Sex differences in interactions between the muscarinic-1 and orexin-1 receptors on cognitive flexibility in rats

Previous research has shown that cognitive flexibility, the ability to adjust to different rules, is affected by manipulations of orexin and acetylcholine (ACh). Because there are strong neural connections between orexin and ACh, these two neurotransmitter systems may interact to impact cognitive flexibility. In the present experiment, the effects of pharmacological manipulations of orexin-1 and muscarinic-1 receptors in rats were tested on cognitive flexibility. Rats received intraperitoneal injections of VU0453595, a positive allosteric modulator for the M1 subtype of ACh receptors, for seven days prior to a rule switch in a measure of cognitive flexibility. On the day of the rule switch, rats were given the orexin-1 receptor antagonist, SB-334867 or vehicle prior to task performance. As expected, SB-334867 increased the number of trials to criterion during the rule switch. Compared to vehicle, when VU0453595 was administered, orexin-1 receptor blockade increased regressive errors for males and perseverative errors for females. These findings support the hypothesis that there are interactions between the orexin and cholinergic systems affecting cognitive flexibility, but that these interactions affect cognitive flexibility differently for males and females.