5-HT₆ receptor antagonists improve performance in an attentional set shifting task in rats

Rationale and objective: Performance on the Wisconsin Card Sorting Test (WCST), which requires patients to 'shift attention' between stimulus dimensions (sorting categories), is impaired in diseases such as schizophrenia. The rat attentional set shifting task is an analogue of the WCST. Given that 5-HT6 receptor antagonists improve cognitive performance and influence cortical neurochemistry in rats, the present study investigated the effects of 5-HT6 receptor antagonists upon attentional set shifting in rats. Methods: Rats were tested in this paradigm following sub-chronic SB-399885-T or SB-271046-A (both 10 mg kg(-1) bid, p.o. for 8 days prior to testing and either 4 or 2 h prior to testing on day 9, respectively). Rats were trained to dig in baited bowls for a food reward and to discriminate based on odour or digging media (Habituation, day 8). In a single session (day 9), rats performed a series of discriminations, including reversals (REV), intra-dimensional (ID) and extra-dimensional (ED) shifts. Results: Neither compound altered performance during Habituation. On the test day, both SB-399885-T and SB-271046-A reduced the total trials to reach criterion and the total errors made when data were collapsed across all discriminations (P < 0.050.01). Further, both compounds significantly reduced the trials to criterion for REV-1 (P < 0.05-0.01) and abolished the ID/ED shift. SB-399885-T, but not SB-271046-A, reduced trials required to complete the ED shift (P < 0.05) and the number of errors made during completion of the ID (P < 0.05) and ED shifts (P < 0.01). Conclusion: 5-HT6 receptor antagonists improved performance in the attentional set shifting task and may have therapeutic potential in the treatment of disorders where cognitive deficits are a feature, including schizophrenia.