-CG microinjection of serotonin (5-HT) or of the direct 5-HT receptor agonist 5-methoxy-N,N-dimethyltryptamine increased the aversive threshold. The anti-aversive effect of 5-HT was potentiated by the selective inhibitor of 5-HT neuronal uptake, zimelidine. Also, the latter drug increased the aversive threshold when given alone. The anti-aversive effect of 5-HT was antagonized by local pretreatment with either metergoline or ketanserin, the latter being a selective blocker of 5-HT2 receptors. In contrast to the GABA antagonists mentioned above, the 5-HT receptor blockers did not evoke aversive behaviour per se. Therefore, both GABAergic and serotonergic mechanisms are likely to play an inhibitory role in the dorsal CG integrating aversive behaviour. The former seem to act tonically, whereas 5-HT would act in a phasic way. The implications of these results for the pathophysiology and drug treatment of chronic anxiety, panic states and pain disorders are briefly discussed.
在我们实验室进行的实验中，通过在大鼠中脑背侧中央灰质（CG）进行电刺激并结合药物微量注射，证明了局部施用γ-氨基丁酸（GABA）或GABAA受体激动剂4,5,6,7-四氢异恶唑并[5,4-c]吡啶-3-醇、异鹅膏蕈氨酸和蝇蕈醇直接刺激GABA受体会提高厌恶阈值，该阈值定义为施加于背侧CG时诱发飞行或逃避行为的最低电流强度。GABAB受体激动剂巴氯芬无效。此外，通过局部注射苯二氮䓬类药物氯氮卓和咪达唑仑或戊巴比妥增强内源性GABA作用会产生抗厌恶作用。Ro 15-1788拮抗氯氮卓和咪达唑仑，提示苯二氮䓬受体介导。与促GABA能药物相反，向CG中微量注射GABA拮抗剂荷包牡丹碱和印防己毒素会引发飞行行为，类似于电刺激。用影响5-羟色胺能神经传递的药物进行的类似实验证明，向CG内微量注射5-羟色胺（5-HT）或直接5-HT受体激动剂5-甲氧基-N,N-二甲基色胺会提高厌恶阈值。5-HT的抗厌恶作用被5-HT神经元摄取的选择性抑制剂齐美利定增强。此外，后一种药物单独给药时也会提高厌恶阈值。5-HT的抗厌恶作用被麦角林或酮色林局部预处理拮抗，后者是5-HT2受体的选择性阻滞剂。与上述GABA拮抗剂不同，5-HT受体阻滞剂本身不会引发厌恶行为。因此，GABA能和5-羟色胺能机制可能在整合厌恶行为的背侧CG中发挥抑制作用。前者似乎以紧张性方式起作用，而5-HT则以阶段性方式起作用。简要讨论了这些结果对慢性焦虑、惊恐状态和疼痛障碍的病理生理学及药物治疗的意义。
