Sex and temporally-dependent effects of methamphetamine toxicity on dopamine markers and signaling pathways

Methamphetamine induces a greater neurodegenerative effect in male versus female mice. In order to investigate this sex difference we studied the involvement of Akt and extracellular signal-regulated kinase (ERK1/2) in methamphetamine toxicity as a function of time post-treatment (30 min, 1 and 3 days). Methamphetamine-induced decreases in dopamine concentrations and dopamine transporter (DAT) specific binding in the medial striatum were similar in female and male mice when evaluated 1 day post-methamphetamine (40 mg/kg). At 3 days post-methamphetamine, striatal dopamine concentration and DAT specific binding continued to decline in males, whereas females showed a recovery with increases in dopamine content and DAT specific binding in medial striatum at day 3 versus day 1 post-methamphetamine. The reduction in striatal vesicular monoamine transporter 2 specific binding observed at 1 and 3 days post-methamphetamine showed neither a sex- nor temporal-dependant effect. Under the present experimental conditions, methamphetamine treatments had modest effects on dopamine markers measured in the substantia nigra. Proteins assessed by Western blots showed similar reductions in both female and male mice for DAT proteins at 1 and 3 days post-methamphetamine. An increase in the phosphorylation of striatal Akt (after 1 day), glycogen synthase kinase 3β (at 1 and 3 days) and ERK1/2 (30 min post-methamphetamine) was only observed in females. Striatal glial fibrillary acidic protein levels were augmented in both females and males at 3 days post-methamphetamine. These results reveal some of the sex- and temporally-dependent effects of methamphetamine toxicity on dopaminergic markers and suggest some of the signaling pathways associated with these responses.

► Female and male mice are initially comparably affected by methamphetamine treatment.
► 3 days post-methamphetamine, females show a rapid capacity for recovery.
► In contrast to females, an increase toxicity is present in males.
► Akt and ERK1/2 are both activated in females and precede the recovery process.
► ERK activation occurs shortly and phosphorylated Akt/GSK3β increase at day 1.