Effects of alpha-lipoic acid in an animal model of mania induced by d-amphetamine

Macêdo DS, Medeiros CD, Cordeiro RC, Sousa FC, Santos JV, Morais TA, Hyphantis TN, McIntyre RS, Quevedo J, Carvalho AF. Effects of alpha‐lipoic acid in an animal model of mania induced by d‐amphetamine. Bipolar Disord 2012: 14: 707–718. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S Objectives: Oxidative stress and neurotrophic factors are involved in the pathophysiology of bipolar disorder (BD). Alpha‐lipoic acid (ALA) is a naturally occurring compound with strong antioxidant properties. The present study investigated ALA effects in an amphetamine‐induced model of mania. Methods: In the reversal protocol, adult mice were first given d‐amphetamine (AMPH) 2 mg/kg, intraperitoneally (i.p.) or saline for 14 days. Between days 8 and 14, the animals received ALA 50 or 100 mg/kg orally, lithium (Li) 47.5 mg/kg i.p., or saline. In the prevention paradigm, mice were pretreated with ALA, Li, or saline prior to AMPH. Locomotor activity was assessed in the open‐field task. Superoxide dismutase (SOD) activity, reduced glutathione (GSH), and thiobarbituric acid‐reactive substance (TBARS) levels were evaluated in the prefrontal cortex (PFC), hippocampus (HC), and striatum (ST). Brain‐derived neurotrophic factor (BDNF) levels were measured in the HC. Results: ALA and Li prevented and reversed the AMPH‐induced increase in locomotor activity. Prevention model: ALA and Li co‐administration with AMPH prevented the decrease in SOD activity induced by AMPH in the HC and ST, respectively; ALA and Li prevented GSH alteration in the HC and TBARS formation in all brain areas studied. Reversal model: ALA reversed the decrease in SOD activity in the ST. TBARS formation was reversed by ALA and Li in all brain areas. Furthermore, ALA reversed AMPH‐induced decreases in BDNF and GSH in the HC. Conclusions: Our findings showed that ALA, similarly to Li, is effective in reversing and preventing AMPH‐induced behavioral and neurochemical alterations, providing a rationale for the design of clinical trials investigating ALA’s possible antimanic effect.