Lack of dopamine supersensitivity in rats after chronic administration of blonanserin: Comparison with haloperidol

Abstract

Long-term treatment with antipsychotic drugs in patients with schizophrenia can lead to dopamine supersensitivity psychosis. It is reported that repeated administration of haloperidol caused dopamine supersensitivity in rats. Blonanserin is an atypical antipsychotic drug with high affinity for dopamine D, D and serotonin receptors. In this study, we investigated whether chronic administration of blonanserin leads to dopamine supersensitivity. Following oral treatment with blonanserin (0.78 mg/kg) or haloperidol (1.1 mg/kg) twice daily for 28 days, the dopamine D agonist quinpirole-induced hyperlocomotion test and a dopamine D receptor binding assay were conducted. We found that haloperidol significantly enhanced both quinpirole-induced hyperlocomotion and striatal dopamine D receptor density in rats. On the other hand, repeated administration of blonanserin had no effect on either locomotor activity or striatal dopamine D receptor density. Further, our results show that mRNA levels of dopamine D and D receptors in several brain regions were unaffected by repeated administration of both agents. In addition, we examined the effect of the dopamine D receptor antagonist PG-01037 on development of dopamine supersensitivity induced by chronic haloperidol treatment and showed that PG-01037 prevents the development of supersensitivity to quinpirole in chronic haloperidol-treated rats. Given the higher affinity of blonanserin at dopamine D receptors than haloperidol, antagonism of blonanserin at dopamine D receptors may play a role in lack of dopamine supersensitivity after chronic administration. The present findings suggest long-term treatment with antipsychotic dose of blonanserin may be unlikely to lead to dopamine supersensitivity.

Effectiveness and safety of blonanserin for improving social and cognitive functions in patients with first-episode schizophrenia: a study protocol for a prospective, multicentre, single-arm clinical trial

“…In patients with schizophrenia, blonanserin brought remarkable clinical benefits in improving social and cognitive functions. Blonanserin may be a favourable option for long-term administration, as a previous study suggested that long-term treatment with an antipsychotic dose of blonanserin may be unlikely to lead to dopamine supersensitivity in an animal model 23. Additionally, blonanserin was favourable for patients with treatment-resistant schizophrenia and dopamine supersensitivity psychosis 24.…”

Dopaminergic mechanisms underlying the expression of antipsychotic-induced dopamine supersensitivity in rats

“…We determined whether selective D1 or D2 stimulation produces an enhanced psychomotor response in haloperidol-treated rats. Locomotion was recorded for 30 min before administration of a D1 (SKF38393 [56,57]; 0, 1 or 10 mg/kg [58,59]) or D2 agonist (quinpirole [23]; 0, 0.15 or 0.5 mg/kg [26,60]) and for 2 hours thereafter. Each rat received 2 agonist injections, counterbalanced.…”

Investigating the Effects of Tolcapone a Catechol-O-Methyltransferase Inhibitor on Learning and Memory in Passive Avoidance Task

“…The latter is a dopamine receptor antagonist that has a higher affinity for dopamine D2 receptors than D3 receptors (D2/D3 Ki ratio, 0,195). Occupancy of the dopamine D2 receptor by haloperidol reaches 99.8% 2 h after oral administration [17]. D2 receptors in the presynaptic endings of dopaminergic input fibres play a role in the regulation of hippocampal dependent learning and memory by modulating long-term depression (LTD) in the CA1 region of the hippocampus [27].…”

“…Haloperidol is a D2/D3 receptor antagonist ensuing blockage of the dopaminergic neurotransmission. It has higher affinity for dopamine D2 receptors than D3 receptors [17]. Haloperidol administration in doses 0.5-5 mg/kg bw induces muscle rigidity and catalepsy [4].…”