Restricted interests and repetitive behaviors represents one of the cardinal features of autism spectrum disorder (ASD). Recent findings indicate that individuals with ASD can flexibly reverse learned response patterns when accurate feedback is provided, but are impaired when feedback is provided in a probabilistic fashion. Comparably, BTBR mice, used as a model of idiopathic ASD, exhibit a strikingly similar deficit in probabilistic reversal learning. Both dopamine and serotonin signaling in the striatum have been shown to affect behavioral flexibility and may represent potential neurochemical systems to target for treating behavioral inflexibility.
Objectives:
The objectives of the present experiments were as follows: 1) determine whether the atypical antipsychotic, risperidone selective serotonin 2A receptor antagonist, M100907 or dopamine D2 receptor antagonist, sulpiride attenuates a probabilistic reversal learning deficit in BTBR mice compared to that of C57 mice; 2) determine whether serotonin output in the dorsomedial striatum changes during probabilistic reversal learning in BTBR and C57 mice.
Methods:
In all experiments, mice were food restricted to 85% of their ad libitum body weight and trained in a spatial discrimination test. In this spatial discrimination test, mice were tested across two consecutive daily sessions. Mice had to discriminate between two spatial locations in which one location was associated with a food reward on 80% trials and the other location contained a food reward on 20% of trials. In the acquisition test, mice learned to select one spatial location in which a food reward was provided on 80% of trials. The following day, the reinforcement probabilities for spatial locations were reversed and a mouse learned to choose the opposite location as on acquisition. Learning criterion in both test sessions was 6 consecutive correct trials. To measure serotonin output during probabilistic reversal learning, mice were prepared for in vivo microdialysis collection in which a probe was placed in the dorsomedial striatum. Following baseline collection, mice were placed in the maze for reversal learning testing while microdialysis samples were collected at 10 min intervals. All samples were measured using HPLC.
Results: The results indicate that risperidone attenuates the probabilistic reversal learning deficit in BTBR mice in a dose-dependent fashion. M100907 also attenuated the reversal learning deficit in BTBR mice. In contrast, initial findings indicate that sulpiride does not attenuate a reversal learning deficit in BTBR. None of the treatments affected performance in C57 mice. Moreover, initial results indicate that serotonin output increases during reversal learning in C57 mice, but is reduced in BTBR mice.
Conclusions:
The present findings suggest that treatments that selectively target the serotonin 2A receptor, but not the dopamine D2 receptor, alleviate behavioral inflexibility deficits in a mouse model of ASD. Further, dampened serotonin signaling in the dorsomedial striatum may contribute to behavioral inflexibility deficits in BTBR mice. Blockade of serotonin 2A receptors may alleviate behavioral flexibility deficits by enhancing serotonin release in the striatum and may be an effective treatment to reduce restricted interests and repetitive behaviors in ASD.