Doxycycline reversal of amphetamine-induced mania-like behavior is related to adjusting brain monoamine abnormalities and antioxidant effects in primary hippocampal neurons

Mania is associated with disturbed dopaminergic transmission in frontotemporal regions. D-amphetamine (AMPH) causes increased extracellular DA levels, considered an acknowledged mania model in rodents. Doxycycline (DOXY) is a second-generation tetracycline with promising neuroprotective properties. Here, we tested the hypothesis that DOXY alone or combined with Lithium (Li) could reverse AMPH-induced mania-like behavioral alterations in mice by the modulation of monoamine levels in brain areas related to mood regulation, as well as cytoprotective and antioxidant effects in hippocampal neurons. Male Swiss mice received AMPH or saline intraperitoneal (IP) injections for 14 days. Between days 8–14, mice receive further IP doses of DOXY, Li, or their combination. For in vitro studies, we exposed hippocampal neurons to DOXY in the presence or absence of AMPH. DOXY alone or combined with Li reversed AMPH-induced risk-taking behavior and hyperlocomotion. DOXY also reversed AMPH-induced hippocampal and striatal hyperdopaminergia. In AMPH-exposed hippocampal neurons, DOXY alone and combined with Li presented cytoprotective and antioxidant effects, while DOXY+Li also increased the expression of phospho-Ser133-CREB. Our results add novel evidence for DOXY’s ability to reverse mania-like features while revealing that antidopaminergic activity in some brain areas, such as the hippocampus and striatum, as well as hippocampal cytoprotective effects may account for this drug’s antimanic action. This study provides additional rationale for designing clinical trials investigating its potential as a mood stabilizer agent. Graphical Abstract Doxycycline combined with Lithium reversed mania-like features induced by D-amphetamine (AMPH), notably risk-taking and vigor-like behaviors and hyperdopaminergic state in mice brain. This combination protected hippocampal neurons in vitro from increased oxidative damage and cytotoxicity. An increase in dopamine transporter (DAT) expression and CREB phospho-activation are potential underlying mechanisms. Abbreviations: AMH: amphetamine; CREB: cAMP response element binding protein; DA: dopamine: DAT: dopamine transporter; NE: noradrenaline. Created with BioRender.com