Adolescence is a transitional period during development that is associated with a greater likelihood of addiction to drugs than any other age. In the prefrontal cortex (PFC), D 1 dopamine receptors mediate motivational salience attribution, which plays a role in addiction. Here, we investigated the relationship of age-related D 1 dopamine receptor expression in the PFC with the maturation of cocaine place conditioning. Confocal microscopy revealed that retrogradely traced cortical output neurons to the nucleus accumbens express higher levels of D 1 receptors during adolescence compared with younger and older ages. D 1 expression does not change on GABAergic interneurons across age. Adolescent differences in D 1 expression occur independently of cortical-accumbens connectivity, which proliferates through adulthood. Behaviorally, adolescent rats are more sensitive to cocaine place conditioning than younger and older rats. However, microinjections of the D 1 antagonist SCH23390 into the PFC blocked adolescent place preferences, whereas microinjections of D 1 agonists dose-dependently increased preferences for cocaine-associated environments previously not preferred by juveniles. These results suggest that the heightened expression of D 1 receptors on cortical-accumbens projections may help explain increased sensitivity to environmental events and addictive behaviors during adolescence, whereas the paucity of D 1 -expressing projections may reduce risk in juveniles.

Adolescence is a transitional period between childhood and adulthood that encompasses vast changes within brain systems that parallel some, but not all, behavioral changes. Elevations in emotional reactivity and reward processing follow an inverted U shape in terms of onset and remission, with the peak occurring during adolescence. However, cognitive processing follows a more linear course of development. This review will focus on changes within key structures and will highlight the relationships between brain changes and behavior, with evidence spanning from functional magnetic resonance imaging (fMRI) in humans to molecular studies of receptor and signaling factors in animals. Adolescent changes in neuronal substrates will be used to understand how typical and atypical behaviors arise during adolescence. We draw upon clinical and preclinical studies to provide a neural framework for defining adolescence and its role in the transition to adulthood.

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Background Early developmental insults can cause dysfunction within parvalbumin (PVB)-containing interneurons in the prefrontal cortex. The neuropsychiatric disorders associated with such dysfunction might involve neuroinflammatory processes. Cyclooxygenase-2 (COX-2) is a key mediator of inflammation and is therefore a potential target for preventive treatment. Here, we investigated whether the developmental trajectories of PVB expression and COX-2 induction in the prelimbic region of the prefrontal cortex are altered after maternal separation stress in male rats. Methods Male rat pups were separated from their mother and littermates for 4 hours/day between postnatal Days 2 and 20. Western blotting and immunohistochemistry were used to analyze PVB and COX-2 expression in the prefrontal cortex and hippocampus. A separate cohort of animals was treated with a COX-2 inhibitor during preadolescence and analyzed for PVB, COX-2, and working memory performance. Results We demonstrate that maternal separation causes a reduction of PVB and an increase in COX-2 expression in the prefrontal cortex in adolescence, with concurrent working memory deficits. Parvalbumin was not affected earlier in development. Prophylactic COX-2 inhibition preadolescence prevents PVB loss and improves working memory deficits induced by maternal separation. Conclusions These data are the first to show a preventive pharmacological intervention for the delayed effects of early life stress on prefrontal cortex interneurons and working memory. Our results suggest a possible mechanism for the relationship between early life stress and interneuron dysfunction in adolescence.