MODULATION OF THE DOPAMINERGIC NEUROTRANSMISSION BY CONTROLLING THE ACTIVITY OF TYROSINE HYDROXYLASE

Abstract Background Dopaminergic neurotransmission is involved in several important issues for determination of our behaviour including motivation, decision-making, and motor-control. Therefore, its dysfunction is deeply involved in movement disorders and neuro-psychiatric disorders. Aims & Objectives Dopamine is synthesized from tyrosine by the action of tyrosine hydroxylase (TH). While TH is known to be a rate-limiting enzyme for the dopamine synthesis, we found that the metabolism of dopamine in the nerve terminal was different from that in the cell body (1,2). Besides, the mice overexpressing the active-form of TH using a micro-injection of AAV-Th into the midbrain showed a dramatically enhanced locomotor activity induced by methamphetamine (METH), while the dopamine levels in the nucleus accumbens (NAc) were almost unchanged. Our findings suggest that the levels of the TH activity rather than the dopamine contents would affect the METH responses. Results Here, we examined the locomotor activity induced by METH in heterozygous Th-knockout mice, in which the TH expression levels are about half of the wild-type while the dopamine levels were not decreased in the brain. We found that the locomotor activities of the heterozygous Th-knockout mice were less than that of the wild-type. Next, we administered a TH inhibitor, a-methyl-p-tyrosine (AMPT) to the mice. Administration of AMPT dose-dependently reduced the locomotor activities to METH. Discussion & Conclusion These results showed that the METH responses were affected by the TH activity and expression levels, and suggest that the TH activity would be a drug-target for patients suffered from addiction disorders by altering the metabolism of dopamine. References 1)TOKUOKA, H., MURAMATSU, S., SUMI-ICHINOSE, C., SAKANE, H., KOJIMA, M., ASO, Y., NOMURA, T., METZGER, D. &ICHINOSE, H. 2011. Compensatory regulation of dopamine after ablation of the tyrosine hydroxylase gene in the nigrostriatal projection. J Biol Chem, 286, 43549-58. 2)NAGO-IWASHITA, Y., MORIYA, Y., HARA, S., OGAWA, R., AIDA, R., MIYAJIMA, K., SHIMURA, T., MURAMATSU, S. I., IDE, S., IKEDA, K. &ICHINOSE, H. 2023. Overexpression of tyrosine hydroxylase in dopaminergic neurons increased sensitivity to methamphetamine. Neurochem Int, 164,105491.