Research reportPositive and negative feedback learning and associated dopamine and serotonin transporter binding after methamphetamine
Introduction
Learning from mistakes and prospectively adjusting behavior in response to negative feedback is an important facet of performance monitoring. This cognitive process has been shown to get poorer with age [1], [2] and is also suboptimal in youth with a history of disruptive behavior [3]. Recent evidence shows that “high learners” utilize errors (or negative feedback) more optimally to update their future reward choices [4]. A plentitude of rodent and nonhuman primate research shows that such integration of feedback occurs via heterogenous reward signals in the prefrontal cortex, and that learning from both positive and negative feedback depends on dopamine (DA) signaling in areas like the orbitofrontal cortex (OFC) and basal ganglia [5]. Not surprisingly DA drugs, such as those given to Parkinson's patients, have been shown to modulate learning from reward feedback [6].
Chronic exposure to cocaine or methamphetamine (mAMPH) results in progressive and long-lasting changes in the mesencephalic DA system [7], [8], [9], [10], [11]. Repeated administration of high doses of mAMPH results in long-lasting reductions in total DA content [12], [13], [14], reduced activity of tyrosine hydroxylase [15], [16], decreased DA transporter binding and density [17], [18], [19], [20], [21], and compromised DA D2-like receptor availability in the striatum [22]. MAMPH administration also produces enduring impairments in cognitive flexibility, when the inhibition of previously-learned responses is required. Animal models of mAMPH addiction provide evidence that pathological neuroplasticity in prefrontal cortex and striatum underlie compulsive drug seeking and relapse [23], [24], [25]. Collectively, the preceding evidence strongly emphasizes the role of DA pathways in feedback-guided learning and suggests that some of the impairments induced by drug exposure as well as the vulnerability to the development of compulsive drug use may arise from altered patterns in feedback monitoring.
Several groups have analyzed how animals use positive and negative trial-by-trial feedback [26], [27], [28], [29], however these parameters have not been previously explored in pharmacological studies. Additionally, to our knowledge the effects of different mAMPH administration regimens on animals’ responses to reward feedback have not been previously examined. Both single-dose exposure (mAMPHsingle) and escalating exposure to mAMPH (mAMPHescal) result in cognitive flexibility impairments, as measured by attenuated reversal learning [30]. Though these regimens of mAMPH treatment produce remarkably similar learning impairments, the DA system may be differentially affected and produce such impairments through unique mechanisms. In the present experiment we compared mAMPHescal, mAMPHsingle, and saline (SAL)-treated animals on measures of feedback learning. Specifically, we assessed sensitivity to reward feedback or omission of anticipated reward on the reversal phase of pairwise visual discrimination learning. It should be noted that the trial-by-trial feedback learning we analyzed here occurred well outside of a drug wash out period and do not represent acute effects of mAMPH. Any changes we observed in performance monitoring therefore, represent enduring effects of the drug on this cognitive process.
Section snippets
Subjects
Previously-collected and published data [30] were reanalyzed in the present study for trial-by-trial feedback performance. Twenty-one male Long–Evans rats (Charles River Laboratories, Raleigh, NC) weighing between 275 and 300 g at the beginning of the study were individually housed during food restriction, given water ad libitum and maintained at a 12-h light/12-h dark cycle, with the temperature at 22 °C. Body weights were monitored daily. Behavioral testing took place between 0800 and 1600 h
Results
We performed fine-grained, trial-by-trial analyses analogous to previous reports on reversal leaning data [28], [29] to examine the effect of positive (rewarded choices) and negative (unrewarded choices) feedback on subsequent choices in mAMPH-treated animals. Analyses were conducted on all trials from only the reversal learning phase of the experiment, following the drug treatment and wash out period. The overall learning data are shown in Table 1. Treatment groups were not different in the
Discussion
Impairments in cognitive flexibility and alterations in learning patterns following mAMPH exposure are well documented [30], [31], [40], [41], [42], yet our knowledge of the performance monitoring and feedback learning mechanisms by which these impairments may manifest remains relatively unexplored. Using a fine-grained trial-by-trial analysis of performance in reversal learning, we provide evidence here that (1) drug exposure leads to long-lasting differences in feedback processing in early
Conclusion
In addition to validating the enduring effects of mAMPH on learning, the present findings demonstrate long-lasting differences in feedback processing in early learning as a consequence of even brief drug exposure. Both mAMPH groups showed increased sensitivity to and reliance on positive feedback, with mAMPHsingle animals showing more pronounced alterations in feedback learning. We provide evidence that negative feedback sensitivity is not altered following mAMPH exposure. Animals’ ability to
Funding and disclosure
There is nothing to disclose nor are there any conflicts of interest. This work was supported by the NIH Minority Biomedical Research Support program at California State University, Los Angeles (CSULA). Partial support also came from NIMH (Grant SC2 MH087974 to AI) and NIDA (Grants 1RO1DA012204 and 1R21 DA033572 to JFM).
Acknowledgements
We acknowledge Alisa Kosheleff and Danilo Rodriguez for behavioral testing and drug treatment and the Jentsch lab for valuable feedback on an early version of the manuscript.
References (49)
- et al.
Aging, probabilistic learning and performance monitoring
Biol Psychol
(2011) - et al.
Neuroscience of addiction
Neuron
(1998) - et al.
Drug addiction: a model for the molecular basis of neural plasticity
Neuron
(1993) - et al.
The longterm effects of neurotoxic doses of methamphetamine on the extracellular concentration of dopamine measured with microdialysis in striatum
Neurosci Lett
(1990) - et al.
Long-term methamphetamine induced changes in brain catecholamines in tolerant rhesus monkeys
Drug Alcohol Depend
(1976) - et al.
Influence of methamphetamine on nigral and striatal tyrosine hydroxylase activity and on striatal dopamine levels
Eur J Pharmacol
(1976) - et al.
The long-term effects of multiple doses of methamphetamine on neostriatal tryptophan hydroxylase, tyrosine hydroxylase, choline acetyltransferase and glutamate decarboxylase activities
Life Sci
(1979) - et al.
Methamphetamine toxicity and messengers of death
Brain Res Rev
(2009) - et al.
Long-lasting decrease in dopamine uptake sites following repeated administration of methamphetamine in the rat striatum
Brain Res
(1993) - et al.
Long-lasting depletions of striatal dopamine and loss of dopamine uptake sites following repeated administration of methamphetamine
Brain Res
(1980)