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.

Keywords: Cognitive flexibility; Methamphetamine; Reinstatement; Reversal; Self-administration.

Fig. 1

Experimental timeline. The top portion depicts behavioral training and testing that occurred in separate behavioral chambers for the ASST. The bottom portion depicts events relating to the self-administration (SA) paradigm. Rats were first pre-trained for the ASST, underwent side-bias testing, and trained on the visual discrimination (Visual Discrim). Following training, rats underwent catheter (or sham) surgery and 14 days of long-access SA (meth or sucrose-pellet control). After 3 days of abstinence, rats were re-trained on the visual discrimination rule (Re-train; rule: light) and then tested on strategy set-shift test (Shift; rule: light to lever) and reversal test (Rev.; rule: lever to opposite lever). Rats then experienced extinction trials in the SA chambers and cue-induced reinstatement testing

Fig. 2

Self-administration (SA) in meth (n = 19) and sucrose (n = 24) rats. a Meth intake (mg/kg) during 14 days of self-administration. Significant differences from the first day of long access are indicated (*p < 0.05). Average nose pokes during self-administration, extinction, and cue-induced reinstatement are shown for meth (b) and sucrose (c) rats

Fig. 3

Performance during the strategy set shift and reversal following self-administration (n = 19–23 per group). During the set shift, the rat shifts from the previous rule (light) to response strategy (side of lever). a Errors to criterion following the rule change during the set shift. b Comparison of the types of errors committed during the ED. During the reversal test, the rat shifts from the previous rule (side of lever) to the opposite lever. c Errors to criterion following the rule change during the reversal. d Comparison of the types of errors committed during the reversal. *p < 0.05; significantly different from sucrose

Fig. 4

Scatter plots and correlation coefficients for the relationships between stable self-administration (last 5 days) and errors committed during the reversal. Meth rats (n = 18) showed significant positive correlations between the number of active nose pokes and total number of errors (a) and perseverative errors (b) committed during the reversal. Sucrose control rats (n = 21) showed no significant correlations between self-administration and total number of errors (c) or perseverative errors (d) committed during the reversal

Fig. 5

Scatter plots and correlation coefficients for the relationships between cue-induced reinstatement and errors committed during the reversal in meth (n = 15) and sucrose (n = 21) rats. No significant correlations were seen between the number of active nose pokes during cue-induced reinstatement and total number of errors or perseverative errors committed during the reversal for meth rats (a, b) or sucrose rats (c, d) changes in cognitive flexibility may reflect symptoms that are independent of motivated meth seeking maintained by drug-paired cues.