Psychostimulant-induced reinstatement of place preferences have been used to investigate underlying physiological mechanisms mediating drug-seeking behavior in adolescent and adult rodents; however, it is still unclear how psychostimulant exposure during adolescence affects neuronal communication in the mesolimbic dopamine (DA) pathway and whether these changes would elicit enhanced drug-seeking behavior later in adulthood. The aim of the present study was to investigate the effects of intra-ventral tegmental area (VTA) or intra-nucleus accumbens septi (NAcc) DA D2 receptor antagonist infusions on cocaine-induced reinstatement of cocaine place conditioning in high and low responders for cocaine reward. Adolescent rats were exposed to cocaine place conditioning [postnatal day (PND 28-39)] and divided into high and low responders for cocaine reward based on their place preference expression score. Place preferences were extinguished and guide cannula were implanted into either the VTA or NAcc followed by one of the following: 1) intra-VTA or intra-NAcc infusion of the DA D2 receptor antagonist sulpiride (100 µM) during a cocaine-primed reinstatement test (10 mg/kg/ip cocaine) or 2) measurement of NAcc DA levels during intra-VTA or intra-NAcc infusion of sulpiride (100 µM), a cocaine prime (10 mg/kg cocaine) and re-exposure to the cocaine paired chamber. Infusion of sulpiride into the VTA but not the NAcc blocked reinstatement of cocaine place conditioning in rats exposed to cocaine during adolescence. Furthermore, re-exposure to cocaine-associated cues and simultaneous local infusion of sulpiride into either the VTA or NAcc attenuated cocaine-induced increases in accumbal DA levels for rats pretreated with cocaine during adolescence, regardless of phenotype. These data suggest intrinsic compensatory mechanisms in the mesolimbic DA pathway mediate adolescent behavioral responsivity to cocaine prime-induced reinstatement of cocaine place conditioning later on in adulthood.

In humans, adolescent exposure to illicit drugs predicts the onset of adult drug abuse and suggests that early drug use potentiates adolescent vulnerability to drug addiction. In experiment 1, it was hypothesized that adolescent rats would show a CPP for a low cocaine dose if in fact adolescents are more vulnerable to cocaine's rewarding effects. Place preferences were measured in early adolescent [postnatal day (PND) 35], late adolescent (PND 45) and young adult (PND 60) rats by injecting either 0, 5 or 20 mg/kg cocaine and conditioning them to environmental cues in a 2-chamber place conditioning apparatus. Significant cocaine preferences were found for all ages at the high dose. Interestingly, PND 35's were the only age group to have a CPP at the low dose suggesting that PND 35 rats are more sensitive than late adolescent and young adult rats to cocaine's rewarding effects. In Experiment 2, it was hypothesized that age-related differences in cocaine CPP may be mediated by differences in the mesolimbic dopaminergic (DA) system throughout development. Extracellular DA levels in the nucleus accumbens septi (NAcc) of early adolescent, late adolescent and adult rats were measured via quantitative microdialysis. PND 35, PND 45 and PND 60 rats were injected daily with either 5 mg/kg/ip or saline for 4 days, surgically implanted with a microdialysis probe aimed at the NAcc. Rats were perfused with either 0, 1, 10 or 40 nM DA and the extracellular DA concentration was measured. Our results show that adolescents differ from adults in basal DA with PND 35 rats having low basal DA (0.4 nM), PND 45 rats having high basal DA (1.8 nM) and PND 60 rats having intermediate basal DA (1.3 nM). PND 45 cocaine treated rats showed a 58% decrease in basal DA. All cocaine treated rats, regardless of age, showed a significant increase in DA over baseline in response to a cocaine challenge. Additionally, there were age-related differences in the extraction fraction (Ed), an indirect measure of DA reuptake, with PND 45 and PND 60's showing a decrease in basal Ed, an effect absent in PND 35's. Together these findings suggest that there are substantial ontogenetic differences in extracellular DA and DA reuptake and that these differences may provide an explanation for adolescent vulnerability to addiction. Future research should investigate DA supply and degradation processes in naïve and cocaine treated adolescent rats and vulnerability to addiction.