Sex influences in the preventive effects of peripubertal supplementation with N-3 polyunsaturated fatty acids in mice exposed to the two-hit model of schizophrenia.

Schizophrenia is a devastating neurodevelopmental disorder. The animal model based on perinatal immune activation, as first-hit, combined with peripubertal stress, as a second hit, has gained evidence in recent years. Omega-3 polyunsaturated fatty acids (n3-PUFAs) is being a promise for schizophrenia prevention. Nevertheless, the influence of sex in schizophrenia neurobiology and prevention has been neglected. Thus, the present study evaluates the preventive effects of n3-PUFAs in both sexes' mice submitted to the two-hit model and the participation of oxidative changes in this mechanism. The two-hit consisted of polyI:C administration from postnatal days (PNs) 5-7, and unpredictable stress from PNs35-43. n3-PUFAs were administered from PNs30-60. Prepulse inhibition of the startle reflex (PPI), social interaction, and Y-maze tests were conducted between PNs70-72 to evaluate positive-, negative-, and cognitive-like schizophrenia symptoms. We assessed brain oxidative changes in brain areas and plasma. Both sexes' two-hit mice presented deficits in PPI, social interaction, and working memory that were prevented by n3-PUFAs. In two-hit females, n3-PUFAs prevented increments in nitrite levels in the prefrontal cortex (PFC), hippocampus, striatum, and plasma TBARS levels. In two-hit males, n3-PUFAs prevented the increase in TBARS in the PFC, hippocampus, and striatum. Notably, male mice that received only n3-PUFAs without hit exposure presented impairments in working memory and social interaction. These results add further preclinical evidence for n3-PUFAs as an accessible and effective alternative in preventing behavioral and oxidative changes related to schizophrenia but call attention to the need for precaution in this indication due to hit- and sex-sensitive issues.

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.