Positive and negative feedback learning and associated dopamine and serotonin transporter binding after methamphetamine.

Learning from mistakes and prospectively adjusting behavior in response to reward feedback is an important facet of performance monitoring. Dopamine (DA) pathways play an important role in feedback learning and a growing literature has also emerged on the importance of serotonin (5HT) in reward learning, particularly during punishment or reward omission (negative feedback). Cognitive impairments resulting from psychostimulant exposure may arise from altered patterns in feedback learning, which in turn may be modulated by DA and 5HT transmission. We analyzed long-term, off-drug changes in learning from positive and negative feedback and associated striatal DA transporter (DAT) and frontocortical 5HT transporter (SERT) binding in rats pretreated with methamphetamine (mAMPH). Specifically, we assessed the reversal phase of pairwise visual discrimination learning in rats receiving single dose- (mAMPHsingle) vs. escalating-dose exposure (mAMPHescal). Using fine-grained trial-by-trial analyses, we found increased sensitivity to and reliance on positive feedback in mAMPH-pretreated animals, with the mAMPHsingle group showing more pronounced use of this type of feedback. In contrast, overall negative feedback sensitivity was not altered following any mAMPH treatment. In addition to validating the enduring effects of mAMPH on early reversal learning, we found more consecutive error commissions before the first correct response in mAMPH-pretreated rats. This behavioral rigidity was negatively correlated with subregional frontocortical SERT whereas positive feedback sensitivity negatively correlated with striatal DAT binding. These results provide new evidence for the overlapping, yet dissociable roles of DA and 5HT systems in overcoming perseveration and in learning new reward rules.

Comparison of single-dose and extended methamphetamine administration on reversal learning in rats.

RATIONALE: Protracted use of methamphetamine (mAMPH) can result in long-term impairments in cognitive function in humans. A previous study reported reversal-specific learning impairments in rats after a binge administration of mAMPH. Several studies show that extended exposure to mAMPH may confer protection against cognitive impairments and the insult to monoamine systems typically observed after larger binge doses. OBJECTIVES: To explore this issue, we compared the effects of escalating and single doses of mAMPH (and saline, SAL) on retention, reversal learning, and post-mortem analysis of dopamine and serotonin transporters, DAT and SERT. METHODS: Rats learned to discriminate equiluminant stimuli and then were treated with either: (1) 4 weeks of mAMPH increasing by 0.3 mg/kg, culminating in 6 mg/kg (mAMPH(escal)); (2) 4 weeks of SAL with a single dose of 6 mg/kg on the last day of treatment (mAMPH(single)); or (3) 4 weeks of SAL. Following treatment, rats were tested on retention and reversal learning, with subsequent analysis of DAT and SERT binding across subregions of the striatum and frontoparietal cortex, respectively. RESULTS: Retention of the pretreatment discrimination was not significantly impaired in either mAMPH treatment group. A significant decrease in ventrolateral striatal DAT binding was observed only in the mAMPH(single) group and frontoparietal SERT was unaffected by either mAMPH treatment. Both treatment groups demonstrated attenuated reversal learning, particularly on measures of accuracy and effort. CONCLUSIONS: These results show that extended and single-dose pretreatment with mAMPH similarly and selectively affect reversal learning, even in the absence of significant DAT or SERT changes.

Work aversion and associated changes in dopamine and serotonin transporter after methamphetamine exposure in rats.

RATIONALE: Methamphetamine (mAMPH) administration in animals can lead to a variety of cognitive and behavioral deficits. We previously reported non-acute reversal learning impairments after a single-day administration of mAMPH, providing evidence of this drug's selective effects on inhibitory control. Effortful decision-making (i.e., how much effort to invest in rewards) is an aspect of cognition that has not yet been explored after mAMPH. OBJECTIVES: Given that frontostriatal circuitry mediating this type of choice is vulnerable to the effects of mAMPH, we tested the hypothesis that mAMPH may also affect decision-making involving effort, another form of cognitive flexibility. METHODS: We examined the non-acute effects of an experimenter-administered single day of mAMPH on effort discounting. In this task, rats previously treated with mAMPH or saline (SAL) could select a high reward at the cost of climbing over a tall barrier or a low reward with no barrier impeding its procurement. RESULTS: Following treatment, mAMPH rats were more work-averse than SAL rats. A control task showed there were no treatment group differences when the high and low rewards involved equal work: all rats chose the high reward preferentially. There were no significant treatment group differences in [(125)I]RTI-55 binding to dopamine and serotonin transporters (DAT, SERT) in any of the regions assayed; however, there were significant correlations of accumbens DAT and cingulate SERT with post-treatment performance. CONCLUSIONS: These findings suggest that even modest dose mAMPH exposure has long-lasting effects on effortful decision-making and may do so through influences on forebrain monoaminergic systems.