title: Age of exposure-dependent effects of amphetamine on behavioral flexibility.
abstract: 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 3mg/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 3mg/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.
authors.affiliation: Department of Psychology, University of Illinois at Urbana-Champaign, 731 Psychology Building MC-716, 603 East Daniel Street, Champaign, IL 61820, USA.
authors.forename: Emily R
authors.initials: ER
authors.lastname: Hankosky
authors.forename: Nikki M
authors.initials: NM
authors.lastname: Kofsky
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Gulley
mesh_terms: D000222:Adaptation, Physiological / Q000187:drug effects*; D000375:Aging; D000661:Amphetamine / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001288:Attention / Q000187:drug effects*; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects*; D005106:Exploratory Behavior / Q000187:drug effects; D005508:Food Deprivation; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009812:Odorants; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000697:Central Nervous System Stimulants; D000661:Amphetamine
keywords: Adolescence; Amphetamine; Behavioral flexibility; Prefrontal cortex