Reduction of dopamine and glycogen synthase kinase-3 signaling in rat striatum after continuous administration of haloperidol

• Published in: Pharmacology, biochemistry and behavior biochemistry and behavior, 2021-03, Vol.202, p.173114-173114, Article 173114
• Main Authors: Kimura, Makoto, Oda, Yasunori, Kimura, Hiroshi, Nangaku, Masahito, Hirose, Yuki, Niitsu, Tomihisa, Kanahara, Nobuhisa, Shirayama, Yukihiko, Hashimoto, Kenji, Iyo, Masaomi
• Format: Article
• Language: English
• Subjects: AKT; Dopamine; Dopamine supersensitivity psychosis; Dopamine supersensitivity state; DRD2; GSK-3
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/j.pbb.2021.173114

Some individuals with schizophrenia present with a dopamine supersensitivity state (DSS) induced by a long-term administration of excessive antipsychotics; this is recognized as dopamine supersensitivity psychosis (DSP). The mechanisms underlying DSP are not established. Here, we investigated dopamine signaling in DSS rats. Haloperidol (HAL; 0.75 mg/kg/day for 14 days) or vehicle was administered to rats via an osmotic mini-pump. We then screened DSS rats from HAL-treated rats by a voluntary locomotion test. The striatal levels of dopamine (DA) and its metabolites 3,4-hydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were determined, as were the levels of protein kinase v-akt murine thymoma viral oncogene homolog (AKT), glycogen synthase kinase-3 (GSK-3), and phosphorylated GSK-3 in the striatal regions. In the DSS rats, the DA, DOPAC, and HVA levels were significantly decreased. In a western blot analysis, the DSS rats exhibited a significant decrease in GSK-3α/β and an increase in the pGSK-3β/GSK-3β ratio, whereas AKT was not changed. Our results indicated that the DSS rats had hypofunction of the basal dopamine release and AKT/GSK-3 signaling even at 7 days after the antipsychotic was discontinued. Protracted reductions in pre- and post-dopamine D2 receptor signaling might cause prolonged DSS. •Dopamine supersensitivity psychosis could contribute the foundation for treatment resistance in individuals with schizophrenia.•Dopamine supersensitivity state (DSS) rats exhibited hypofunction in the basal striatal level of dopamine even at 1 week after the cessation of haloperidol.•The expression and activity of glycogen synthase kinase-3 were also significantly decreased in DSS rats.•These alterations of both the pre- and post-dopamine D2 receptor signaling attenuation might cause persistent DSS.