Increase in rat regional brain cyclic nucleotides by thyrotropin-releasing hormone (TRH) and its analog DN-1417.
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概要
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The effects of thyrotropin-releasing hormone (TRH) and its analog γ-butyrolactone-γ-carbonyl-L-histidyl-L-prolinamide citrate(DN-1417) on adenosine 3', 5'-monophosphate (cyclic AMP) and guanosine 3', 5'-monophosphate (cyclic GMP) levels in rat brain were investigated using a radioimmunoassay method. The time course of elevation of these nucleotides in various brain regions after administration of DN-1417 showed a peak at 5 to 15 min followed by a gradual decrease. DN-1417 (1 to 10 mg/ kg i.p.) caused a dose-related increase in cyclic AMP levels in the cerebellum, cerebral cortex, striatum, nucleus accumbens, thalamus, hypothalamus and brain stem; whereas significant increases in cyclic GMP were observed in the cerebellum, nucleus accumbens and brain stem. TRH (3 to 10 mg/kg i.p.) caused significant increases of cyclic AMP in the cerebellum, cerebral cortex, nucleus accumbens, thalamus and brain stem and also caused an increase in cerebellar cyclic GMP. With one exception, DN-1417, apomorphine (Apo), methamphetamine (MAP) (all, 3 mg/kg i.p.) and TRH (10 mg/kg i.p.)-induced increases in cyclic nucleotides were blocked by pimozide (1 mg/kg i.p., 4 hr before), a dopamine receptor blocker; the exception was a TRH-induced increase in cerebellar cyclic GMP. These increases were not blocked by propranolol (10 mg/kg i.p., 30 min before), an adrenergic β-receptor blocker. α-Methyl-p-tyrosine (α-MT, 250 mg/kg i.p., 4 hr before), a tyrosine hydroxylase inhibitor, almost completely blocked DN-1417- and MAP-induced increases in cyclic nucleotides, slightly blocked TRH-effects, and had no effect on Apo-effects. These in vivo results were confirmed in an in vitro system using brain slices. The addition of DN-1417 (10<SUP>-4</SUP> M) or TRH (10<SUP>-3</SUP> M) significantly enhanced the spontaneous [<SUP>3</SUP>H]-dopamine and [<SUP>3</SUP>H]-norepinephrine release from the superfused slices of the rat nucleus accumbens and cerebral cortex in vitro. The addition of DN-1417 (10<SUP>-4</SUP> M) or TRH (10<SUP>-4</SUP>M) had no effect on the activities of adenylate cyclase and guanylate cyclase, although only a high concentration (10<SUP>-3</SUP> M) of DN-1417 inhibited the cyclic AMP- and cyclic GMP-hydrolytic activities in various brain region homogenates. These results suggest that DN-1417 does not produce an increase in the levels of cyclic nucleotides by direct receptor-enzyme activation, but that DN-1417 like MAP causes the increase through endogenous catecholaminergic, particularly dopaminergic activation.
- 公益社団法人 日本薬理学会の論文
著者
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NAGAWA YUJI
Central Research Division, Takeda Chemical Industries, Ltd.
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NAGAI YASUO
Central Research Division, Takeda Chemical Industries, Ltd.
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NARUMI SHIGEHIKO
Central Research Division, Takeda Chemical Industries, Ltd.
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Nagawa Yuji
Central Research Division Takeda Chemical Industries Ltd.
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Nagai Yasuo
Central Research Division Takeda Chemical Industries Ltd.
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SAJI Yoshiaki
Central Research Division, Takeda Chemical Industries, Ltd.
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SAJI YOSHIAKI
Central Research Division, Takeda Chemical Industries Ltd.
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