TRH analog MK-771 reverses neurochemical and learning deficits in medial septal-lesioned rats.

Microinjection of ibotenic acid into medial septum of rats decreased choline acetyltransferase (CAT) and high-affinity choline uptake (HACU) activities in hippocampus and retarded the learning of a spatial memory task in the radial-arm maze. Administration of MK-771, a stable TRH analog, to such animals restored HACU activity in hippocampus to normal levels. Daily treatment of rats with MK-771 prior to maze running also restored the animals' learning ability. MK-771 did not enhance hippocampal HACU activity or maze performance in sham-lesioned rats. These results suggest that MK-771 reversed the ibotenic acid-induced memory deficit by restoring septohippocampal cholinergic function. MK-771 and other TRH analogs may represent novel agents for improving memory deficits produced by cholinergic insufficiency in Alzheimer's disease.

Effects of intraseptal drug administration on pentobarbital-induced narcosis and hippocampal choline uptake.

Effects of injection of drugs into the septum on pentobarbital anesthesia were investigated in the rat. Intraseptal microinjection of bicuculline (5 micrograms), arecoline (2 micrograms), and phenylephrine (5 micrograms) shortened, MK-212 (5 micrograms) prolonged, and atropine (2 micrograms) had no significant effect on the duration of pentobarbital-induced loss of righting reflex. Bicuculline and arecoline increased and MK-212 reduced hippocampal cholinergic activity as measured by change in hippocampal sodium-dependent high-affinity choline uptake after intraseptal drug injection. It is concluded that activation of the septal-hippocampal cholinergic pathway might be an important neuromechanism for recovery from pentobarbital-narcosis.

Neural mechanisms mediating the hyperthermia elicited by prostaglandin E2 injected into the preoptic-anterior hypothalamus.

The neuromechanism mediating the hyperthermia induced by injection of PGE2 into the preoptic/anterior hypothalamus (PO/AH) was investigated in the rat. Pretreatment of rats with intraperitoneal injection of atropine sulfate blocked, whereas pretreatment with atropine methyl bromide had no significant effect on the hyperthermia. In a second series of experiments, atropine sulfate was microinjected into different regions of the hypothalamus and the thalamus in an attempt to locate the central cholinergic synapses involved in the PGE2-induced hyperthermia. The hyperthermia was blocked by atropine injection into the dorsal/dorsomedial hypothalamic area (DH), but was not significantly affected by injection into the PO/AH, ventromedial hypothalamus, or the thalamic area above the DH. Moreover, microinjection of the cholinergic agonist carbachol (0.5 microgram) into the DH could also elicit hyperthermia. Thus, our data suggest that the hyperthermia induced by PGE2 administration into the PO/AH is mediated by a cholinergic mechanism in the DH.

Sodium-dependent, high-affinity choline uptake in hippocampus and frontal cortex of the rat affected by acute restraint stress.

Acute (45-min) restraint stress decreased sodium-dependent, high-affinity choline uptake in the hippocampus and frontal cortex of rats. The effect of restraint on the hippocampus was blocked, whereas that on the frontal cortex was not significantly affected, by pretreatment of the rats with the narcotic antagonist naltrexone (1 mg/kg, i.p.) immediately prior to restraint.

Central action of low-molecular weight polyphloretin phosphate fraction in rats.

The central effects of a low-molecular weight fraction of polyphloretin phosphate (PPP) with molecular weight about 4600 were studied using several behavioural tests in animals (Lat's test, open-field test, hold-board test, irritability, spontaneous motor activity), chlorpromazine-induced catalepsy test, body temperature measurements, hexobarbital-induced sleep duration, reaction to thermal painful stimulus, measurements of arterial blood pressure, heart rate and respiratory rate. The activity of prostaglandin synthetase was determined also in the microsomes of bovine hypothalamic cells in vitro. Using some of the above tests the effect of PPP was studied on the central action of prostaglandins F2 alpha and E2 (PGF2 alpha and PGE2). PPP was administered intraventricularly (i.c.v.) in various doses (doses producing the lowest pharmacological effect in a given test) 10 minutes before i.c.v. administration of these prostaglandins in doses of 1 or 10 microgram. It was shown that PPP (low-molecular weight fraction) injected into the lateral cerebral ventricle of the rat exerted a biological effect on the central nervous system manifesting itself as behaviour changes in the tests used, and as changes of the arterial blood pressure. PPP i.c.v. antagonized certain central effects of PGF2 alpha and PGE2. The degree of inhibition of various prostaglandins differed in relation to the test used and was somewhat stronger in the case of PGF2 alpha.

Mediation of central prostaglandin effects by serotoninergic neurons.

Ten days after administration of 5,6-dihydroxytryptamine, which causes degeneration of central serotoninergic neurons, the depressive behavioral effects of PGF2 alpha and PGE2 were evidently inhibited. Central chemical serotoninectomy abolished the hyperthermic and hypertensive effects of PGF2 alpha, but only slightly affected those of PGE2. It is concluded that serotoninergic neurons mediate the depressive behavioral action of both PGF2 alpha and PGE2. They also mediate the hyperthermic and hypertensive action of PGF2 alpha but not of PGE2. This suggests that these prostaglandins have different central modes of action.

Effect of prostaglandin F2 alpha on temperature and behaviour of centrally sympathectomized rats.

Prostaglandin F2 alpha (PG F2 alpha) in doses of 1 and 10 micrograms applied intraventricularly causes a rise in body temperature and exerts a sedative action on rat behaviour. Chemical sympathectomy of the central nervous system (CNS) induced by a twofold intraventricular administration of 250 micrograms of 6-hydroxydopamine reduces the influence of PG F2 alpha on the body temperature and behaviour. Reserpine administered to rats with chemical sympathectomy of the central nervous system reverses or prevents the PG F2 alpha action on body temperature of the animals. The results of the experiments seem to indicate that the central monoaminergic mechanisms play a role in the central action of PG F2 alpha on body temperature and behaviour.

Influence of polyphloretin phosphate on the central effects of prostaglandin E2 and F2alpha in rats.

The possibility that polyphloretin phosphate (PPP) antagonizes the central effects elicited by prostaglandin (PG) E2 and F2alpha was investigated. PPP was administered i.c.v. to male Wistar rats (10 or 25 microgram) 10 or 30 min before i.c.v. injection of PGF2 or PGF2alpha (1 or 10 microgram). The duration of several component of behavior, the degree of irritability, and the rectal temperature of rats were measured; the levels of noradrenaline, dopamine, 5-hydroxytryptamine, and 5-hydroxyindoleacetic acid were measured spectrophoto-fluorometrically in discrete brain areas. PPP antagonized temperature and behaviroal changes induced in rats by PGF2alpha, but not those induced by PGE2. The magnitude of antagonism depended on the dose of PPP and on the time of the pretreatment before PGF2alpha administration. Changes in the level of biogenic amines in discrete brain areas evoked by PGs were not affected by PPP. We found that PPP antagonizes the central effects of PGF2alpha but not those of PGE2, and that changes of biogenic amines in discrete brain areas elicited by PGs are not specific.

The influence of central chemical sympathectomy and reserpine on peripheral effects of noradrenaline and cyclic AMP dibutyrate injected into the cerebral ventricles.

Chemical sympathectomy of the central nervous system by injection of 6-hydroxy-dopamine (2 X 250 mug) or 6-hydroxydopa (90 mug) intensified some of the peripheral effects of noradrenaline and cyclic AMP dibutyrate injected into the cerebral ventricles. Reserpine (5 mg/kg) injected intraperitoneally weakened the peripheral reactions to noradrenaline injected intraventricularly. The results of the experiments indicate that peripheral reactions to intraventricularly injected noradrenaline depend on changes in the content of endogenous narodrenaline in the brain and on the mechanisms leading to these changes.

Central action of prostaglandin F2alpha on circulatory system in rats.

PGF2alpha administered into the lateral brain ventricle of anesthetized rats caused an increase of the blood pressure and heart rate. Reserpine, chemical sympathectomy of the CNS with 6-hydroxydopamine (6-OHDA), atropine, and vagotomy weakened the central action of PGF2alpha on the peripheral circulation. Propranolol and phenoxybenzamine exerted no influence. Neither reserpine nor 6-OHDA changed the influence of iv injected PGF2alpha on the circulation. The results of the experiments indicate to the participation of the central catecholamines in the mechanism of central action of the PGF2alpha on the circulatory system.

Action of biogenic amines injected intracerebrally on duration of hexobarbital-induced sleep in rats.

The influence of intracerebrally injected biogenic amines and cyclic AMP dibutyrate on duration of sleep induced with hexobarbital (50 mg/kg i.v.) in rats was studied. Duration of sleep was markedly prolonged by adrenaline, noradrenaline, dopamine, 5-hydroxydopamine and acetylcholine. Cyclic AMP dibutyrate injected 30 minutes before hexobarbital shortened time of sleep. The role of biogenic amines in hexobarbital-induced sleep is discussed.