Cocaine self-administration in male and female rats perinatally exposed to PCBs: Evaluating drug use in an animal model of environmental contaminant exposure

Abstract

Polychlorinated biphenyls (PCBs) are ubiquitous environmental toxicants known to adversely impact human health. Ortho-substituted PCBs affect the nervous system, including the brain dopaminergic system. The reinforcing effects of psychostimulants are typically modulated via the dopaminergic system, so this study used a preclinical (i.e., rodent) model to evaluate whether developmental contaminant exposure altered intravenous self-administration (IV SA) for the psychostimulant cocaine. Long-Evans rats were perinatally exposed to 6 or 3 mg/kg/day of PCBs throughout gestation and lactation and compared with nonexposed controls. Rats were trained to lever press for a food reinforcer in an operant chamber under a fixed-ratio 5 (FR5) schedule and later underwent jugular catheterization. Food reinforcers were switched for infusions of 250 μg of cocaine, but the response requirement to earn the reinforcer remained. Active lever presses and infusions were higher in males during response acquisition and maintenance. The same sex effect was observed during later sessions which evaluated responding for cocaine doses ranging from 31.25-500 μg. PCB-exposed males (not females) exhibited an increase in cocaine infusions (with a similar trend in active lever presses) during acquisition, but no PCB-related differences were observed during maintenance, examination of the cocaine dose-response relationship, or progressive ratio (PR) sessions. Overall, these results indicated perinatal PCB exposure enhanced early cocaine drug-seeking in this preclinical model of developmental contaminant exposure (particularly the males), but no differences were seen during later cocaine SA sessions. As such, additional questions regarding substance abuse proclivity may be warranted in epidemiological studies evaluating environmental contaminant exposures. (PsycINFO Database Record

Figure 1

The stock solution of the Fox River PCB mix was dissolved in corn oil to yield 0, 7.5, and 15.0 mg/ml concentrations. Based on the body weight of the dam, one concentration was pipetted onto half a vanilla wafer to yield a daily PCB dose of either 0 (corn oil only; n = 11 litters), 3 (n=13 litters), or 6 mg/kg body weight (n=14 litters). Each dosed cookie was orally consumed by the dam. At weaning, one male and female from each litter were retained and at approximately 75 days of age, these offspring were food restricted (85% of free-feeding weight) and trained to lever press for a food reinforcer using an autoshaping program and fixed ratio schedule beginning around PND 90. At approximately 120 days of age, jugular catheterization surgery occurred and around PND 180, i.v. self-administration sessions began during at which point the food reinforcer was replaced with an intravenous infusion of 250 μg of cocaine. GD = gestational day, PND = postnatal day, i.v. SA = intravenous self-administration

Figure 2

The number of active lever presses (top panel) and infusions of 250 μg of cocaine (bottom panel) during the acquisition phase in male and female rats perinatally exposed to either 0 (corn oil only; n = 11 litters), 3 (n=13 litters), or 6 mg/kg body weight (n=14 litters). One male and one female offspring from each litter were tested during adulthood. (A) Although males exposed to PCBs appeared to exhibit an increase in the number of active lever presses during acquisition compared to males in the 0 mg/kg/day PCB group, the effect of PCB exposure in the males was not statistically significant (p=.064). No difference was found on the number of active lever presses that occurred during acquisition in the female offspring. Error bars represent standard error of the mean. (B) A significant effect of PCB dose on the number of cocaine infusions earned occurred in the males but not in the females. PCB exposure appeared to increase variation in the males, be extending the upper end of the distribution. Statistical analysis revealed that only the males perinatally exposed to 6 mg/kg/day PCBs received a greater number of infusions than non-exposed (i.e., 0 mg/kg/day PCBs) males. *p=.015; Error bars represent standard error of the mean.

Figure 3

The number of infusions received across the 14 days of maintenance responding in male (top panel) and female (bottom panel) rats perinatally exposed to either 0 (corn oil only; n = 11 litters), 3 (n=13 litters), or 6 mg/kg body weight (n=14 litters). One male and one female offspring from each litter were tested during adulthood. Males received more cocaine infusions (i.e., reinforcers) than females across all 14 maintenance sessions. However, there were no obvious PCB-related differences in either the males or females (see insets). Error bars represent standard error of the mean.

Figure 4

Male (top panel) and female (bottom panel) rats perinatally exposed to either 0 (corn oil only; n = 11 litters), 3 (n=13 litters), or 6 mg/kg body weight (n=14 litters) were tested across a range of cocaine doses. One male and one female offspring from each litter were tested during adulthood. Males had a higher number of infusions (i.e., reinforcers) than females and the overall number of infusions decreased with increasing cocaine dose. However, there were no PCB-related differences in either the males or females across any of the cocaine doses examined or on the total amount of cocaine self-administered during the dose-effect phase (see insets). Error bars represent standard error of the mean.

Figure 5

The breakpoint (top panel) and number of infusions (bottom panel) during the progressive ratio phase in male and female rats perinatally exposed to either 0 (corn oil only; n = 11 litters), 3 (n=13 litters), or 6 mg/kg body weight (n=14 litters). One male and one female offspring from each litter were tested during adulthood. (A) Females had a higher breakpoint than males, but there were no PCB-related differences in either the males or females. Error bars represent standard error of the mean. (B) Males earned a higher number of reinforcers than females, but there were no PCB-related differences in either the males or females. Error bars represent standard error of the mean.