Zanoveli Janaina M, Nogueira Regina L, Zangrossi Hélio
Department of Pharmacology, School of Medicine, University of São Paulo, 14049-900 Ribeirão Preto, SP, Brazil.
Eur J Pharmacol. 2003 Jul 25;473(2-3):153-61. doi: 10.1016/s0014-2999(03)01970-8.
The dorsal periaqueductal gray has been implicated in the modulation of escape behavior, a defensive behavior that has been related to panic disorder. Intra-dorsal periaqueductal gray injection of serotonin or drugs that mimic its effects inhibits escape induced by electrical or chemical stimulation of this brainstem area. In this study, we investigate whether intra-dorsal periaqueductal gray injection of 5-HT receptor agonists attenuates escape generated by an ethologically based model of anxiety, the elevated T-maze. This test also allows the measurement of inhibitory avoidance, which has been related to generalized anxiety disorder. The effects of the 5-HT receptor agonists were compared in animals with or without a previous exposure to the open arms of the elevated T-maze. In these two test conditions, intra-dorsal periaqueductal gray injection of the endogenous agonist serotonin or the 5-HT(2B/2C) receptor agonist m-chlorophenylpiperazine (mCPP) enhanced inhibitory avoidance, suggesting an anxiogenic effect. The 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) impaired this response, suggesting an anxiolytic effect, and the preferential 5-HT2A receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) was ineffective. All these agonists inhibited escape behavior. Apart from mCPP, the effect on escape was detected only in animals pre-exposed to the open arm. None of the drugs tested affected locomotion in the open-field test. Taken altogether, our findings suggest that 5-HT1A and 5-HT2c receptors in the dorsal periaqueductal gray exert opposed control on inhibitory avoidance, implicating these receptors in anxiety conditioning. As previously observed in tests employing the aversive stimulation of the dorsal periaqueductal gray, 5-HT1A and 5-HT2A receptors in this brain area are involved in escape inhibition. Therefore, in different animal models, the activation of these two subtypes of receptors in the dorsal periaqueductal gray consistently attenuates the expression of a panic-related behavior.
中脑导水管周围灰质背侧与逃避行为的调节有关，逃避行为是一种与惊恐障碍相关的防御行为。向中脑导水管周围灰质背侧注射5-羟色胺或模拟其作用的药物，可抑制由该脑干区域的电刺激或化学刺激所诱发的逃避行为。在本研究中，我们探究向中脑导水管周围灰质背侧注射5-羟色胺受体激动剂是否能减弱由基于行为学的焦虑模型——高架T迷宫所产生的逃避行为。该测试还可测量抑制性回避，其与广泛性焦虑障碍有关。在曾暴露于高架T迷宫开放臂或未暴露于高架T迷宫开放臂的动物中，比较了5-羟色胺受体激动剂的作用。在这两种测试条件下，向中脑导水管周围灰质背侧注射内源性激动剂5-羟色胺或5-羟色胺（2B/2C）受体激动剂间氯苯哌嗪（mCPP）可增强抑制性回避，提示有致焦虑作用。5-羟色胺1A受体激动剂8-羟基-2-（二正丙基氨基）四氢萘（8-OH-DPAT）损害了这种反应，提示有抗焦虑作用，而选择性5-羟色胺2A受体激动剂2,5-二甲氧基-4-碘苯丙胺（DOI）则无效。所有这些激动剂均抑制逃避行为。除mCPP外，仅在预先暴露于开放臂的动物中检测到对逃避行为的影响。所测试的药物均未影响旷场试验中的运动。综上所述，我们的研究结果表明，中脑导水管周围灰质背侧的5-羟色胺1A和5-羟色胺2C受体对抑制性回避发挥相反的控制作用，提示这些受体参与焦虑条件反射。如先前在采用中脑导水管周围灰质背侧厌恶性刺激的试验中所观察到的，该脑区的5-羟色胺1A和5-羟色胺2A受体参与逃避抑制。因此，在不同的动物模型中，中脑导水管周围灰质背侧这两种受体亚型的激活均持续减弱与惊恐相关行为的表达。
