Neurotensin-like peptides acting as functional antagonists of serotonin receptors were revealed in the head-shaking test on mice. The neurotensin-like peptides block the serotonin-induced platelet aggregation in humans. Radioligand binding assay showed that neurotensin-like peptides modulate specifi c binding of 5НТ2 serotonin receptor antagonist ketanserin, but have no effect on binding of ligands of 5HT2c receptor mesulergine and 5HT1а receptors NAN-190. Similar effects of neurotensin-like peptides in the experiments in vivo and in vitro suggest that the mechanisms of the detected antipsychotic effect of the peptides can be mediated by serotonin receptors.
The distribution of the glyprolines Pro-Gly-Pro and Thr-Lys-Pro-Arg-Pro-Gly-Pro (Selanc) was analyzed and compared in tissues of rat organs after different ways of their administration using the peptides uniformly labeled with tritium. Comparative data on changes in concentrations of the peptides in the rat organs after their intraperitoneal, intranasal, intragastric, and intravenous administration are given. The intranasal administration of both peptides was shown to be optimal for the delivery of glyproline molecules in the CNS. A high affinity of the studied glyprolines for gastric tissues was found for all the ways of their administration. We suggest that a high efficiency of action of glyprolines on homeostasis of the gastric mucous tunic was partially provided by accumulation of these peptides (to high concentrations) in gastric tissues.
Peptide anxiolytic selank (Thr-Lys-Pro-Arg-Pro-Gly-Pro) applied intraperitoneally in doses of 0.01, 0.1, 1.0, and 10.0 mg/kg to mice reduces behavioral manifestations of dopaminergic system induced by apomorphine in the verticalization test. This effect was comparable to that of atypical antipsychotic olanzapine in near-therapeutic doses (0.1 and 1.0 mg/kg, intraperitoneally) and was blocked with nonselective opioid receptor antagonist naloxone (10 mg/kg, intraperitoneally). Radioreceptor assay showed that selank did not displace nonselective D2-dopamine receptor antagonist (3)H-spiperone (EC50>100 microM) and delta- and micro-opioid receptor ligand 3H-DADLE (EC50>40 microM) from specific binding sites on rat brain membranes. It is hypothesized that the revealed behavioral effect of selank is mediated by its modulating effect on the endogenous opioid system and specifically, by its effect on activity of enkephalin-degrading enzymes.
Comparative study of plasma activities of enkephalin-degrading enzymes in mice with different phenotypes of emotional and stress reactions revealed significant differences between intact BALB/c and C57Bl/6 mice by the half-life of plasma leu-enkephalin. Selank in a dose of 100 micrograms/kg produced an anxiolytic effect in the open-field test and increased the half-life of plasma leu-enkephalin in BALB/c mice, but had no effect on behavioral reactions and enkephalinase activities in C57Bl/6 mice. Our results suggest that anxiolytic activity of Selank is associated with inhibition of enkephalin-degrading enzymes.
The anxiolytic effects of the 6-opioid receptor agonist dalargin revealed in two behavioral tests in outbred albino rats were blocked by naloxone. The effect of dalargin depended on the initial locomotor activity and was observed after central and peripheral administration of the drug. The ~t-opioid receptor agonist DAGO produced no behavioral effects. It is suggested that the development of behavioral manifestations of anxiety and phobia is related to more than one opioid-dependent mechanism, which can explain the peculiarities of the anxiolytic effect of dalargin.
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