Synergistic effect of galantamine with risperidone on impairment of social interaction in phencyclidine-treated mice as a schizophrenic animal model

Social withdrawal is the first sign and key component of the negative symptoms of schizophrenia. The efficacy of risperidone, an atypical antipsychotic, on the symptom is practically limited by dose-dependent side effects in clinical trials, therefore there is the need for adjuvant treatments. In the present study, we aimed to investigate the synergistic effect and mechanism of risperidone and galantamine, which is a nicotinic acetylcholine receptor (nAChR)-allosteric modulator and a modest cholinesterase inhibitor, on phencyclidine (PCP)-treated mouse model of social withdrawal. At non-effective doses by themselves, co-administration of galantamine (0.05 mg/kg) and risperidone (0.05 mg/kg) showed synergistic effects on PCP-induced impairments of social interaction and dopamine release in the medial prefrontal cortex (mPFC). The behavioral synergistic effect was abolished by the administration of a dopamine-D₁ receptor antagonist, SCH 23390 (0.02 mg/kg, systemic; or 0.02 μg/0.5 μL/mouse, intra-mPFC), and a nAChR antagonist, mecamylamine (3 mg/kg), but not a muscarinic receptor antagonist, scopolamine (0.1 mg/kg). Mecamylamine (3 mg/kg) also abolished the synergistic effect on dopamine release in the mPFC. We conclude that galantamine may have synergistic effect with risperidone on the negative symptom of social withdrawal in schizophrenia, which is mediated by dopamine-D₁ receptors in the mPFC through nAChR activation-increased dopamine release.