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Brainstem DOPAergic System
18
THEME A Catecholamine Biosynthesis and Storage
Brainstem DOPAergic System Yoshio Goshima Yokohama City University School of Medicine, Japan
L-3,4-Dihydroxyphenylalanine (DOPA) has been recognized as merely an intermediate in the catecholamine biosynthetic pathway. Since 1986, we have proposed that DOPA plays a role of neurotransmitter as well (Goshima et al., Brit J Pharmacol 89: 229, 1986; TiPS 14: 119, 1993). There are neurons that are tyrosine hydroxylase (TH) positive but aromatic amino acid decarboxylase (AADC)-negative, suggesting that these neurons probably contain DOPA as an end product. DOPA is released in a transmitter-like manner in vitro and in vivo (Goshima et al., J Neurochem 50, 1725, 1988; Yue et al., Neuroscience 62, 145, 1994). Under the inhibition of AADC, DOPA can produce pre- and postsynaptic responses. For example, microinjection of DOPA into the nucleus tractus solitarii (NTS), induces depressor and bradycardic responses in the anaesthetized in anaesthetized rats. This action is antagonized by DOPA cyclohexyl ester (DOPA CHE), a competitive antagonist of DOPA (Jpn J Pharmacol, 75, 305, 1995). However, specific receptor(s) for DOPA have not been identified yet. Recently, the gene product of ocular albinism 1 (OA1) was shown to possess DOPA-binding activity. Herein we investigate whether OA1 is a functional receptor of DOPA in the NTS. The effects of DOPA microinjected into depressor sites of the NTS on blood pressure and heart rates were examined in anesthetized rats. DOPA CHE microinjected into the NTS blocked phenylephrine-induced bradycardic response. The specific binding of [3H]-DOPA in OA-1 expressing cell line was displaced by DOPA CHE with a Ki value of 14.1 mM. Immunohistochemical examination revealed that OA1-positive cells adjacent to tyrosine hydroxylase (TH)-positive cell bodies and nerve fibers were detected in depressor sites of the NTS. In animals treated with the OA1 shRNA, OA1 expression in the NTS was suppressed, and depressor and bradycardic responses to DOPA microinjected into the NTS were almost completely blocked, while those to glutamate were not affected. We propose that OA1 is a receptor for DOPA that mediates baroreceptor reflex in the NTS. Ourfinding will provide insights into new physiological roles of DOPA, and may lead to a fundamental review of levodopa therapy.
THEME A Catecholamine Biosynthesis and Storage
Brainstem DOPAergic System Yoshio Goshima Yokohama City University School of Medicine, Japan
L-3,4-Dihydroxyphenylalanine (DOPA) has been recognized as merely an intermediate in the catecholamine biosynthetic pathway. Since 1986, we have proposed that DOPA plays a role of neurotransmitter as well (Goshima et al., Brit J Pharmacol 89: 229, 1986; TiPS 14: 119, 1993). There are neurons that are tyrosine hydroxylase (TH) positive but aromatic amino acid decarboxylase (AADC)-negative, suggesting that these neurons probably contain DOPA as an end product. DOPA is released in a transmitter-like manner in vitro and in vivo (Goshima et al., J Neurochem 50, 1725, 1988; Yue et al., Neuroscience 62, 145, 1994). Under the inhibition of AADC, DOPA can produce pre- and postsynaptic responses. For example, microinjection of DOPA into the nucleus tractus solitarii (NTS), induces depressor and bradycardic responses in the anaesthetized in anaesthetized rats. This action is antagonized by DOPA cyclohexyl ester (DOPA CHE), a competitive antagonist of DOPA (Jpn J Pharmacol, 75, 305, 1995). However, specific receptor(s) for DOPA have not been identified yet. Recently, the gene product of ocular albinism 1 (OA1) was shown to possess DOPA-binding activity. Herein we investigate whether OA1 is a functional receptor of DOPA in the NTS. The effects of DOPA microinjected into depressor sites of the NTS on blood pressure and heart rates were examined in anesthetized rats. DOPA CHE microinjected into the NTS blocked phenylephrine-induced bradycardic response. The specific binding of [3H]-DOPA in OA-1 expressing cell line was displaced by DOPA CHE with a Ki value of 14.1 mM. Immunohistochemical examination revealed that OA1-positive cells adjacent to tyrosine hydroxylase (TH)-positive cell bodies and nerve fibers were detected in depressor sites of the NTS. In animals treated with the OA1 shRNA, OA1 expression in the NTS was suppressed, and depressor and bradycardic responses to DOPA microinjected into the NTS were almost completely blocked, while those to glutamate were not affected. We propose that OA1 is a receptor for DOPA that mediates baroreceptor reflex in the NTS. Ourfinding will provide insights into new physiological roles of DOPA, and may lead to a fundamental review of levodopa therapy.