Effects of adolescent exposure to methylmercury and d-amphetamine on reversal learning and an extradimensional shift in male mice.

Abstract

Adolescence is associated with the continued maturation of dopamine neurotransmission and is implicated in the etiology of many psychiatric illnesses. Adolescent exposure to neurotoxicants that distort dopamine neurotransmission, such as methylmercury (MeHg), may modify the effects of chronic d-amphetamine (d-AMP) administration on reversal learning and attentional-set shifting. Male C57Bl/6n mice were randomly assigned to two MeHg-exposure groups (0 ppm and 3 ppm) and two d-AMP-exposure groups (saline and 1 mg/kg/day), producing four treatment groups (n = 10–12/group): Control, MeHg, d-AMP, and MeHg + d-AMP. MeHg exposure (via drinking water) spanned postnatal day 21–59 (the murine adolescent period), and once daily i.p. injections of d-AMP or saline spanned postnatal day 28–42. As adults, mice were trained on a spatial-discrimination-reversal (SDR) task in which the spatial location of a lever press predicted reinforcement. Following two SDRs, a visual-discrimination task (extradimensional shift) was instated in which the presence of a stimulus light above a lever predicted reinforcement. Responding was modeled using a logistic function, which estimated the rate (slope) of a behavioral transition and trials required to complete half a transition (half-max). MeHg, d-AMP, and MeHg + d-AMP exposure increased estimates of half-max on the second reversal. MeHg exposure increased half-max and decreased the slope term following the extradimensional shift, but these effects did not occur following MeHg + d-AMP exposure. MeHg + d-AMP exposure produced more perseverative errors and omissions following a reversal. Adolescent exposure to MeHg can modify the behavioral effects of chronic d-AMP administration.

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

“…Adolescent d-AMP administration impairs reversal learning in rodents (Boomhower and Newland, 2017;Hankosky et al, 2013), but no impairment was reported in monkeys (Soto et al, 2012). In combination with adolescent MeHg exposure, chronic d-AMP enhanced the effects of MeHg on reversal learning but prevented MeHg-induced impairment on an extradimensional shift (Boomhower and Newland, 2017). These findings suggest the adolescent brain may be vulnerable to d-AMP and MeHg exposure, both alone and in combination.…”

“…All mice had previous experience pressing levers (see Boomhower & Newland, 2017 for details) so lever-press training was not necessary for this experiment. At approximately PND 200, mice were trained on a multiple fixed-ratio (FR) schedule of reinforcement based on Reilly (2003) with some modifications.…”

“…The control and d-AMP groups were given tap water, and the MeHg and d-AMP + MeHg groups were given 3 ppm MeHg (calculated as Hg) as methylmercuric chloride (Sigma) dissolved in their drinking water. MeHg exposure spanned PND 21 through 59 ( Figure 2) and resulted in a daily dose of about 400 μg/kg MeHg (see Boomhower and Newland, 2017).…”

“…d-AMP also increases striatal and prefrontal cortical DA (Andersen et al, 2001) but the effects of chronic adolescent d-AMP on choice in adulthood are mixed. Adolescent d-AMP administration impairs reversal learning in rodents (Boomhower and Newland, 2017;Hankosky et al, 2013), but no impairment was reported in monkeys (Soto et al, 2012). In combination with adolescent MeHg exposure, chronic d-AMP enhanced the effects of MeHg on reversal learning but prevented MeHg-induced impairment on an extradimensional shift (Boomhower and Newland, 2017).…”

“…MeHg increases DA efflux and inhibits DA reuptake both in vitro and in the striatum of behaving rats (Dreiem et al, 2009;Faro et al, 2002). Adolescent MeHg exposure dose-dependently reduces sensitivity to reinforcement magnitude (Boomhower and Newland, 2016) and slows spatial-discrimination reversals and extradimensional shift in adult mice (Boomhower and Newland, 2017). d-AMP also increases striatal and prefrontal cortical DA (Andersen et al, 2001) but the effects of chronic adolescent d-AMP on choice in adulthood are mixed.…”