d-Amphetamine and methylmercury exposure during adolescence alters sensitivity to monoamine uptake inhibitors in adult mice

Abstract

Gestational exposure to methylmercury (MeHg), an environmental neurotoxicant, and adolescent administration of d-amphetamine (d-AMP) disrupt dopamine neurotransmission and alter voluntary behavior in adult rodents. We determined the impact of adolescent exposure to MeHg and dAMP on monoamine neurotransmission in mice by assessing sensitivity to acute dAMP , desipramine, and clomipramine, drugs that target dopamine, norepinephrine, and serotonin reuptake, respectively. Male C57Bl/6n mice were given 0 (control) or 3 ppm MeHg via drinking water from postnatal day 21 to 60 (murine adolescence). Within each group, mice were given once-daily injections of dAMP or saline (i.p.) from postnatal day 28 to 42. This exposure regimen produced four treatment groups (n = 10-12/group): control, dAMP , MeHg, and dAMP + MeHg. As adults, the mice lever pressed under fixed-ratio schedules of reinforcement (FR 1, 5, 15, 30, 60, and 120). Acute i.p. injections of dAMP (.3-1.7 mg/kg), desipramine (5.6-30 mg/kg), and clomipramine (5.6-30 mg/kg) were administered in adulthood after a stable behavioral baseline was established. Adolescent MeHg exposure increased saturation rate and minimum response time, an effect that was mitigated by chronic administration of dAMP in adolescence. In unexposed mice, the three monoamine reuptake inhibitors had separable behavioral effects. Adolescent dAMP increased sensitivity to acute dAMP , desipramine, and clomipramine. Adolescent MeHg exposure alone did not alter drug sensitivity. Combined adolescent dAMP + MeHg exposure enhanced sensitivity to acute d-AMP's and desipramine's effects on minimum response time. Adolescence is a vulnerable developmental period during which exposure to chemicals can have lasting effects on monoamine function and behavior.

Developmental exposure to methylmercury and ADHD, a literature review of epigenetic studies

“…In another study with male rats exposed to MeHg during adolescent development, it was shown that the effects of MeHg exposure on adult neurobehaviors including attention and memory were augmented by the dopamine agonist, d-amphetamine [ 57 ]. A follow-up study concluded that adolescence was vulnerable to MeHg and d-amphetamine, and the effect persisted in adulthood [ 58 ]. These studies provide important bases for the involvement of dopamine neurotransmission system in behavioral toxicity of MeHg, particularly in the behaviors related to ADHD [ 57 ].…”