Fabrizio Venturi

Mapping of brain sites sensitive to the antidipsogenic effect of tachykinins

The present study investigated the sensitivity of 12 forebrain and midbrain structures to the antidipsogenic effect of eledoisin, physalaemin and substance P on angiotensin-induced drinking. The three tachykinins elicited the most potent effects when injected into the nucleus preopticus medialis, the nucleus anterior hypothalami and the subfornical organ. In other sites (nuclei lateralis, ventromedialis and posterior hypothalami, nucleus septi lateralis, nucleus interpeduncularis and substantia grisea periventricularis) the effect was lower, and most of these sites showed different sensitivity to the three tachykinins. Finally, the nucleus septi medialis, the nucleus preopticus lateralis and the substantia nigra were refractory to the three tachykinins. These results show that: (1) the antidipsogenic effect of tachykinins can be elicited not only in forebrain, but also in midbrain structures such as the substantia grisea periventricularis and the nucleus interpeduncularis; (2) the distribution of brain sites sensitive to the antidipsogenic effect of substance P and physalaemin is always overlapping, while this is not true for eledoisin. This probably reflects selective distribution and/or activation of distinct subtypes of tachykinin receptors.

Physalaemin, a new potent antidipsogen in the rat

Abstract In this paper the effect on water intake of intracerebroventricular administration of the naturally occurring endecapeptide physalaemin is reported. Drinking was induced by intracerebroventricular injection of angiotensin II (100 ng/rat) or carbachol (300 ng/rat), water deprivation or NaCl load. Physalaemin produced a dose-dependent inhibition of water intake induced by angiotensin II. The inhibition was virtually complete at the dose of 500 ng/rat. The minimum dose employed (50 ng/rat) produced a 6% drinking inhibition. Physalaemin inhibited drinking induced by carbachol. The threshold dose was 125 ng rat . A virtually complete inhibition was produced by physalaemin, 1μg. The effect was dose-dependent. In water deprived rats 10 μg, but not lower doses, of the peptide produced a significant inhibition of water intake. The effect was short-lasting and ceased 30 min after the injection. Physalaemin was completely ineffective in sodium chloride-loaded rats, in spite of the very large doses employed (up to 5 mg/rat). The results of these experiments demonstrate that physalaemin is a potent antidipsogenic agent, but do not allow any conclusion to be made about the mechanism of its inhibitory effect. However, it is reasonable to propose that the effect is specific to the CNS and not simply due to the very marked vascular activity of the peptide.

Behavioural and electrocortical modifications induced in the rat by intraventricular injection of physalaemin and eledoisin

The effects of intraventricular injection of eledoisin and physalaemin in the rat were studied. Both peptides reduced explorative behaviour; eledoisin, but not physalaemin, produced catatonia, reduction of muscular strength, tremor and sialorrhea. The electrocorticogram showed the signs of a depressive effect both after physalaemin and eledoisin administration.

Indolizine derivatives with biological activity VI 1-(2-aminoethyl)-3-benzyl-7-methoxy-2-methylindolizine, benanserin structural analogue

In continuing the search for new biologically active agents in the indolizine field, 1-(2-aminoethyl)-3-benzyl-7-methoxy-2-methyl-indolizine was synthesized and evaluated for its in vitro activities on smooth muscle. Anti-histamine, anti-acetylcholine and anti-5-hydroxytryptamine activities, in comparison to those of the indole analogue benanserin, are reported.

Application of taste reactivity to study the mechanism of alcohol intake inhibition by the tachykinin aminosenktide.

Tachykinin NK-3 receptor agonists reduce alcohol intake in alcohol-preferring rats; the nucleus basalis magnocellularis (NBM) is highly sensitive to their effect. Tachykinins and their receptors are widely distributed in gustatory pathways and NK-3 receptor agonists have been reported to modify taste reactivity to salt solutions in rats. The present study evaluated whether the TK NK-3 receptor agonist aminosenktide (NH2-SENK) influences taste reactivity to ethanol solutions. Genetically selected Marchigian Sardinian alcohol-preferring (msP) rats were employed. In response to the intraoral infusion (0.8 ml in 1 min) of 10, 20, 40, or even 60% ethanol solution, ethanol-naive rats showed a large number of ingestive reactions and a much lower number of aversive reactions. Two min before the intraoral infusion of 10 or 40% ethanol, NH2-SENK was injected either into the lateral ventricle (LV) or into the NBM. Doses of NH2-SENK that markedly reduce alcohol intake, 125 ng/rat into the LV or 5 ng/site into the NBM, did not modify the ingestive reactions and, in some instances, reduced the aversive reactions to ethanol solutions in ethanol-naive rats. Injections of 125 ng/rat into the LV failed to modify taste reactions in ethanol-experienced rats. The present results show that msP rats have an innate hedonic evaluation of ethanol solutions, even of high concentration. Moreover, they indicate that reduction of ethanol intake induced by TK NK-3 receptor agonists in alcohol-preferring rats does not depend on influences on gustatory processes.

Synthesis and pharmacological properties of 2-azabicyclo[2.2.2]octane derivatives representing conformational restricted isopethidine analogues

Abstract The synthesis and preliminary pharmacological evaluation of the epimeric 2-methyl-6-phenyl-6-carbethoxy-2-azabicyclo[2.2.2]octanes, representing conformationally restricted isopethidine analogues, are reported.

Indolizine derivatives with biological activity V. 1-(2-Aminoethyl)-2-methylindolizine and its N-alkyl derivatives

Abstract In continuing the search for new biologically active agents in the indolizine field, 1-(2-aminoethyl)-2-methylindolizine and some N -alkyl derivatives have been synthesized. Preliminary pharmacological evaluation showed that these compounds exhibited anti-acetylcholine, anti-histamine and central nervous system (CNS) depressant activities.

Hypotensive effect in dogs and rats of intravenous injections of the α1-adrenoreceptor antagonist benoxathian

The hypotensive effect of the alpha 1-adrenoreceptor antagonist benoxathian has been evaluated in rats and dogs, in comparison to that evoked by WB 4101 and prazosin. In anaesthetized dogs, i.v. injection of benoxathian (25-100 micrograms/kg), WB 4101 (5-25 micrograms/kg) and prazosin (50 micrograms/kg) produced an immediate fall in diastolic blood pressure, which reached a maximum at about 30 sec after drug administration. Whereas the hypotensive effect of prazosin persisted up to 3 hr following injection, the effect of both benoxathian and WB 4101 completely disappeared after 30-60 min. The hypotensive effect of benoxathian was dose-dependent. Pressor responses to i.v. noradrenaline (5 micrograms/kg), adrenaline (5 micrograms/kg) and phenylephrine (20 micrograms/kg) were markedly inhibited (60-75%) by benoxathian (100 micrograms/kg) whilst the pressor response to angiotensin II (0.05 micrograms/kg) was not reduced, but indeed slightly increased. The hypotensive effect of benoxathian (100 micrograms/kg) was abolished following pre-treatment with prazosin (50 micrograms/kg) or hexamethonium (1000 micrograms/kg). In anaesthetized rats similar results were obtained although recovery in blood pressure from the initial drop after i.v. injection of the drugs was slower than in dogs. Benoxathian was slightly more toxic than WB 4101 in rats. In conclusion, present findings show that benoxathian causes a profound hypotensive effect in dogs and in rats through postsynaptic alpha-adrenoreceptor blockade; however its effect, as well as that of WB 4101, is shorter lasting than that of prazosin.

Inhibition of Ang II-Induced Drinking by Dermorphin Given into the SFO or into the Lateral Ventricle of Intact or of SFO Lesioned Rats

Dermorphin is an opioid heptapeptide found in the skin of South American frogs of the Phyllomedusa genus1,2. Afterwards, dermorphin-like immunoreactivity has been detected in the central nervous system of rats, pigs and frogs3.