Research reportPharmacological characterizations of memantine-induced disruption of prepulse inhibition of the acoustic startle response in mice: Involvement of dopamine D2 and 5-HT2A receptors

It has recently been reported that psychotic symptoms in patients such as those with Parkinson's disease dementia (PDD) and Lewy body dementia (LBD) may worsen following treatment with memantine, a non-competitive NMDA receptor antagonist. Prepulse inhibition (PPI) of the acoustic startle response (ASR) is used as a measure for sensorimotor gating and it has been reported that PPI is disrupted by memantine. However, the mechanism of memantine-induced PPI disruption remains unclear. In the present study, we investigated the effects of memantine on PPI of the ASR in mice. Memantine (1.25-20 mg/kg, intraperitoneally) increased the ASR and dose-dependently decreased PPI for all prepulse intensities tested. This effect of memantine on PPI was attenuated by pretreatment with the antipsychotics clozapine (3 and 6 mg/kg), risperidone (0.3 mg/kg) and haloperidol (0.5 mg/kg), the selective D2 antagonist sulpiride (40 mg/kg) and 5-HT2A/2C antagonist ketanserin (2 and 4 mg/kg) but not with the selective D1 antagonist SCH23390 (0.05 and 0.1 mg/kg). Clozapine (6 mg/kg) and risperidone (0.3 mg/kg) significantly attenuated the increased startle amplitude in the memantine-treated groups. These results suggest that involvement of dopaminergic and/or serotonergic neurotransmission may play a crucial role in memantine-induced PPI disruption, and additionally, indicate that blockade of either the D2 or 5-HT2A receptor may prevent disruption of PPI induced by memantine in mice. Conceivably, memantine may exacerbate psychotic symptoms in patients with PDD and LBD.

Research highlights▶ Memantine dose-dependently decreased prepulse inhibition. ▶ The PPI disruption was attenuated by clozapine, risperidone and haloperidol. ▶ The PPI disruption was attenuated by D2 receptor antagonists but not a D1 receptor antagonist. ▶ The PPI disruption was attenuated by a 5-HT2A antagonist. ▶ Central D2 or 5-HT2A receptors are involved in the disruption of PPI by administration of memantine.