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

Abstract

Prepulse inhibition (PPI) represents a normal sensorimotor gating response that is typically impaired in schizophrenic patients. It is known that cannabinoid CB1 agonists reduce sensorimotor gating in rats, suggesting that the CB1 receptor and the cannabinoid system are involved in sensorimotor gating. 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 CB1 receptors. 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. 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.