Acute serotonin 2A receptor activation impairs behavioral flexibility in mice

Serotonin 2A (5-HT_2A) receptors are the primary site of action of hallucinogenic drugs and the target of atypical antipsychotics. 5-HT_2A receptors are also implicated in executive function, including behavioral flexibility. Previous studies showed that 5-HT_2A receptor blockade improved behavioral flexibility in rodent models related to autism spectrum disorder and schizophrenia. The current study instead was conducted to examine the impact of acute 5-HT_2A receptor activation on behavior flexibility in the control C57BL/6 J strain. Because of the therapeutic potential of serotonergic hallucinogens and the unknown impact of many of these compounds on cognition, the present study examined how the 5-HT_2A/2C agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the more selective 5-HT_2A agonist 25CN-NBOH impacted behavioral flexibility in C57BL/6 J mice. Male mice were tested on a probabilistic spatial discrimination and reversal learning task after an intraperitoneal injection of vehicle, 2.5 mg/kg DOI, 1.0 mg/kg 25CN-NBOH, 1.0 mg/kg of the 5-HT_2C receptor antagonist SER-082 or combined treatment with SER-082 (1.0 mg/kg) and 2.5 mg/kg DOI before testing of probabilistic reversal learning. All groups demonstrated comparable performance on the initial spatial discrimination, i.e. similar trials to criterion. DOI alone did not impair reversal learning, whereas 25CN-NBOH increased the number of trials to criterion during reversal learning. Because 5-HT_2A and 5-HT_2C receptors have been shown to functionally antagonize each other in several behavioral paradigms, we also tested whether blockade of 5-HT_2C receptors would unmask 5-HT_2A receptor activation by DOI and impair reversal learning. Mice treated with SER-082 in combination with DOI required significantly more trials to reach criterion. In an additional experiment, a dose response experiment with 25CN-NBOH revealed that the 1.0 mg/kg dose tested in reversal learning did not affect locomotor activity. Together, these findings indicate that activation of 5-HT_2A receptors impairs probabilistic reversal learning and that 5-HT_2A and 5-HT_2C receptors exert opposing effects on behavioral flexibility in male mice.