Sensorimotor gating in mice is disrupted after AM404, an anandamide reuptake and degradation inhibitor

Rationale: Prepulse inhibition (PPI) represents a normal sensorimotor gating response that is typically impaired in schizophrenic patients. It is known that cannabinoid CB I agonists reduce sensorimotor gating in rats, suggesting that the CBI receptor and the cannabinoid system are involved in sensorimotor gating. Objective: The objective was to study the effects of AM404, an anandamide reuptake and degradation inhibitor, on PPI and startle response in Swiss mice. Methods: AM404 was injected either acutely (0, 2.5 and 5 mg/kg i.p.) or chronically (5 mg/kg daily, 7 days). The PPI protocol was based on standard methodologies using acoustic stimuli (pulse 120 dB; prepulses 70 dB and 80 dB). SR141716A, a CB1 antagonist, was employed for further confirmation of the involvement of CBI receptors. Results: Acute AM404 (5 mg/kg) disrupted PPI (70-dB prepulse, P<0.05) and enhanced the startle response after the 2.5-mg/kg dose (P<0.01). Chronic AM404 disrupted PPI after both 70-dB (P<0.01) and 80-dB prepulses (P<0.05). These effects were blocked after SR141716A cotreatment. Conclusions: The data indicate that AM404 (5 mg/kg) acts as a psychodysleptic, altering PPI through stimulation of cannabinoid CB1 receptors, pointing to a possible "psychosis-like" state after enhancement of anandamide bioavailability. The startle response was enhanced only following a lower AM404 dose (2.5 mg/kg), indicating that AM404 induced hyperreactivity at a dose that did not affect PPI, further reinforcing a selective disruption of PPI.