Gomita Yutaka, Ichimaru Yasuyuki, Moriyama Minehiro, Araki Hiroaki, Futagami Koujiro
Department of Hospital Pharmacy, Okayama Medical School, Okayama 700-8558, Japan.
Acta Med Okayama. 2003 Jun;57(3):95-108. doi: 10.18926/AMO/32836.
In considering the characteristics of the action of anxiolytic drugs and their mechanism in the brain, it may be necessary not only to study the behavioral pharmacology but also to perform brain site research. In the present study, the action of anxiolytic drugs was examined with respect to various behaviors that were induced by stimulating the brain areas related to emotions such as reward (pleasure) or aversion in rats. First, the low rate of response in lateral hypothalamic self-stimulation behavior was induced by schedules of low current brain stimulation, variable interval (VI) and differential reinforcement of low rate (DRL). Anxiolytic drugs such as benzodiazepines facilitated these low-rate responses. The drug susceptibility was highest in the low current stimulation, lower in the VI stimulation, and lowest in the DRL stimulation schedules. Furthermore, it was found by the auto-titration method in intracranial self-stimulation behavior that anxiolytic drugs decreased the threshold of stimulation reward. Second, it was recognized using the decremental lever pressing (DLP) paradigm that anxiolytic drugs increased the threshold of aversive stimulation of mesencephalic dorsal central gray (DCG), and this increasing effect of the drug was antagonized by GABA receptor blockers such as biccuculline. Finally, it was examined whether or not the conflict situation is established by combining brain stimulation reward and aversion, such as foot-shock or DCG stimulation. As a result, the conflict behavior was established by combining not only the brain stimulation reward and foot-shock aversion, but also the brain stimulation reward and DCG stimulation aversion. Further anxiolytic drugs exhibited anti-conflict action in both situations. The susceptibility of anxiolytic drugs was higher with respect to the conflict behavior induced by intracranial reward and aversion than to that induced by the conventional method based on milk reward and foot-shock aversion. These results suggest that behavioral methods using brain stimulation can examine the mechanisms of direct drug action at the brain stimulation site. Indeed, in the present brain stimulation behavioral study, anxiolytic drugs such as benzodiazepines increased the stimulation threshold in lateral hypothalamic self-stimulation and inhibited the DCG aversive stimulation, thus resulting in an anticonflict action of the drugs.
在考虑抗焦虑药物的作用特点及其在大脑中的作用机制时，可能不仅需要研究行为药理学，还需要进行脑区研究。在本研究中，针对通过刺激大鼠大脑中与奖赏（愉悦）或厌恶等情绪相关区域所引发的各种行为，对抗焦虑药物的作用进行了研究。首先，通过低电流脑刺激、可变间隔（VI）和低反应率差异强化（DRL）等程序，诱导出下丘脑外侧自我刺激行为的低反应率。苯二氮䓬类等抗焦虑药物促进了这些低反应率。药物敏感性在低电流刺激时最高，在VI刺激时较低，在DRL刺激程序中最低。此外，通过颅内自我刺激行为的自动滴定法发现，抗焦虑药物降低了刺激奖赏的阈值。其次，使用递减式压杆（DLP）范式发现，抗焦虑药物提高了中脑背侧中央灰质（DCG）厌恶刺激的阈值，并且这种药物的增强作用被荷包牡丹碱等GABA受体阻断剂所拮抗。最后，研究了通过结合脑刺激奖赏与厌恶（如足部电击或DCG刺激）是否能建立冲突情境。结果表明，不仅脑刺激奖赏与足部电击厌恶相结合，而且脑刺激奖赏与DCG刺激厌恶相结合，都能建立冲突行为。此外，抗焦虑药物在这两种情境中均表现出抗冲突作用。与基于乳汁奖赏和足部电击厌恶的传统方法所诱导的冲突行为相比，抗焦虑药物对颅内奖赏与厌恶所诱导的冲突行为的敏感性更高。这些结果表明，利用脑刺激的行为方法可以研究药物在脑刺激部位的直接作用机制。实际上，在本脑刺激行为研究中，苯二氮䓬类等抗焦虑药物提高了下丘脑外侧自我刺激的刺激阈值，并抑制了DCG厌恶刺激，从而导致药物的抗冲突作用。
