title: Behavioural and biochemical evidence for the release of noradrenaline in mouse brain by TRH and some of its biologically stable analogues.
abstract: Small doses of clonidine probably induce hypoactivity (a distinct form of sedation) by stimulating presynaptic alpha 2-adrenoceptors. This was attenuated by injection of 0.1-10 mg/kg of thyrotropin releasing hormone (TRH) or its biologically stable analogues, CG3509, CG3703 and RX77368, when these were given 10 min before clonidine. This effect was dose-dependent in all cases, but the analogues were more potent than TRH. The TRH metabolites, TRH acid and histidyl-proline diketopiperazine (10 mg/kg) were without effect. This response was still attenuated by the analogues, but not TRH, when these were given 1 hr before clonidine. The results, therefore, suggested that it was the basic tripeptide structure which was active and TRH was less potent than its analogues because of rapid metabolism. Attenuation of hypoactivity by TRH and analogues was not due to increased dopaminergic function because apomorphine (5 mg/kg) was ineffective. Thyrotropin releasing hormone (20 mg/kg), CG3509 (10 mg/kg) and CG3703 (1 mg/kg) also induced locomotor activity and produced various other behavioural changes. This was inhibited by prazosin (3 mg/kg) and haloperidol (0.5 mg/kg) but not by yohimbine (1 mg/kg). Apomorphine (5 mg/kg)-induced activity was inhibited by haloperidol and yohimbine but not by prazosin. This indicated that the activity produced by the TRH compounds, but not apomorphine, was partly mediated by alpha 1-adrenoceptors. Both CG3509 (10(-5) and 10(-4) M) and RX77368 (10(-4) M) evoked the release of endogenous noradrenaline from slices of hypothalamus in vitro. The TRH analogues, however, had no affinity for alpha 1- or alpha 2-adrenoceptors in ligand-receptor binding experiments. Viewed overall, the data showed that TRH and its analogues induced the release of noradrenaline in the brain. In addition, a comparison of the behavioural effects of TRH compounds with dopamine and alpha 1-adrenoceptor agonists suggested that in mice these behavioural responses resulted from stimulation of both noradrenergic and dopaminergic function.
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003000:Clonidine / Q000494:pharmacology; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism*; D011761:Pyrrolidonecarboxylic Acid / Q000031:analogs & derivatives; D013973:Thyrotropin-Releasing Hormone / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*
chemical_list: D000317:Adrenergic alpha-Antagonists; C036430:orotirelin; C031926:montirelin; D013973:Thyrotropin-Releasing Hormone; C027979:L-pyroglutamyl-L-histidyl-3,3-dimethylprolinamide; D003000:Clonidine; D001058:Apomorphine; D011761:Pyrrolidonecarboxylic Acid; D009638:Norepinephrine