2-(3-trifluoromethylphenyl)histamine and 2-(2-aminoethyl)thiazole

The aim of this study was to elucidate the effect caused by the inhibition of histamine catabolism by means of metoprine and the activation of histamine H(1) receptors by selective agonists on learning and memory processes, using a modified method of the mouse passive avoidance test. The administration of scopolamine 1 mg/kg (i. p.) immediately after the training session caused statistically-significant amnesia during the retention trial performed 24 h later. Piracetam (30 mg/kg (i.p.)), used as a positive control, and administered 20 min before the training session, prevented scopolamine-induced memory impairment. The histamine-N-methyltransferase inhibitor, metoprine, (2 and 5 mg/kg (s.c.)) had effects similar to those of this nootropic drug. The highly-selective H(1) receptor agonist, 2-(3-trifluoromethylphenyl)histamine (FMPH) (2.65 and 6.5 microg/mouse (i.c.v.)) and the less selective agonist, 2-thiazolylethylamine (2-TEA) (0.1 and 0.3 microg/mouse (i.c.v.)) both antagonized the scopolamine-induced amnesia significantly and in a dose-related manner. The selective H(1) receptor antagonist, pyrilamine (20 mg/kg (i.p.)), revealed no effect by itself, but significantly prevented the antiamnesic action both that of the H(1) receptor agonists, and that of endogenous histamine, released by metoprine, thus suggesting a cognitive improvement via the activation of H(1) receptors.

Topics: Amnesia; Animals; Avoidance Learning; Enzyme Inhibitors; Histamine; Histamine Agonists; Histamine H1 Antagonists; Histamine N-Methyltransferase; Male; Memory; Mice; Mice, Inbred Strains; Muscarinic Antagonists; Nootropic Agents; Piracetam; Pyrilamine; Pyrimethamine; Receptors, Histamine H1; Scopolamine; Thiazoles

1. Effects of substances which are able to alter brain histamine levels and two histamine H1 receptor agonists were investigated in mice by means of an animal model of depression, the forced swim test. 2. Imipramine (10 and 30 mg kg(-1), i.p.) and amitriptyline (5 and 15 mg kg(-1), i.p.) were used as positive controls. Their effects were not affected by pretreatment with the histamine H3 receptor agonist, (R)-alpha-methylhistamine, at a dose (10 mg kg(-1), i.p.) which did not modify the cumulative time of immobility. 3. The histamine H3 receptor antagonist, thioperamide (2-20 mg kg(-1), s.c.), showed an antidepressant-like effect, with a maximum at the dose of 5 mg kg(-1), which was completely prevented by (R)-alpha-methylhistamine. 4. The histamine-N-methyltransferase inhibitor, metoprine (2-20 mg kg(-1), s.c.), was effective with an ED50 of 4.02 (2.71-5.96) mg kg(-1); its effect was prevented by (R)-alpha-methylhistamine. 5. The histamine precursor, L-histidine (100-1000 mg kg(-1), i.p.), dose-dependently decreased the time of immobility [ED30 587 (499-712) mg kg(-1)]. The effect of 500 mg kg(-1) L-histidine was completely prevented by the selective histidine decarboxylase inhibitor, (S)-alpha-fluoromethylhistidine (50 mg kg(-1), i.p.), administered 15 h before. 6. The highly selective histamine H1 receptor agonist, 2-(3-trifluoromethylphenyl)histamine (0.3-6.5 microg per mouse, i.c.v.), and the better known H1 agonist, 2-thiazolylethylamine (0.1-1 microg per mouse, i.c.v.), were both dose-dependently effective in decreasing the time of immobility [ED50 3.6 (1.53-8.48) and 1.34 (0.084-21.5) microg per mouse, respectively]. 7. None of the substances tested affected mouse performance in the rota rod test at the doses used in the forced swim test. 8. It was concluded that endogenous histamine reduces the time of immobility in this test, suggesting an antidepressant-like effect, via activation of H1 receptors.

Topics: Animals; Antidepressive Agents; Histamine; Histamine Agonists; Male; Mice; Receptors, Histamine H1; Reference Standards; Stress, Physiological; Thiazoles

To characterize the mechanism of the analgesic action of H1 antihistaminics the effects of a new, highly selective agonist, 2-(3-trifluoromethylphenyl)histamine dihydrogenmaleate (FMPH), and of the better known H1 agonist, 2-thiazolylethylamine (2-TEA), were studied on pain threshold by means of three different kinds of tests for nociception (mouse hot plate and abdominal constriction, and rat paw pressure tests). Low doses of both substances (2.65 and 6.5 microg/animal i.c.v. for FMPH in the hot plate and paw pressure tests, and 0.3 microg/rat i.c.v. for 2-TEA in the paw pressure test) were slightly but significantly hypernociceptive. The selective H1 receptor antagonist, pyrilamine maleate (10-30 mg/kg s.c.), induced a dose-dependent antinociception in all three tests, and both FMPH and 2-TEA prevented its effect, but not that of morphine, thus indicating action on H1 receptors. The same low doses of FMPH were also able to enhance animals' spontaneous motility and curiosity. High doses of FMPH (13.23-132.3 microg/mouse i.c.v.) raised the pain threshold, but due to the severe motor impairment evidenced by the rota rod test, this cannot be considered as real antinociception. An increase in the pain threshold lacking any motor impairment was observed for tenfold higher doses of 2-TEA (3 and 10 microg/mouse i.c.v.). This may be due to action on H2 receptors, with the reported relative potency of 2-TEA for H1 and H2 receptors being about 12:1. It is therefore suggested that H1 receptor activation increases sensitivity to noxious stimuli.

Topics: Animals; Histamine; Histamine Agonists; Histamine H1 Antagonists; Male; Mice; Nociceptors; Pain Measurement; Pyrilamine; Rats; Rats, Wistar; Receptors, Histamine H1; Receptors, Histamine H2; Thiazoles