The neurobiological mechanisms underlying the pathophysiology and
therapeutics of
bipolar disorder are still unknown. In recent years,
protein kinase C (PKC) has emerged as a potential key player in
mania. To further investigate the role of this signaling system in mood regulation, we examined the effects of PKC modulators in behavioral tests modeling several facets of
bipolar disorder and in adult hippocampal cell proliferation in rats. Our results showed that a single injection of the PKC inhibitors
tamoxifen (80 mg/kg, i.p.) and
chelerythrine (3 mg/kg, s.c.) attenuated
amphetamine-induced hyperlocomotion and decreased risk-taking behavior, supporting the efficacy of PKC blockade in acute
mania. Moreover, chronic exposure to
tamoxifen (10 mg/kg/day, i.p., for 14 days) or
chelerythrine (0.3 mg/kg/day, s.c., for 14 days) caused depressive-like behavior in the forced swim test, and resulted in a reduction of cell proliferation in the dentate gyrus of the hippocampus. Finally, we showed that, contrary to the PKC inhibitors, the PKC activator
phorbol 12-myristate 13-acetate (PMA) enhanced risk-taking behavior and induced an
antidepressant-like effect. Taken together, these findings support the involvement of PKC in regulating opposite facets of
bipolar disorder, and emphasize a major role for PKC in this disease.