Abstract
Effects of a TRH (thyrotropin-releasing hormone) analog, DN-1417 (r-butyrolactone-r-carbonyl-L-histidyl-L-prolinamide citrate), with regard to the rate of local cerebral glucose utilization (LCGU) were assessed using the autoradiographic 2-deoxy-D-[14C]glucose method to clarify the possible sites of action in conscious and pentobarbitalized rats. DN-1417 (0.5-5 mg/kg, i.v.) significantly shortened the pen-tobarbital-induced sleeping time in a dose dependent manner, and this effect of DN-1417 was reduced by intracerebroventricular (i.e.v.) pretreatment with atropine methylbromide (20 βg). DN-1417 (5 mg/kg, i.v.) by itself slightly increased the LCGU in the thalamus dorsomedial nucleus and mammillary body and significantly increased it in the septal nucleus. Pentobarbital (30 mg/kg, i.v.) alone produced a marked and diffuse reduction in LCGU throughout the brain at a rate of about 46% of the control. DN-141 7 (5 mg/kg,i.v.) markedly reversed the reduction of LCGU induced by pentobarbital. The antagonistic effect of DN-1417 in LCGU was about twice as potent as that of TRH. Locally, significant reversal effects by DN-1417 were observed in the hypothalamus, septal nucleus,hippocampus, mammillary body, thalamus dorsomedial nucleus, caudate-putamen,nucleus accumbens, pontine gray matter and so on. These actions of DN-1417 were almost completely abolished in all areas except for the visual cortex under the conditionof pretreatment with atropine methylbromide (20 μ, i.c.v.). On the other hand, pimozide (1 mg/kg, i.p.) augmented the actions of DN-1417. Thus, DN-1417 seems to act on thelevel of consciousness via a reticulo-thalamo-cortical system, and reverses the LCGU reduction induced by pentobarbital via a cholinergic mechanism. The hypothalamus appears to be a crucial site in mediation of the antagonistic action of DN-1417 on pentobarbital.
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