Different effects of fenfluramine isomers and metabolites on extracellular 5-HIAA in nucleus accumbens and hippocampus of freely moving rats.

The effects of optical isomers of fenfluramine and their metabolites, d- and l-norfenfluramine on the serotonergic system were studied in the nucleus accumbens and hippocampus of freely moving rats by in vivo voltammetry. Both isomers and the metabolites induced a slow, sustained decrease in 5HIAA but only d-fenfluramine and its metabolite, d-norfenfluramine, increased the 5HIAA levels in nucleus accumbens shortly after injection, the increase being greater after the metabolite. No effect could be detected in the hippocampus after the higher dose of d-fenfluramine.

Influence of verapamil on central and peripheral effects of prostacyclin on circulatory system in rats.

The influence of verapamil on cardiovascular effects of prostacyclin (PGI2) in rats was examined. PGI2 administered into the lateral brain ventricle (i.c.v.) or intravenously (i.v.) in a dose of 2.7 x 10(-8)mol evoked hypotension and tachycardia. Pretreatment with verapamil in a dose of 2.0 x 10(-5)mol/kg given intraperitoneally (i.p.) diminished hypotensive effect of PGI2 i.c.v. as well as inhibiting the influence of PGI2 i.c.v. and i.v. upon the heart rate. Bolus injection of PGI2 in a dose of 2.7 x 10(-10), 2.7 x 10(-9) or 2.7 x 10(-8)mol evoked biphasic inotropic and chronotropic effects on isolated rat heart. Short-term increase of the contractile force together with bradycardia and afterwards long-lasting decrease of contractility with sustained, slight tachycardia were observed. Verapamil in a concentration of 1.0 x 10(-6)M blocked biphasic inotropic effect and bradycardia after PGI2 administration. Because some central and peripheral cardiovascular effects of PGI2 were inhibited by verapamil, it is concluded that PGI2 may participate in transmembrane calcium ions movements.

Central effects of leukotriene C4 and D4 in rats and mice.

Leukotrienes (LTs) C4 or D4 in a dose of 12 nmoles were administered into the lateral ventricle (i.c.v.) of the rat brain under urethane anaesthesia, and the changes in the blood pressure, heart and respiratory rate were investigated. In other animals the behaviour was evaluated by means of the open field test, and the rectal body temperature was measured. Besides, the content of noradrenaline, 5-hydroxytryptamine and 5-hydroxyindole acetic acid was estimated in different parts of the brain following i.c.v. application of LTs. In mice the antinociceptive effect of LTs in a dose of 1.5 nmoles was examined in the hot plate test; furthermore, the effect of LTs on chlorpromazine catalepsy was measured. Only LTC4 caused a slight rise of the peripheral blood pressure, a decreased respiratory rate and affected the behaviour of rats. Both LTs decreased the rectal body temperature but did not alter the content of biogenic amines in the brain of rats. In mice both LTs did not change the reactivity to thermic pain stimulus; only LTC4 intensified chlorpromazine catalepsy. The results indicate that both LTs exert slight biological effects upon the central nervous system; however, it should be emphasized that LTC4 has a stronger effect.

Influence of H2 receptors blockade upon some central effects of prostacyclin in rats.

Prostacyclin (PGI2) administered icv into the lateral rat brain ventricle in a dose of 1 and 10 micrograms caused hypothermia and catalepsy. Joint administration of PGI2 and chlorpromazine produced a greater cataleptic effect than that observed after the neuroleptic alone. Cimetidine (CMT) 2 g/kg po administered 60 min before PGI2 icv injection inhibited hypothermic and cataleptogenic action of PGI2. CMT blocked the cataleptogenic effect of chlorpromazine as well as combination of it with PGI2. CMT inhibited cataleptogenic effect of haloperidol, but it did not block the catalepsy induced by joint administration of haloperidol and PGI2. PGI2 did not change concentration of noradrenaline and dopamine in different brain areas. The results indicate that H2 receptors take part in some central pharmacological effects of PGI2 in rats.

Effect of H2 receptor blockade upon hypothermic, cataleptogenic and antinociceptive action of prostacyclin (PGI)2 administered into the lateral rat brain ventricle.

Prostacyclin (PGI2) administered i.c.v. into the lateral rat brain ventricle in a dose of 1 and 10 micrograms causes hypothermia, catalepsy as well as a mild analgesic effect. Joint administration of PGI2 along with chloropromazine or morphine produces a greater cataleptic effect than that observed after application of neuroleptics and morphine alone. Cimetidine (CMT) (2 g/kg p.o.) administered 60 min before intraventricular PGI2 injection inhibits hypothermic and cataleptogenic action of the investigated prostaglandin. CMT blocks cataleptogenic effect of chloropromazine and morphine as well as the combination of these two substances with PGI2. CMT inhibits the cataleptogenic effect of haloperidol, but it does not block the catalepsy induced by joint administration of haloperidol and PGI2. CMT does not modify the analgesic action of PGI2. The results indicate that H2 receptors take part in some central pharmacological effects of PGI2 in rats.

Antinociceptive and behavioral effects of leu-enkephalin (LENK) or D-Ala2-met-enkephalinamide (DAMEA) in rats after central chemical sympathectomy or serotoninectomy.

In rats with central chemical sympathectomy induced by two injections into the lateral brain ventricle (icv) of 250 micrograms of 6-hydroxydopamine or with central chemical serotoninectomy induced by 75 micrograms of 5,6-dihydroxytryptamine icv the antinociceptive and behavioral effects of LENK (200 micrograms icv) or DAMEA (10 or 20 micrograms icv) were examined. The chemical lesion of central noradrenaline or dopamine neurons or specific lesion of serotonin neurons abolished antinociceptive effects of LENK and DAMEA. Both peptides inhibited exploratory activity of rats. Central chemical serotoninectomy but not sympathectomy reversed some behavioral effects induced by LENK and DAMEA. These results suggest modulatory influence of the central noradrenaline and serotonin neurons in the antinociceptive mechanism of action of enkephalins and the participation of the central serotonin neurons on the behavior of rats induced by enkephalins.

Central effects of D-Ala2-met-enkephalinamide on the blood pressure of rats after central chemical sympathectomy or serotoninectomy.

D-Ala2-met-enkephalinamide (DAMEA) in ethyl urethane anesthetised rats increased the blood pressure, decreased heart rate and frequency of respirations. DAMEA could act centrally as well as peripherally after the penetration from the cerebro-spinal into the blood stream. These effects were blocked by naloxone. 6-Hydroxydopamine inhibited the circulatory and respiratory action of DAMEA. 5,6-Dihydroxytryptamine reversed this action of DAMEA. It is suggested that central presynaptic catecholamine and serotonin neurons modulate the central effects of DAMEA on the circulatory system and respiration in rats.

Role of H2 receptors in the central and peripheral effects of prostacyclin [PGI2] on circulatory system in rats.

PGI2 1 or 10 micrograms iv caused a decrease of blood pressure and bradycardia in rats. PGI2 administered into lateral ventricle of rat brain [icv] exerted hypotensive effect and tachycardia. PGI2 10 micrograms icv increased histamine level in the hypothalamus and cortex of rat's brain, but it did not influence histamine content in the blood. Cimetidine [CMT] given 60 min earlier per os inhibited bradycardia caused by PGI2 iv administration and diminished hypotensive action and tachycardia produced by PGI2 icv.