Changes in neural circuitry regulating response-reversal learning and Arc-mediated consolidation of learning in rats with methamphetamine-induced partial monoamine loss

Abstract

Methamphetamine (METH)-induced neurotoxicity results in long-lasting depletions of monoamines and changes in basal ganglia function. We previously reported that rats with METH-induced neurotoxicity no longer engage dorsomedial striatum during a response-reversal learning task, as their performance is insensitive to acute disruption of dorsomedial striatal function by local infusion of an N-methyl-D-aspartate receptor antagonist or an antisense oligonucleotide against the activity-regulated cytoskeleton-associated (Arc) gene. However, METH-pretreated rats perform the task as well as controls. Therefore, we hypothesized that the neural circuitry involved in the learning had changed in METH-pretreated rats. To test this hypothesis, rats were pretreated with a neurotoxic regimen of METH or with saline. After 3-5 weeks, rats were trained on the reversal-learning task and in situ hybridization for Arc was performed. A significant correlation between Arc expression and performance on the task was found in nucleus accumbens shell of METH-, but not saline-, pretreated rats. Consistent with the idea that the correlation between Arc expression in a brain region and behavioral performance implicates that brain region in the learning, infusion of an antisense oligonucleotide against Arc into the shell impaired consolidation of reversal learning in METH-, but not saline-, pretreated rats. These findings provide novel evidence suggesting that METH-induced neurotoxicity leads to a shift from dorsal to ventral striatal involvement in the reversal-learning task. Such reorganization of neural circuitry underlying learning and memory processes may contribute to impaired cognitive function in individuals with METH-induced neurotoxicity or others with striatal dopamine loss, such as patients with Parkinson's disease.

Figure 1

METH neurotoxicity results in decreases in DAT and SERT binding. Graphs showing METH-induced decreases in (a) striatal DAT and (b) prefrontal cortical SERT as revealed by [¹²⁵I]RTI-55 binding. As DAT and SERT binding between rats in the Arc correlation experiment and Arc antisense infusion experiment were not significantly different, binding values from both sets of rats are combined into one graph. Saline (SAL)-pretreated, n=21; METH-pretreated, n=22. *Significantly different from SAL, p<0.001.

Figure 2

Correlations between Arc mRNA in striatal subregions and trials to criterion on the response-reversal learning task. Arc mRNA expression was determined by densitometric analysis of film autoradiograms using ImageJ and is expressed as background-subtracted average gray values (arbitrary units). Significant correlations (as indicated by box around R² and p-values) were in DM striatum of saline (SAL)-pretreated rats (R²=0.56, p=0.013) and NAc shell of methamphetamine (METH)-pretreated rats (R²=0.44, p=0.0497). METH-pretreated rats were given a neurotoxic regimen of (±)-METH•HCl (4 × 10 mg/kg free base, s.c., at 2-h intervals) approximately 7 weeks before reversal learning. DLS, dorsolateral striatum; DMS, dorsomedial striatum; NAcC, nucleus accumbens core; NAcSh, nucleus accumbens shell.

Figure 3

Diagrams (Paxinos and Watson, 1998) showing placement of infusion sites (black dots) in the NAc shell of rats infused with an Arc antisense or Arc nonsense oligonucleotide or with PBS. Numbers indicate mm from Bregma.

Figure 4

Knockdown of Arc in NAc shell impairs consolidation of reversal learning in METH-, but not saline-, pretreated rats. Rats were infused with an Arc antisense oligonucleotide, Arc nonsense oligonucleotide, or PBS into NAc shell 2 h before response-reversal learning on a T-maze. (a) None of the compounds had any effect on reversal learning in saline- or METH-pretreated rats. (b) Rats were tested on reversal retention 24 h after reversal learning. Knockdown of Arc mRNA in NAc shell via an Arc antisense oligonucleotide impaired reversal retention in METH-, but not saline-, pretreated rats. Values are average trials to criterion (9/10 correct consecutive trials; ±SEM, n=3–6 per group) on the reversal-learning task (a) or on the reversal-retention test 24 h later (b). *Significantly different from all other groups, all p-values<0.05.