Chronic methamphetamine self-administration alters cognitive flexibility in male rats

Abstract

Rationale Methamphetamine (meth) addiction is a chronically relapsing disorder that often produces persistent cognitive deficits. These include decreased cognitive flexibility, which may prevent meth addicts from altering their habitual drug abuse and leave them more susceptible to relapse. Multiple factors including low rates of compliance with research study participation and varied drug use patterns make the relationship between cognitive flexibility and relapse difficult to establish in clinical populations. Objectives Here, we combined an extended-access meth self-administration paradigm with an automated set-shifting task in rats to directly compare cognitive flexibility performance with meth-seeking behavior. Methods Rats were pre-trained on an automated visual discrimination task, followed by 14 days of extended access (6 h/day) of meth or sucrose self-administration. They were then tested in the set-shifting task on strategy shift and reversal and subsequently assessed for cue-induced reinstatement of meth seeking. Results Rats with a history of meth, but not sucrose, self-administration had selective deficits in reversal learning. Specifically, meth rats had an increase in the total number of errors and perseverative errors (corresponding to the old stimulus-reward association) following the reversal shift, which correlated with prior stable meth self-administration. However, no relationship was seen between errors during the reversal and cue-induced reinstatement. Conclusion The lack of association between meth-induced reversal deficits and cue-induced reinstatement to meth seeking indicates that these two domains may constitute independent pathologies of meth addiction.

Age and sex differences in behavioral flexibility, sensitivity to reward value, and risky decision-making

“…This effect was specific to reversal learning, as adolescents acquired the extradimensional shift from visual to response strategies just as rapidly as adults. It is important to note, however, that rats in the present study required considerably more trials to acquire the visual strategy than those in previous studies Cox et al, 2016), which could be due to strain differences in visual acuity (Kumar, Talpos, & Steckler, 2015). Like Kumar and colleagues' study, some of our Sprague-Dawley rats failed to acquire the initial visual discrimination.…”

“…Notably, adult rats that self-administer psychostimulants have been shown to have deficits in reward processing (Green, Dykstra, & Carelli, 2015), impaired behavioral flexibility (Cox et al, 2016), and increased risk taking (Mitchell et al, 2013). An alternative approach that avoids these potentially confounding drug effects on behavior is to substitute non-drug reinforcers in the analysis of potential age effects.…”

Withdrawal from escalated cocaine self-administration impairs reversal learning by disrupting the effects of negative feedback on reward exploitation: a behavioral and computational analysis

“…An important objective of this research was to investigate the nature of the widely reported impairing effects of cocaine on the flexibility of goal-directed behavior [17,28,[62][63][64][65]. Our finding that lose-shift behavior is decreased in HE rats who had some reversal experience is consistent with findings in rats exposed to methamphetamine [34,35] and in human addicts [66][67][68].…”

Steep effort discounting of a preferred reward over a freely-available option in prolonged methamphetamine withdrawal in male rats

“…Additionally, there is similarity in the effects of behavioral flexibility assays between self- and experimenter-administered mAMPH in male rats (Cox et al 2016). Changes in effort allocation for rewards may relate to relapse vulnerability in protracted withdrawal from mAMPH in humans.…”