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 days 21-59 (the murine adolescent period), and once daily intraperitoneal injections of d-AMP or saline spanned postnatal days 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 2 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. (PsycINFO Database Record

Figure 1

Mice were given tap water (control) or water containing 3 ppm methylmercury (MeHg) from postnatal day (PND) 21 through 59. Within these groups, mice received acute i.p. injections of saline or d-amphetamine (d-AMP; 1.0 mg/kg/day) from PND 28 through 42.

Figure 2

Left panel: Mean (±SD) estimated water consumption (triangles, left axis) and body mass (circles, right axis) for mice exposed to MeHg alone and MeHg + d-AMP during adolescence. Mean water consumption and body mass for Control are shown also for comparison. Right panel: Mean estimated dose of MeHg for mice exposed to MeHg alone and MeHg + d-AMP during adolescence. Note all error bars represent one standard deviation.

Figure 3

Representative data from four mice for the first reversal (left column), second reversal (middle column) and extradimensional shift (right column). Each row of panels presents data from an individual mouse in Control (Mouse 101), MeHg (Mouse 309), d-AMP (Mouse 201), and MeHg + d-AMP (Mouse 410). The best fit of Eq. 1, showing the probability of a correct response [p(correct)] as a function of trial, is shown as the solid line with its corresponding parameter estimates. Trial-by-trial responses are shown as vertical dashes at the bottom of each panel, classified as left and right responses (for the reversals) or light and no-light responses (for the extradimensional shift). Trial 0 indicates when a reversal or extradimensional shift was imposed, and data from trials before Trial 0 show performance in the last three sessions of the previous experimental phase. The first correct lever (left or right) experienced was counterbalanced, but data are presented as if all subjects experienced the same lever first. Note the X-axis for Mouse 309 in the extradimensional shift had to be expanded to incorporate his entire data set.

Figure 4

Top row: Probability of a correct response [p (correct)] as a function of trial across each experimental phase for the four treatment groups. Lines were generated using mean parameter estimates from Eq. 1. Bottom row: Parameter estimates (+SEM) derived from Eq. 1 of trials to half-max (left), asymptotic accuracy (middle), and slope of the transition (right) for the first reversal (R1), second reversal (R2), and extradimensional shift (EDS). *p < .05 relative to Control

Figure 5

Mean (+SEM) errors (left) and omissions (right) to criterion for mice exposed to MeHg, d-AMP, MeHg + d-AMP, and controls during adolescence. The original discrimination (OD), first reversal (R1), and second reversal (R2) of the spatial discrimination as well as the extradimensional shift (EDS) to a visual discrimination are shown. *p < .05 relative to Control