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RationaleDrug addiction can be described as aberrant allocation of effort toward acquiring drug, despite associated costs. It is unclear if this behavioral pattern results from an overvaluation of reward or to an altered sensitivity to costs.ObjectivePresent experiments assessed reward sensitivity and effortful choice in rats following 1 week of withdrawal from methamphetamine (mAMPH).MethodsRats were treated with either saline or an escalating dose mAMPH regimen, then tested after a week without the drug. In experiment 1, rats were given a free choice between water and various concentrations of sucrose solution to assess general reward sensitivity. In experiment 2, rats were presented with a choice between lever-pressing for sucrose pellets on a progressive ratio schedule or consuming freely-available chow.ResultsIn experiment 1, we found no differences in sucrose preference between mAMPH- and saline-pretreated rats. In experiment 2, when selecting between two options, mAMPH-pretreated rats engaged in less lever-pressing for sucrose pellets (p

RationalePoor cognitive control, including reversal learning deficits, has been reported in children with attention deficit hyperactivity disorder, in stimulant-dependent humans, and in animal models of these disorders; these conditions have each been associated with abnormal catecholaminergic function within the prefrontal cortex.ObjectivesIn the current studies, we sought to explore how elevations in extracellular catecholamine levels, produced by pharmacological inhibition of catecholamine reuptake proteins, affect behavioral flexibility in rats and monkeys.Materials and methodsAdult male Long-Evans rats and vervet monkeys were trained, respectively, on a four-position discrimination task or a three-choice visual discrimination task. Following systemic administration of pharmacological inhibitors of the dopamine and/or norepinephrine membrane transporters, rats and monkeys were exposed to retention or reversal of acquired discriminations.ResultsIn accordance with our a priori hypothesis, we found that drugs that inhibit norepinephrine transporters, such as methylphenidate, atomoxetine, and desipramine, improved reversal performance in rats and monkeys; this was mainly due to a decrease in the number of perseverative errors. Interestingly, the mixed dopamine and norepinephrine transporters inhibitor methylphenidate, if anything, impaired performance during retention in both rats and monkeys, while administration of the selective dopamine transporter inhibitor GBR-12909 increased premature responses but did not alter reversal learning performance.ConclusionsOur results suggest that pharmacological inhibition of the membrane norepinephrine, but not membrane dopamine, transporter is associated with enhanced behavioral flexibility. These data, combined with earlier reports, may indicate that enhanced extracellular catecholamine levels in cortical regions, secondary to norepinephrine reuptake inhibition, improves multiple aspects of inhibitory control over responding in rats and monkeys.

Rationale. Psychotomimetic N-methyl-d-aspartate/glutamate receptor antagonists, such as phencyclidine (PCP), have been shown to produce a spectrum of behavioral, neurochemical and anatomical changes in rats that are relevant to aspects of schizophrenia, including impairments of working memory and visual attention. The alpha2 noradrenergic receptor agonist clonidine prevents some of the behavioral effects of NMDA antagonists, suggesting that monoaminergic systems mediate some aspects of these deficits. Objectives. We sought to determine the ability of clonidine to modify the PCP-induced deficits of visual attention and spatial working memory in rats. Results. In a lateralized reaction time task, a lower dose of clonidine (10 μg/kg) ameliorated the impairment of choice accuracy produced by PCP (2.5 mg/kg, IP), while the higher dose of clonidine (50 μg/kg) slowed response times and induced a deficit of choice accuracy on its own. The high dose of clonidine effectively prevented the motor impulsivity produced by PCP. In addition, clonidine (10 μg/kg) prevented PCP-induced performance deficits in a delayed non-match to sample task. Conclusions. These data indicate that clonidine may attenuate deficits of attention and working memory produced by PCP, perhaps in part by preventing some of the downstream neurochemical and anatomical effects of this psychotomimetic drug. [ABSTRACT FROM AUTHOR]