A TRH analog (DN-1417): Motor stimulation with rearing related to catecholaminergic mechanisms in rats

Abstract

The effect of an analog of TRH, γ-butyrolactone-γ-carbonyl-histidyl-prolinamide citrate (DN-1417) on motor activity was studied in rats. Peripheral administration of DN-1417 (0.2–20 mg kg , i.p.) caused a significant, dose-dependent increase in total spontaneous motor activity, with a definite increase in rearing behaviour. Both increases in spontaneous motor activity and rearing behaviour were markedly inhibited by pretreatment with chlorpromazine (1, 5 mg kg , i.p.), haloperidol (0.1, 0.5 mg kg , i.p.), pimozide (1 mg kg , i.p.) or α-methyltyrosine (250 mg kg , i.p.). Only stimulation of rearing behaviour was selectively attenuated by phenoxybenzamine (5 mg kg , i.p.) or FLA-63 (25 mg kg , i.p.) at doses producing no significant effect on spontaneous motor activity. Although propranolol (10 mg kg , i.p.) and methysergide (10 mg kg , i.p.) had no effect, atropine (10 mg kg , i.p.) and mecamylamine (10 mg kg , i.p.) respectively potentiated and counteracted the effects of DN-1417. Concerning the stimulation of spontaneous motor activity, the nucleus accumbens and lateral hypothalamic area were most sensitive to DN-1417, and the lateral hypothalamic area was the most sensitive site for the stimulation of rearing. Furthermore, DN-1417 (5 × 10 −5 M) significantly enhanced the spontaneous release of [ 3H]dopamine from the rat nucleus accumbens slices in vitro. These findings indicate that the motor stimulatory action of DN-1417 appears to be mediated primarily via a dopaminergic mechanism by enhancing the release of dopamine from nerve terminals, including the nucleus accumbens in the mesolimbic dopamine system, and, in turn, the rearing may be mediated via noradrenergic mechanism.