Neurochemical study on pharmachological action of antimanic drugs using by microdialysis method

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Two animal experiments and one human study were performed for investigating the mode of action of antimanic drugs.In a human study, growth hormone(GH)response to desmethylimipramine(DMI)and clonidine was measured in healthy subjects. Of six subjects tested three times at 6-month intervals, five always showed a stable growth hormone response, whereas only one had a rather instable GH response. The blunted GH response to DMI and clonidine was seen in a subject. These results suggested that DMI and clonidine stimulated GH secretion test may be vulnerability markers for central postsynaptic a2 adrenergic function. Those were published in "Seishinigaku".In animal studies, locomotor activity counts were determined in Fischer 344 rats after a single administration of a phenylethanolamine-N-methyltransferase(PNMT)inhibitor, DCMB. This drug inhibits PNMT as well as az adrenoceptor. Then, yohimbine, pure az adrenoceptor inhibitor, was used as a positive control. In Fischer 344 rats, a2 adrenocep … More tor subsensitivity and higher PNMT activity were found in the hypothalamus and lower brainstem compared with Buffalo rats. These drugs profused hyperactivity in Fischer 344 rats, but DCMB induced hyperactivity was significantly higher than that induced by yohimbine. This result suggested that adrenergic neuron may regulate central alpha_2 adrenoceptor sensitivity. The effect of yohimbine on 3 methoxy 4 hydroxyphenylethylenglycol(MHPG)in extra cellular fluid of hypothalamus was determined by brain dialysis method in Wistar strain rats. MHPG levels were measured by high performance liquid chromatography. MHPG levels were increased after a single intraperitoneal injection of yohimbine. This result suggested that yohimbine may produce presynaptic alpha_2 adrenoceptor inhibition and that MHPG may a biological marker of presynaptic alpha_2 adrenoceptor sensitivity in hypothalamus. These results were reported at the 5th international Congress of Biological Psychiatry, the 20th Congress of Japanese Psychopharmacology and the 12th Congress of Japanese Biological Psychiatry. Less