Cabral Alicia, Ruggiero Rafael N, Nobre Manoel J, Brandão Marcus L, Castilho Vanessa M
Instituto de Neurociências & Comportamento-IneC, Campus USP, Ribeirão Preto, SP, 14040-901, Brazil.
Prog Neuropsychopharmacol Biol Psychiatry. 2009 Mar 17;33(2):334-44. doi: 10.1016/j.pnpbp.2008.12.012. Epub 2008 Dec 25.
Anxiety is an affective symptom common to withdrawal from acute or chronic opiate treatment. Although the potentiation of the acoustic startle reflex has been proposed as an index of increased anxiety, there are variable effects of the opiate withdrawal on the startle reflex in chronic dependence models. On the other hand, withdrawal from acute morphine treatment consistently potentiates the acoustic startle reflex, a response that seems to be mediated by the central nucleus of the amygdala (CeA). However, the underlying neurochemical mechanisms have not been elucidated yet. In the present study, we firstly made a comparison between the effects of the withdrawal from both acute and chronic treatments with morphine on the motor activity and the anxiety-like behavior of rats tested in two experimental models, the acoustic startle reflex and the open-field tests. Our second objective was to investigate the role of GABAergic and opioid mechanisms of the CeA in the modulation of the withdrawal-potentiated startle as a measure of anxiety induced by morphine withdrawal. For the production of chronic dependence, rats received morphine injections (10 mg/kg; s.c.) twice daily during 10 days. Forty-eight hours after the interruption of this treatment, independent groups were probed in the startle reflex and open-field tests. For the acute dependence model, groups of rats were tested in the open field and startle tests under control conditions and under withdrawal from a single injection of morphine (10 mg/kg; s.c.) precipitated by naltrexone injections (0.1 mg/kg; s.c.). The results obtained showed that withdrawal from chronic and acute morphine treatments produced anxiety-like behavior in the open field test, although the anxiogenic-like effects could not be dissociated from the motor effects in the acute dependence model. On the other hand, only the withdrawal from acute morphine treatment significantly potentiated the startle response. Next, we examined the effects of intra-CeA microinjections of muscimol-a GABA(A) receptors agonist-and DAMGO-a mu-opioid receptors agonist-on the potentiated startle induced by acute morphine withdrawal. The results obtained showed that intra-CeA injections of muscimol (1 nmol) and DAMGO (0.5 and 1 nmol) significantly inhibited this response. These findings suggest that the acute dependence model is more suitable to study the aversive effects of morphine withdrawal on the acoustic startle response than the chronic opiate dependence model. Besides, mechanisms mediated by mu- and GABA(A)-receptors in the CeA appear to exert an inhibitory influence on the anxiety-like behavior induced by withdrawal from acute morphine treatment.
焦虑是急性或慢性阿片类药物治疗戒断时常见的情感症状。虽然有人提出听觉惊吓反射增强可作为焦虑增加的指标，但在慢性依赖模型中，阿片类药物戒断对惊吓反射有不同的影响。另一方面，急性吗啡治疗戒断会持续增强听觉惊吓反射，这种反应似乎由杏仁核中央核（CeA）介导。然而，其潜在的神经化学机制尚未阐明。在本研究中，我们首先比较了急性和慢性吗啡治疗戒断对大鼠运动活动和焦虑样行为的影响，这些行为在听觉惊吓反射和旷场试验这两种实验模型中进行测试。我们的第二个目标是研究CeA的GABA能和阿片类机制在调节戒断增强的惊吓反应中的作用，以此作为吗啡戒断诱导焦虑的指标。为了产生慢性依赖，大鼠在10天内每天两次接受吗啡注射（10mg/kg；皮下注射）。中断该治疗48小时后，独立的组在惊吓反射和旷场试验中接受测试。对于急性依赖模型，将大鼠组在对照条件下以及在由纳曲酮注射（0.1mg/kg；皮下注射）引发的单次吗啡注射（10mg/kg；皮下注射）戒断情况下进行旷场和惊吓试验。获得的结果表明，慢性和急性吗啡治疗戒断在旷场试验中产生了焦虑样行为，尽管在急性依赖模型中，这种致焦虑样效应无法与运动效应区分开来。另一方面，只有急性吗啡治疗戒断显著增强了惊吓反应。接下来，我们研究了向CeA内微量注射蝇蕈醇（一种GABA(A)受体激动剂）和DAMGO（一种μ-阿片受体激动剂）对急性吗啡戒断诱导增强的惊吓反应的影响。获得的结果表明，向CeA内注射蝇蕈醇（1nmol）和DAMGO（0.5和1nmol）显著抑制了这种反应。这些发现表明，与慢性阿片类药物依赖模型相比，急性依赖模型更适合研究吗啡戒断对听觉惊吓反应的厌恶效应。此外，CeA中由μ-和GABA(A)-受体介导的机制似乎对急性吗啡治疗戒断诱导的焦虑样行为发挥抑制作用。
