Alterations in central nervous system serotonergic and dopaminergic synaptic activity in adulthood after prenatal or neonatal chlorpyrifos exposure

Abstract

Exposure to chlorpyrifos (CPF) alters neuronal development of serotonin (5HT) and dopamine systems, and we recently found long-term alterations in behaviors related to 5HT function. To characterize the synaptic mechanisms underlying these effects, we exposed developing rats to CPF regimens below the threshold for systemic toxicity, in three treatment windows: gestational days (GD) 17-20, postnatal days (PN) 1-4, or PN11-14. In early adulthood (PN60), we assessed basal neurotransmitter content and synaptic activity (turnover) in brain regions containing the major 5HT and dopamine projections. CPF exposure on GD17-20 or PN1-4 evoked long-term increases in 5HT turnover across multiple regions; the effects were not secondary to changes in neurotransmitter content, which was unaffected or even decreased. When the treatment window was shifted to PN11-14, there were no long-term effects. Dopamine turnover also showed significant increases after CPF exposure on GD17-20, but only when the dose was raised above the threshold for overt toxicity; however, hippocampal dopamine content was profoundly subnormal after exposures below or above the acute, toxic threshold, suggesting outright neurotoxicity. These results indicate that, in a critical developmental period, apparently nontoxic exposures to CPF produce lasting activation of 5HT systems in association with 5HT-associated behavioral anomalies.

Figure 1

Effects of GD17–20 CPF exposure on (A) 5HT content and (B) turnover. ANOVA across treatment, region, and sex: (A), treatment, p < 0.03; control versus 5 mg/kg, p < 0.03; (B), treatment, p < 0.007; control versus 1 mg/kg, p < 0.05; control versus 5 mg/kg, p < 0.002. Separate ANOVAs were not conducted for each region because of the absence of treatment × region interactions. Similarly, values are shown combined for males and females because of the lack of treatment × sex interactions.

Figure 2

Effects of GD17–20 CPF exposure on (A) DA content and (B) turnover. ANOVA across treatment, region, and sex: (A), treatment, p < 0.04; treatment × region, p < 0.02; (B), treatment, p < 0.007; treatment × region, p < 0.02. *Individual treatments and regions are significantly different; values are shown combined for males and females because of the lack of treatment × sex interactions.

Figure 3

Effects of PN1–4 CPF (1 mg/kg) exposure on (A) 5HT content and (B) turnover. ANOVA across treatment, region, and sex: (A), treatment × sex, p < 0.04; male, not significant; female, p < 0.03; (B), treatment, p < 0.0001 (separate ANOVAs for males and females were not evaluated because of the lack of a treatment × sex interaction). Separate ANOVAs were not conducted for each region because of the absence of treatment × region interactions.

Figure 4

Effects of PN11–14 CPF (5 mg/kg) exposure on (A) 5HT content and (B) turnover. ANOVA across treatment, region, and sex: not significant. Separate ANOVAs were not conducted for each region because of the absence of treatment × region interactions; similarly, values are shown combined for males and females because of the lack of treatment × sex interactions.