title: Perseverative behavior in rats with methamphetamine-induced neurotoxicity.
abstract: Methamphetamine induces monoamine depletions thought to contribute to cognitive and behavioral dysfunctions. Previously, we reported that methamphetamine-induced neurotoxicity is associated with impaired formation of stimulus-response associations. Additionally, subjective observations suggested that behavioral flexibility might be affected. Thus, the present study examined whether methamphetamine neurotoxicity induces perseverative behavior. Rats were pretreated with (±)-methamphetamine (4 × 10 mg/kg, 2-hr intervals) or saline. Three weeks later, rats were trained to press a lever on one side of an operant chamber and then retrieve the reinforcer from a magazine on the opposite side until they reached criterion (>50 reinforcers/30-min). After four consecutive sessions performing the task at criterion, rats were sacrificed and brains removed for monoamine determinations. Methamphetamine-pretreated rats had ∼50% loss of striatal dopamine and prefrontal serotonin. Methamphetamine- and saline-pretreated rats were not different in the number of sessions required to reach criterion or in the total numbers of lever presses and/or head entries made across the four consecutive sessions at criterion-level performance. However, methamphetamine-pretreated rats earned fewer reinforcers, because they made extra lever-presses and head entries when they should have been retrieving the reinforcer or returning to the lever. Latencies for methamphetamine-pretreated rats to switch between the two behaviors also were significantly slower than latencies for controls. Interestingly, the degree of additional lever-presses negatively correlated with serotonin-transporter binding in the prefrontal cortex, even in saline-pretreated controls. These data suggest that methamphetamine-induced partial monoamine toxicity is associated with perseveration and that the degree of perseveration may depend on serotonin innervation of the frontal cortex.
authors.affiliation: Department of Pharmacology and Toxicology, 30 S. 2000 E., Rm 201, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Jong-Hyun
authors.initials: JH
authors.lastname: Son
authors.forename: James
authors.initials: J
authors.lastname: Kuhn
authors.forename: Kristen A
authors.initials: KA
authors.lastname: Keefe
mesh_terms: D000818:Animals; D003216:Conditioning, Operant / Q000187:drug effects* / Q000502:physiology; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects* / Q000502:physiology; D012055:Reinforcement Schedule; D012701:Serotonin / Q000378:metabolism
chemical_list: D012701:Serotonin; D008694:Methamphetamine