Effects of amphetamine exposure during adolescence on behavior and prelimbic cortex neuron activity in adulthood

Abstract

Repeated exposure to psychostimulants during adolescence produces long-lasting changes in behavior that may be mediated by disrupted development of the mesocorticolimbic dopamine system. Here, we tested this hypothesis by assessing the effects of amphetamine (AMPH) and dopamine receptor-selective drugs on behavior and neuron activity in the prelimbic region of the medial prefrontal cortex (PFC). Adolescent male, Sprague-Dawley rats were given saline or 3 mg/kg AMPH between postnatal day (P) 27 and P45. In Experiment 1, locomotor behavior was assessed during adulthood following challenges with a dopamine D1 (SKF 82958) or D2 (quinpirole) receptor-selective agonist. In Experiment 2, pre-exposed rats were challenged during adulthood with AMPH and a D1 (SKF 83566) or D2 (eticlopride) receptor-selective antagonist. In Experiment 3, the activity of putative pyramidal cells in the prelimbic cortex was recorded as rats behaved in an open-field arena before and after challenge injections with AMPH and one of the antagonists. We found that compared to controls, adolescent pre-exposed rats were more sensitive to the stimulant effects of AMPH and the dopamine receptor agonists, as well as to the ability of the antagonists to reverse AMPH-induced stereotypy. Prelimbic neurons from AMPH pre-exposed rats were also more likely to respond to an AMPH challenge in adulthood, primarily by reducing their activity, and the antagonists reversed these effects. Our results suggest that exposure to AMPH during adolescence leads to enduring adaptations in the mesocorticolimbic dopamine system that likely mediate heightened response to the drug during adulthood.

AMPed-up adolescents: The role of age in the abuse of amphetamines and its consequences on cognition and prefrontal cortex development

“…These effects were mediated at least in part by reduced sensitivity of D1 receptors, which is in line with our work demonstrating that D1 receptor expression in the PFC, but not the nucleus accumbens, is reduced for at least 3 weeks following this same AMP exposure during adolescence (Kang et al, 2016b). We also showed that adult rats pre-treated with AMP during adolescence were more sensitive to the behavioral effects of D1 agonists, which is one predicted result of AMP-induced disruptions in D1 receptor expression (Sherrill and Gulley, 2018). However, it is important to note that we have also recently reported no reduction in D1 receptor expression in the PFC following LgA METH self-administration that began during adolescence (P41) or adulthood (P91; .…”