Antimanic activity of minocycline in a GBR12909-induced model of mania in mice: Possible role of antioxidant and neurotrophic mechanisms.

Background: Mania/hypomania is the cardinal feature of bipolar disorder. Recently, single administration of the dopamine transporter (DAT) inhibitor, GBR12909, was related to mania-like alterations. In the present study we aimed at testing behavioral and brain oxidant/neurotrophic alterations induced by the repeated administration of GBR12909 and its prevention/reversal by the mood stabilizing drugs, lithium (Li) and valproate (VAL) as well as by the neuroprotective drug, minocycline (Mino).

Methods: Adult Swiss mice were submitted to 14 days protocols namely prevention and reversal. In the reversal protocol mice were given GBR12909 or saline and between days 8 and 14 received Li, VAL, Mino (25 or 50mg/kg) or saline. In the prevention treatment, mice were pretreated with Li, VAL, Mino or saline prior to GBR12909.

Results: GBR12909 repeated administration induced hyperlocomotion and increased risk taking behavior that were prevented and reversed by the mood stabilizers and both doses of Mino. Li, VAL or Mino were more effective in the reversal of striatal GSH alterations induced by GBR12909. Regarding lipid peroxidation Mino was more effective in the prevention and reversal of lipid peroxidation in the hippocampus whereas Li and VAL prevented this alteration in the striatum and PFC. Li, VAL and Mino25 reversed the decrease in BDNF levels induced by GBR12909.

Conclusion: GBR12909 repeated administration resembles manic phenotype. Similarly to classical mood-stabilizing agents, Mino prevented and reversed GBR12909 manic-like behavior in mice. Thus, our data provide preclinical support to the design of trials investigating Mino's possible antimanic effects.