Souza-Pinto Luiz F S, Castilho Vanessa M, Brandão Marcus Lira, Nobre Manoel Jorge
Instituto de Neurociências & Comportamento - INeC, Campus USP, Av. Bandeirantes 3900, Monte Alegre, Ribeirão Preto-SP, 14040-901, Brazil.
Pharmacol Biochem Behav. 2007 Jun-Jul;87(2):250-7. doi: 10.1016/j.pbb.2007.04.021. Epub 2007 May 5.
It is well established that the most persistent sign of withdrawal from chronic benzodiazepine use in humans is anxiety. In contrast to other types of drugs of abuse, the emergence of this anxiety does not seem to be linked directly to alterations in the levels of dopamine in the mesolimbic system. Some studies have proposed that fear-like behaviors elicited by benzodiazepine withdrawal could be the result either of alterations in the sensitivity of GABAA receptors or in the neuronal hyperexcitability that results from neuroadaptative responses to chronic treatment, probably mediated by glutamate. The increased fear-like behaviors induced by benzodiazepine withdrawal are similar to the defense reaction displayed by animals exposed to dangerous situations or submitted to electrical or chemical stimulation of the dorsal periaqueductal gray (dPAG), a key structure of the brain aversive system. However, the involvement of the dPAG in drug abuse has been investigated only in the context of the physical effects of drug dependence. Thus, in this study we investigated the effects of injections into the dPAG of the glutamic acid diethyl ester (GDEE) and 2-amino-7-phosphonoheptanoate (AP-7) (AMPA-kainate and NMDA receptors antagonists, respectively) on fear-like behaviors promoted by benzodiazepine withdrawal in rats submitted to aversive events (foot-shocks) immediately before chronic diazepam administration in a conditioning place-preference paradigm, using a light-dark box. Our results showed that inhibition of the glutamatergic neurotransmission in the dPAG reduces the consequence of the diazepam withdrawal in rats, implicating the excitatory amino acids of the dPAG in the modulation of the aversive state induced by benzodiazepine drugs withdrawal.
众所周知，人类长期使用苯二氮卓类药物后最持久的戒断症状是焦虑。与其他类型的滥用药物不同，这种焦虑的出现似乎与中脑边缘系统中多巴胺水平的改变没有直接联系。一些研究提出，苯二氮卓类药物戒断引发的恐惧样行为可能是由于GABAA受体敏感性改变，或者是由对慢性治疗的神经适应性反应导致的神经元兴奋性过高所致，这可能由谷氨酸介导。苯二氮卓类药物戒断引起的恐惧样行为增加类似于动物在暴露于危险情况或接受中脑导水管周围灰质背侧（dPAG）的电刺激或化学刺激时所表现出的防御反应，dPAG是大脑厌恶系统的关键结构。然而，dPAG在药物滥用中的作用仅在药物依赖的身体影响方面进行了研究。因此，在本研究中，我们在条件性位置偏爱范式中，于慢性地西泮给药前立即对大鼠施加厌恶事件（足部电击），并使用明暗箱，研究了向dPAG注射谷氨酸二乙酯（GDEE）和2-氨基-7-膦酰庚酸（AP-7）（分别为AMPA-海人藻酸受体和NMDA受体拮抗剂）对苯二氮卓类药物戒断所促进的恐惧样行为的影响。我们的结果表明，抑制dPAG中的谷氨酸能神经传递可减轻大鼠地西泮戒断的后果，这表明dPAG中的兴奋性氨基酸参与了苯二氮卓类药物戒断所诱导的厌恶状态的调节。
