Age of exposure-dependent effects of amphetamine on behavioral flexibility

Drug use typically begins during adolescence, which is a period of ongoing neurobiological development that may confer heightened vulnerability to develop drug dependence. Previously, our lab has shown that amphetamine (AMPH)-induced deficits in a medial prefrontal cortex (mPFC)-sensitive working memory task are greater in rats exposed to the drug during adolescence compared to adulthood. Here, we examine potential age-dependent effects of AMPH exposure on behavioral flexibility tasks that are sensitive to disruptions in mPFC and orbitofrontal cortex (OFC) function. Male Sprague-Dawley rats were injected (i.p.) with saline or 3 mg/kg AMPH every other day between postnatal days (PNDs) 27-45 and PNDs 85-103. Starting around PND 125, rats were tested in an attentional set-shifting task and a subset of those was then tested in an operant strategy shifting task. Following completion of the operant task, rats were challenged with 3 mg/kg AMPH and monitored in open field chambers. Our results demonstrate that AMPH-exposed rats were faster to acquire simple and compound discriminations, but were impaired during the first stimulus-reward reversal when compared to controls. In the operant strategy shifting task, adolescent-exposed rats shifted more rapidly between strategies and completed reversals faster than adult-exposed and control rats, respectively. The final AMPH challenge revealed evidence for sensitization in drug pre-exposed rats, with adult-exposed animals exhibiting the most significant effects. Together, these results suggest that AMPH induces long-lasting changes in behavioral flexibility that are at least partially dependent on age of exposure and may be due to adaptations in OFC function. (C) 2013 Elsevier B.V. All rights reserved.