PMAT Deficiency Sex‐Selectively Contributes to Cocaine and Amphetamine Locomotor Sensitization

Abstract

Background The plasma membrane monoamine transporter (PMAT) is a polyspecific cation transporter that, in the brain, predominantly takes up monoamines such as dopamine and serotonin. We hypothesize the functional contribution of PMAT emerges when impairment of higher affinity transporters, including dopamine transporter (DAT) or serotonin transporter (SERT), occurs. An example would be under conditions of pharmacological blockade, as occurs from psychostimulants like cocaine, which inhibits both DAT and SERT, or D-amphetamine, which reverses transport of dopamine by DAT. No studies have evaluated the contribution of PMAT to psychostimulant responses. Mice constitutively deficient in PMAT were utilized for the present experiments, because no selective inhibitor of PMAT currently exists. We hypothesized that relative to wildtype controls, mice with reduced or diminished PMAT function would exhibit augmented cocaine and D-amphetamine sensitization, because compensatory monoamine uptake by PMAT is impaired in these mice when DAT and SERT are pharmacologically inhibited. Methods To analyze the effects of cocaine and amphetamine in PMAT-deficient mice, males and females went through a cocaine- or D-amphetamine-induced locomotor sensitization paradigm for 5 total days. Each day, after a baseline test (30 min) of locomotor activity in an open field arena, injections of saline (vehicle) then cocaine or D-amphetamine were administered. Subsequent locomotor responses to each injection were recorded in 10-minute intervals using ANY-maze software. The total (cumulative) doses used for cocaine were 5-40 mg/kg every day for 5 days; for D-amphetamine, 0.1-4.62 mg/kg every 3 days for a total of 5 days of injections. The drug dose-response for each day was converted to an area under the curve (AUC), and sensitization was assessed by normalizing each day's AUC to the first injection day (Day 1) AUC. Data were analyzed using a two-way repeated measures ANOVA, with Tukey's post-hoc tests. Results : Preliminary data indicate a sex-specific effect of PMAT deficiency on cocaine-induced locomotor sensitization, where male heterozygous mice had reduced sensitization to cocaine relative to wildtypes. Our data also revealed decreased responses to D-amphetamine in female PMAT-deficient mice relative to same-sex wildtypes. However, male heterozygotes exhibited augmented D-amphetamine sensitization relative to male knockouts (trending vs wildtypes). Conclusion Our findings suggest PMAT deficiency attenuates cocaine-induced locomotor sensitization in males but not females, and that partial PMAT deletion sex-specifically affects D-amphetamine-induced locomotor sensitization. These results indicate that PMAT is not inhibited by cocaine, but PMAT contributes to D-amphetamine-induced dopamine efflux. Moreover, PMAT may sex-specifically influence psychostimulant sensitization processes. Future examinations will determine how PMAT function might influence other dimensions related to psychostimulant use and abuse, such as subjective drug experience and drug reinforcing effects.