Reversal-specific learning impairments after a binge regimen of methamphetamine in rats: possible involvement of striatal dopamine

Abstract

A growing body of evidence indicates that protracted use of methamphetamine (mAMPH) causes long-term impairments in cognitive function in humans. Aside from the widely reported problems with attention, mAMPH users exhibit learning and memory deficits, particularly on tasks requiring response control. Although binge mAMPH administration to animals results in cognitive deficits, few studies have attempted to test behavioral flexibility in animals after mAMPH exposure. The aim of this study was to evaluate whether mAMPH would produce impairments in two tasks assessing flexible responding in rats: a touchscreen-based discrimination-reversal learning task and an attentional set shift task (ASST) based on a hallmark test of executive function in humans, the Wisconsin Card Sort. We treated male Long-Evans rats with a regimen of four injections of 2 mg/kg mAMPH (or vehicle) within a single day, a dosing regimen shown earlier to produce object recognition impairments. We then tested them on (1) reversal learning after pretreatment discrimination learning or (2) the ASST. Early reversal learning accuracy was impaired in mAMPH-treated rats. MAMPH pretreatment also selectively impaired reversal performance during ASST testing, leaving set-shifting performance intact. Postmortem analysis of [(125)I]RTI-55 binding revealed small (10-20%) but significant reductions in striatal dopamine transporters produced by this mAMPH regimen. Together, these results lend new information to the growing field documenting impaired cognition after mAMPH exposure, and constitute a rat model of the widely reported decision-making deficits resulting from mAMPH abuse seen in humans.

Figure 1

Retention of a pretreatment visual discrimination problem. Rats were given a ‘reminder session' where they were exposed to the discrimination problem just learned. Three days after treatment with mAMPH or SAL, they were given a retention test. There were no significant differences between the mAMPH- and SAL-treated groups (n=7 mAMPH, n=5 SAL). Data are means±SEM.

Figure 2

Early discrimination reversal learning differs between mAMPH- and SAL-treated groups. Performance on reversal learning was subdivided into early (sessions 1–3), middle (sessions 4–6), and late (session 7–9) phases. MAMPH-pretreated rats scored lower percent correct on early reversal phase only (n=7 mAMPH, n=5 SAL). Bars represent group means±SEM ^*p=0.05 vs SAL.

Figure 3

Reversal learning is impaired and set shifting is intact in the ASST task after mAMPH treatment. (a) mean (±SEM) trials to reach criterion (six successive correct trials) for each phase of the attentional set shift paradigm. (b) mean (±SEM) errors made in each phase of the ASST paradigm (n=9 mAMPH, n=7 SAL). See Materials and Methods for details. ^*p⩽0.05; ^**p<0.001.

Figure 4

[¹²⁵I]RTI-55 binding to striatal dopamine transporters (DAT). Mean±SEM values (in μCi/g) for DAT binding in the striatum of Long-Evans rats exposed to 4 × 2 mg/kg, s.c. methamphetamine (mAMPH; N=6) or saline (SAL; N=3) dosing regimen 1 week earlier. Values were generated by quantitative autoradiography of ligand binding. Initial readings were taken from whole caudate-putamen (CP, areas labeled a and b), followed by readings in the dorsal (dCP, labeled a) and ventral (vCP, labeled b) subdivisions of the CP, and in the nucleus accumbens septi (NAc, labeled c). Representative section=Bregma +1.44 mm. ^*mAMPH different from SAL, p<0.02.