Inactivation of the 5-HT7 receptor partially blocks phencyclidine-induced disruption of prepulse inhibition

Background: Studies have implicated the serotonin (5-HT)(7) receptor in physiological and pathophysiological phenomena, including thermoregulation, central control of micturition and locomotion, regulation of circadian rhythm, sleep, and depression. Further, several antidepressant and antipsychotic drugs have high affinity for the 5-HT7 receptor. Methods: We examined the role of 5-HT7 receptors in a rodent analogue of sensorimotor gating deficits in schizophrenia: phencyclidine (PCP)-induced disruption of prepulse inhibition (PPI) of acoustic startle. We used mice lacking the 5-HT7 receptor due to a targeted inactivation of this receptor gene and the selective 5-HT7 receptor antagonist SB-269970. Results: SB-269970 did not affect either baseline PPI or PCP-disrupted PPI. There was no difference between 5-HT7+/+ and 5-HT7-/- mice in startle reactivity or PPI regardless of prepulse intensity (74-82 dB), interstimulus interval (25-500 msec), or pulse intensity (90-120 dB). Nevertheless, disruption of PPI produced by PCP (10 mg/kg) in wild-type mice was reduced in 5-HT7-/- mice, although it was not affected by the 5-HT7 antagonist SB-269970. By contrast, the PPI-disruptive effects of apomorphine (5 mg/kg) and amphetamine (7.5 mg/kg) were comparable in both genotypes. Conclusions: The results indicate a partial role for the 5-HT7 receptor in the glutamatergic PPI model of sensorimotor gating deficits in schizophrenia that is sensitive to atypical antipsychotics and no involvement of this receptor in the dopaminergic PPI model that is sensitive to typical antipsychotics. Thus, the 5-HT7-/- mice may provide a useful tool to study the role of 5-HT7 receptor in the action of atypical antipsychotic drugs and schizophrenia.