Upregulation of heat-shock protein HSP-70 and glutamate transporter-1/glutamine synthetase in the striatum and hippocampus in haloperidol-induced dopamine-supersensitivity-state rats

• Published in: Pharmacology, biochemistry and behavior Vol. 211; p. 173288
• Main Authors: Kimura, Makoto, Oda, Yasunori, Hirose, Yuki, Kimura, Hiroshi, Yoshino, Kouhei, Niitsu, Tomihisa, Kanahara, Nobuhisa, Shirayama, Yukihiko, Hashimoto, Kenji, Iyo, Masaomi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2021
• Subjects: Animals; Antipsychotic; Antipsychotic Agents - pharmacology; Astrocyte; Brain - metabolism; Corpus Striatum - metabolism; Dopamine - metabolism; Dopamine supersensitivity state; DSS; Excitatory Amino Acid Transporter 2 - metabolism; GLT-1; Glutamate transporter-1; Glutamate-Ammonia Ligase - metabolism; Glutamine synthetase; Haloperidol - pharmacology; Heat shock protein-70; Hippocampus - metabolism; HSP-70; HSP70 Heat-Shock Proteins - metabolism; Male; Nucleus Accumbens - metabolism; Psychotic Disorders - metabolism; Rats; Rats, Wistar; Receptors, Dopamine D2 - metabolism; Schizophrenia, Treatment-Resistant - metabolism; Up-Regulation - drug effects; Dopamine supersensitivity state; HSP-70; DSS; Antipsychotic; Glutamate transporter-1; Glutamine synthetase; Astrocyte; GS; Heat shock protein-70; GLT-1
• ISSN: 0091-3057; 1873-5177
• DOI: 10.1016/j.pbb.2021.173288

The excessive blockade of dopamine D2 receptors (DRD2s) with long-term antipsychotic treatment is known to induce a dopamine supersensitivity state (DSS). The mechanism of DSS is speculated to be a compensatory up-regulation of DRD2s, but an excess blockade of DRD2s can also cause glutamatergic neuronal damage. Herein, we investigated whether antipsychotic-induced neuronal damage plays a role in the development of DSS. Haloperidol (HAL; 0.75 mg/kg/day for 14 days) or vehicle was administered to rats via an osmotic mini-pump. Haloperidol-treated rats were divided into groups of DSS rats and non-DSS rats based on their voluntary locomotion data. We then determined the tissue levels of glutamate transporter-1 (GLT-1)/glutamine synthetase (GS) and heat shock protein-70 (HSP-70) in the rats' brain regions. The levels of HSP-70 in the striatum and CA-3 region of the DSS rats were significantly higher than those of the control and non-DSS rats, whereas the dentate gyrus HSP-70 levels in both the DSS and non-DSS rats were increased versus the controls. The levels of GLT-1/GS in the CA-3 and nucleus accumbens were increased in the DSS rats. These results suggest that the DSS rats experienced striatal neuronal damage and indicate that a HAL-induced upregulation of HSP-70 and the GLT-1/GS system in the CA3 may be involved in the development of DSS. It remains unknown why the non-DSS rats did not suffer neuronal damage. In view of the need for therapeutic strategies for treatment-resistant schizophrenia, dopamine supersensitivity psychosis, and tardive dyskinesia, further investigations of our findings are warranted. •Dopamine supersensitivity state (DSS) rats, but not the non-DSS rats, experienced striatal neuronal damage.•Upregulation of the GLT-1/GS and HSP-70 in the hippocampal CA-3 might also be involved in the development of the DSS.•Chronic treatment with high doses of HAL may become largely destructive by causing neuronal damage in the dentate gyrus.