Evaluation of age differences in locomotor activity following psychostimulant administration in adolescent versus adult mice

In humans, the brain continues to develop over the course of adolescence. One implication is that drugs of abuse are likely to impact adolescents differently than adults. Rodent literature has added credibility to this idea. Following administration of an equivalent dose of psychostimulant (e.g. cocaine, amphetamine, methamphetamine), adolescent rodents are commonly observed to locomotor stimulate to a lesser magnitude than that of adults. However, recently conflicting reports have been published showing adolescents to stimulate equally or greater than adults. The cause for variability in the literature is unclear, but may be a result of genetic differences between subjects or other dissimilarities in experimental design. Therefore, in Chapter 2 adolescent (postnatal day 30) and adult (postnatal day 65) mice of both sexes from four different inbred strains (C57BL/6J, BALB/cByJ, DBA/2J, FVB/NJ) were screened for differences in locomotor stimulation following cocaine. The greatest difference in stimulation between age groups was observed in C57BL/6J, but BALB/cByJ and female FVB/NJ mice also showed attenuated stimulation in adolescents as compared to adults. Since locomotor stimulation differences were greatest in C57BL/6J mice, they were used in all subsequent chapters. Chapter 3 tests the hypothesis that attenuated stimulation in adolescents may be caused by lower concentrations of drug in the brain as compared to adults. Concentrations of cocaine and methamphetamine were measured in blood and brain samples of each age group at varying time points following administration. Overall, the pattern of drug concentration levels over time was similar between age groups, suggesting alternative explanations for behavioral differences. Chapter 4 investigates the possibility that developmental changes in the brain may contribute to behavioral differences by examining neural activity as measured by Fos induced from cocaine in 16 different brain areas. Results showed that for a given level of locomotor activity, adolescents had greater levels of Fos expression in the dorsal caudate as compared to adults. This posed the question of how greater Fos expression could relate to relatively lower locomotor stimulation in adolescents. Chapter 5 attempts to answer this question by examining the hypothesis that adolescents experience greater activation of a negative feedback circuit within the caudate called the striosomal pathway. Fos expression was localized using a striosomal marker, MOR1 antibody stain, following cocaine administration. No differences were observed between age groups, suggesting the striosomal pathway is not differentially activated between adolescents and adults. Overall, the mechanism underlying the phenomenon of attenuated stimulation in adolescents as compared to adults following psychostimulant administration remains unknown, but the dorsal caudate remains an area of interest.