Behavioral and Neurobiological Consequences of Alprazolam Exposure During Adolescence

Abstract

Rationale: There is evidence of increased use and abuse of alprazolam (Xanax; ALP) during adolescence, yet most available neurobiological evidence has been derived from studies using adult organisms. Objectives: This study was designed to investigate the behavioral and neurobiological consequences of ALP exposure during adolescence. Methods: For experiment 1, adolescent male mice [postnatal day PD 35]) were pretreated with ALP (0, 0.5, 1.0 mg/kg) once daily from PD 35-49. Changes in behavioral responsiveness to morphine (2.5 and 5.0 mg/kg), using the conditioned place preference paradigm (CPP), were assessed 24 h after the end of drug treatment. Results: Findings showed that ALP pretreated mice developed strong preference to the compartment paired with subthreshold dose of morphine (2.5 mg/kg), while demonstrating aversion to the compartments paired with a moderate dose (5.0 mg/kg). Methods: In experiment 2, PD35 male mice were exposed to a single ALP injection (0.5 mg/kg). ERK1/2-related gene and protein expression changes were assessed within the ventral tegmental area (VTA) and nucleus accumbens (NAc), using qPCR and western blot analysis ninety-minutes after the drug treatment. Results: Acute ALP exposure during adolescence decreased mRNA and protein expression of ERK1/2, its downstream target cAMP response element-binding protein (CREB), and protein kinase B (AKT) within the VTA. Within the NAc, ALP increased ERK1/2, CREB, and AKT mRNA expression while it had no effect on protein expression. Methods: In experiment 3, adolescent male mice were pretreated with ALP (0.5 mg/kg), once daily from PD 35-49. Gene expression changes within VTA and NAc, using qPCR and western blot, were assessed 24 h after the end of drug treatment. Results: Within the VTA repeated ALP exposure during adolescence decreased mRNA expression of ERK1/2, CREB, and AKT. Moreover, ALP exposure increased protein expression of ERK1 and AKT. Within the NAc, ALP increased mRNA and protein expression of ERK1/2, CREB, and AKT when compared to controls. Conclusions: These findings suggest that exposure to ALP during adolescence potentiates the rewarding effects of opiates such as morphine. ALP exposure during this period results in changes of ERK-signaling within the VTA and NAc, brain regions implicated in regulation of both drug-reward and mood-related disorders.