Protective effects of alpha-lipoic acid on anxiety-like behavior, memory and prevention of hippocampal oxidative stress in methamphetamine-treated rats.

RATIONALE: Alpha-lipoic acid is an essential cofactor for aerobic metabolism and acts as a potent antioxidant in the body. It has been shown that acute exposure to methamphetamine induces oxidative stress, which is responsible for severe cognitive deficits in animals. The hippocampus plays a crucial role in the processing of memory and anxiety-like behavior. OBJECTIVES: In this study, preventive effect of the alpha-lipoic acid on memory impairment in methamphetamine-induced neurotoxicity was investigated. METHODS: Wistar male rats (200-220 g) were allocated to five groups (seven rats in each group): (1) saline + saline, (2) saline + vehicle (sunflower oil as alpha-lipoic acid solvent), (3) methamphetamine + vehicle, (4) methamphetamine + alpha-lipoic acid 10 mg/kg, and (5) methamphetamine + alpha-lipoic acid 40 mg/kg. Rats received intraperitoneal methamphetamine repeatedly (2 × 20 mg/kg, 2 h interval). Alpha-lipoic acid was injected 30 min, 24 h, and 48 h after the last injection of methamphetamine. The passive avoidance test and open field were used for evaluation of memory retrieval and anxiety, respectively. After behavioral test, rats were anesthetized, their brains were extracted, and after preparing hippocampal homogenates, malondialdehyde (MDA) level, catalase, and superoxide dismutase (SOD) activities were evaluated. RESULTS: Statistical analysis showed that injection of saline or sunflower oil had no significant effect on anxiety, memory, or oxidative stress markers. Methamphetamine induced memory impairment, increased anxiety-like behavior and MDA level, but it reduced catalase and SOD activity. Treatment with alpha-lipoic acid decreased MDA, increased catalase and SOD activity, and also prevented memory impairment and anxiety-like behavior. Our results showed that alpha-lipoic acid protected the hippocampus from oxidative stress by elevating SOD and CAT activities and reduced memory impairment following acute methamphetamine injection. These findings suggest that alpha-lipoic acid may have a protective effect against the adverse effects of methamphetamine exposure on the hippocampus. Therefore, the current data indicated that ALA can reduce oxidative stress predominantly by its antioxidant property.

Orexin A presynaptically decreases inhibitory synaptic transmission in rat locus coeruleus neurons.

Locus coeruleus nucleus (LC) is a major noradrenergic nucleus in the brain. It receives dense orexinergic projections from lateral hypothalamus. Whilst it is known that orexin A increases firing rate of LC neurons, its effect on spontaneous and evoked inhibitory postsynaptic currents (sIPSCs and eIPSCs, respectively) has not been yet identified. In this research, we investigated the effect of orexin A on eIPSCs and sIPSCs in LC neurons. Whole-cell recordings revealed that orexin A suppresses eIPSCs amplitude in which this effect was blocked by an orexin type-1 receptors antagonist (SB-334867) and cannabinoid type-1 (CB1) receptors antagonist (AM251). Moreover, exposure of neurons to BAPTA (Ca2+ chelator) and U73122 (phospholipase C inhibitor) prevented orexin A-induced eIPSCs depression. On the other hand, orexin A increased pair pulse ratio and sIPSCs frequency but had no effect on sIPSCs amplitude. Our results revealed that eIPSCs suppression in the LC is mediated by CB1 receptor through a presynaptic mechanism.