The antagonistic effect of a TRH (Thyrotropin-releasing hormone) analog, DN-1417 (gamma-butyrolactone-gamma-carbonyl-L-histidyl-L-prolinamide citrate) against reserpine-induced reduction of electroconvulsive threshold (EC50) and the involvement of monoaminergic mechanism were studied in mice. Reserpine (2 mg/kg, i.p.) reduced the EC50 to 55-77% of the control in association with the depletion of brain monoamine. TRH and DN-1417 significantly reversed the EC50 reduced by reserpine. DN-1417 partially recovered 5-HT level and increased in the brain levels of 3-methoxy-4-hydroxyphenylglycol, homovanillic acid and 5-hydroxyindoleacetic acid in reserpinized mice. Monoaminergic receptor blockers attenuated, but muscarinic blockers accelerated the antagonistic effects of DN-1417 on the EC50. Neither alpha-methyl-p-tyrosine nor FLA-63 inhibited the effects of DN-1417, whereas p-chlorophenylalanine not only inhibited the antagonistic effect of DN-1417 on the EC50 but also prevented the stimulation effect on 5-HT turnover. Therefore, the antagonistic effect of DN-1417 against reserpine on the EC50 is most likely mediated by the stimulation of monoamine turnover, especially 5-HT in mice.
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Department of Pharmacology, University of Colorado Health Sciences Center, Denver 80262, USA.
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