Role of 5-HT receptor mechanisms in sub-chronic PCP-induced reversal learning deficits in the rat

Abstract

5-HT receptor mechanisms have been suggested to mediate improvements in cognition in schizophrenia. The aim of this study was to investigate the involvement of 5-HT receptor mechanisms in sub-chronic phencyclidine (PCP)-induced reversal learning deficits in female rats, a task of relevance to schizophrenia. Adult female hooded Lister rats were trained to perform an operant reversal learning task and then received sub-chronic PCP (2 mg/kg) or vehicle intraperitoneally (i.p.) twice daily for 7 days, followed by 7-day washout. Rats then received an acute dose of the 5-HT(7) receptor antagonist SB-269970A (1.0, 3.0, and 10.0 mg/kg, i.p.) or vehicle. In experiment 2, PCP-treated rats received the selective 5-HT(2C) receptor antagonist, SB-243213A acutely (1.0, 3.0, and 10.0 mg/kg, i.p.) or vehicle. In experiment 3, PCP-treated rats received the 5-HT(1A) receptor partial agonist, buspirone (0.15625, 0.3125, and 0.625 mg/kg, i.p.) in combination with the selective 5-HT(1A) receptor antagonist WAY-100635 (0.3 and 1.0 mg/kg). In all experiments, sub-chronic PCP significantly impaired reversal phase performance (P < 0.01-0.001), with no effect in the initial phase. SB-269970A at 3.0 and 10.0 mg/kg significantly improved the PCP-induced deficit (P < 0.05). SB-243213A also significantly attenuated the deficit at 10 mg/kg (P < 0.05). In experiment 3, buspirone attenuated the deficit with significant effects at 0.3125 and 0.625 mg/kg (P < 0.05). WAY-100635 at 0.3 and 1.0 mg/kg produced a partial attenuation of buspirone's effect as buspirone (0.3125 mg/kg) in the presence of WAY-100635 did not significantly reverse the PCP-induced deficit. These studies implicate the role of 5-HT(7), 5-HT(2C), and 5-HT(1A) receptors in the improvement of cognitive dysfunction of relevance to schizophrenia.