Risperidone and the 5-HT2A receptor antagonist M100907 improve probabilistic reversal learning in BTBR T + tf/J mice

Abstract

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interactions with restricted interests and repetitive behaviors (RRBs). RRBs can severely limit daily living and be particularly stressful to family members. To date, there are limited options for treating this feature in ASD. Risperidone, an atypical antipsychotic, is approved to treat irritability in ASD, but less is known about whether it is effective in treating "higher order" RRBs, for example cognitive inflexibility. Risperidone also has multiple receptor targets in which only a subset may be procognitive and others induce cognitive impairment. 5HT2A receptor blockade represents one promising and more targeted approach, as various preclinical studies have shown that 5HT2A receptor antagonists improve cognition. The present study investigated whether risperidone and/or M100907, a 5HT2A receptor antagonist, improved probabilistic reversal learning performance in the BTBR T + tf/J (BTBR) mouse model of autism. The effects of these treatments were also investigated in C57BL/6J (B6) mice as a comparison strain. Using a spatial reversal learning test with 80/20 probabilistic feedback, similar to one in which ASD individuals exhibit impairments, both risperidone (0.125 mg) and M100907 (0.01 and 0.1 mg) improved reversal learning in BTBR mice. Risperidone (0.125 mg) impaired reversal learning in B6 mice. Improvement in probabilistic reversal learning performance resulted from treatments enhancing the maintenance of the newly correct choice pattern. Because risperidone can lead to unwanted side effects, treatment with a specific 5HT2A receptor antagonist may improve cognitive flexibility in individuals with ASD while also minimizing unwanted side effects.

Keywords: BTBR; autism; cognitive flexibility; reversal learning; risperidone; serotonin.

Figure 1

Acquisition and reversal learning of a spatial discrimination. [A] Training and testing schedule for B6 and BTBR mice. [B] Mice were tested on acquisition and reversal learning of a spatial discrimination with a 80/20 probabilistic reinforcement schedule.

Figure 2

Risperidone treatment improves probabilistic reversal learning in BTBR mice. Each mouse was tested across two consecutive days in a spatial discrimination test. Each mouse received an i.p. injection of vehicle 30 minutes prior to an acquisition session. In reversal learning, mice received either vehicle or risperidone 30 minutes prior to testing. The treatments on the x-axis represent the treatment received prior to acquisition [top] and prior to reversal learning [bottom]. [A] Mean [±SEM] trials to criterion on acquisition. All mice received vehicle treatment in acquisition. B6: vehicle-vehicle [n = 9], vehicle-0.0125 [n = 8]; BTBR: vehicle-vehicle [n = 10], vehicle-0.0125 [n = 10], vehicle-0.125 [n = 10]. [B] Mean [±SEM] trials to criterion on reversal learning. B6 mice treated with vehicle required significantly less trials to criterion than BTBR vehicle-treated mice and BTBR mice receiving the low dose of risperidone. Risperidone at 0.125 mg/kg treatment in BTBR mice significantly improved reversal learning performance compared to that of BTBR mice treated with vehicle and low dose of risperidone.* = p < .05 vs. B6-vehicle and # = p < .05 vs BTBR-vehicle and BTBR-0.0125.

Figure 3

Risperidone attenuates regressive errors committed by BTBR mice. Analysis of the errors committed in reversal learning was conducted to determine whether a treatment affected the ability to initially inhibit the previously relevant choice pattern [perseverative errors] and/or the ability to maintain the new choice pattern after initially being selected [regressive errors]. [A] Mean [±SEM] perseverative errors committed during reversal learning. Risperidone treatment did not affect perseverative errors committed. [B] Mean [±SEM] regressive errors committed during reversal learning. B6 mice did not differ on the number of regressive errors committed during reversal learning. BTBR mice treated with vehicle or the low dose of risperidone had significantly more regressive errors than B6 mice receiving vehicle. The high dose of risperidone in BTBR mice significantly decreased regressive errors compared to that of BTBR mice treated with vehicle. * = p < .05 vs. B6-vehicle; # = p < .05 vs. BTBR-vehicle.

Figure 4

M100907 treatment improves probabilistic reversal learning in BTBR mice. Each mouse received an i.p. injection of vehicle 30 minutes prior to an acquisition session. In reversal learning, mice received either vehicle or M100907 30 minutes prior to testing. The treatments on the x-axis represent the treatment received prior to acquisition [top] and prior to reversal learning [bottom]. [A] Mean [±SEM] trials to criterion on acquisition. All mice received vehicle treatment in acquisition. B6: vehicle-vehicle [n = 8], vehicle-0.01 [n = 8], vehicle-0.1 [n=8]; BTBR: vehicle-vehicle [n = 13], vehicle-0.01 [n = 12], vehicle-0.1 [n = 11]. [B] Mean [±SEM] trials to criterion on reversal learning. M100907 treatment did not affect reversal performance in B6 mice. Vehicle-treated BTBR mice required significantly more reversal learning trials compared to that of B6 vehicle-treated mice and BTBR mice receiving the high dose of M100907, as well as the BTBR mice receiving the low dose of M100907.* = p < .01 vs. B6-vehicle; and # p < 0.05 vs. BTBR-vehicle.

Figure 5

M100907 treatment effects on perseverative and regressive errors. [A] Mean [±SEM] perseverative errors committed during reversal learning. [B] Mean [±SEM] regressive errors committed during reversal learning. B6 mice did not differ on the number of perseverative errors committed during reversal learning. Vehicle-treated BTBR mice committed significantly more regressive errors than B6 mice. The high dose of M100907 in BTBR mice significantly reduced regressive errors compared to that of vehicle-treated BTBR mice. * = p < .05 vs. B6-vehicle; # = p < .05 vs. BTBR-vehicle.