Zanoveli J M, Nogueira R L, Zangrossi H
Department of Pharmacology, School of Medicine, University of São Paulo, Ribeirão Preto, SP, Brazil.
Behav Pharmacol. 2005 Nov;16(7):543-52. doi: 10.1097/01.fbp.0000179280.05654.5a.
The dorsal periaqueductal gray matter (DPAG) has been implicated in the mediation of escape, a defensive behavior associated with panic disorder (PD). Chronic treatment with the anti-panic agent imipramine enhances the inhibitory effect on escape evoked by DPAG electrical stimulation of intra-DPAG administration of the 5-HT1A receptor agonist (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and the preferential 5-HT 2 A receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI). In the present study we further explore the hypothesis that sensitization of 5-HT1A and 5-HT 2 A receptors in the DPAG is involved in the anti-panic effect of imipramine. To this end, Wistar rats, subchronically or chronically treated with imipramine, were intra-DPAG injected with 8-OH-DPAT (0.4 or 3.2 nmoles) or DOI (16 nmoles), and tested in the elevated T-maze. In addition to its possible relevance to panic disorder, this test also measures inhibitory avoidance, a behavior that has been associated with generalized anxiety disorder (GAD). The effects of these 5-HT agonists in the DPAG were also investigated in animals chronically injected with buspirone, a drug clinically effective in treating GAD, but not PD. The results showed that intra-DPAG administration of the highest dose of 8-OH-DPAT and of DOI inhibited escape, and this panicolytic-like effect was significantly higher in animals previously treated chronically, but not subchronically, with imipramine. 8-OH-DPAT (0.4 nmole), although not affecting escape in animals systemically treated with saline, had a panicolytic-like effect in those receiving long-term treatment with imipramine. Microinjection of 8-OH-DPAT (3.2 nmoles), but not of DOI, impaired inhibitory avoidance, and this anxiolytic effect did not differ between animals treated with saline or imipramine. Chronic buspirone did not change the effect of 8-OH-DPAT and DOI on inhibitory avoidance and escape. Therefore, chronic imipramine seems to sensitize both 5-HT1A and 5-HT 2 A receptors in the DPAG, strengthening the view that these receptors are involved in the mode of action of anti-panic drugs.
中脑导水管周围灰质背侧（DPAG）与逃避反应的调节有关，逃避是一种与惊恐障碍（PD）相关的防御行为。用抗惊恐药物丙咪嗪进行长期治疗可增强对DPAG电刺激、向DPAG内注射5-HT1A受体激动剂（±）-8-羟基-2-（二正丙基氨基）四氢萘（8-OH-DPAT）以及优先的5-HT2A受体激动剂（±）-2,5-二甲氧基-4-碘苯丙胺盐酸盐（DOI）所诱发的逃避反应的抑制作用。在本研究中，我们进一步探讨DPAG中5-HT1A和5-HT2A受体的敏化参与丙咪嗪抗惊恐作用这一假说。为此，对经丙咪嗪亚慢性或慢性治疗的Wistar大鼠，向DPAG内注射8-OH-DPAT（0.4或3.2纳摩尔）或DOI（16纳摩尔），并在高架T迷宫中进行测试。除了其与惊恐障碍可能的相关性外，该测试还测量抑制性回避，这是一种与广泛性焦虑障碍（GAD）相关的行为。还在长期注射丁螺环酮的动物中研究了这些5-HT激动剂在DPAG中的作用，丁螺环酮是一种临床上对治疗GAD有效但对PD无效的药物。结果表明，向DPAG内注射最高剂量的8-OH-DPAT和DOI可抑制逃避反应，且这种类抗惊恐作用在先前接受丙咪嗪长期而非亚慢性治疗的动物中显著更强。8-OH-DPAT（0.4纳摩尔）虽然对全身用生理盐水处理的动物的逃避反应无影响，但对接受丙咪嗪长期治疗的动物具有类抗惊恐作用。微量注射8-OH-DPAT（3.2纳摩尔）而非DOI会损害抑制性回避，且这种抗焦虑作用在用生理盐水或丙咪嗪处理的动物之间无差异。长期使用丁螺环酮不会改变8-OH-DPAT和DOI对抑制性回避和逃避反应的作用。因此，长期使用丙咪嗪似乎会使DPAG中的5-HT1A和5-HT2A受体均发生敏化，强化了这些受体参与抗惊恐药物作用模式的观点。
