International journal of neuropharmacology最新文献

The differential actions of i.v. arecoline and nicotine were determined on neocortical and limbic system EEG activation in acute rostral and caudal midbrain transected cats. All animals were prepared under diethyl ether anesthesia and after surgery, paralyzed with decamethonium and maintained on artificial respiration. The peripheral effects of these cholinergic agonists were reduced by methyl atropine (250 μg/kg ) and/or trimethidinium (1 mg/kg) pretreatment.

In the caudal midbrain transected preparation, nicotine (20–40 μg/kg) induced marked EEG activation in both the neocortex and hippocampus. After bilateral lesions of the midbrain reticular formation in the same preparation, EEG activation was not observed with nicotine in doses up to 100 μg/kg. The EEG effects of nicotine were blocked by atropine (1 mg/kg) and mecamylamine (1 mg/kg) but not trimethidinium (1 mg/kg). In the rostral midbrain transected preparation no EEG activation was noted with nicotine in doses up to 100 μg/kg. Sporadic sharp waves appeared in the hippocampus with the larger doses indicating a convulsant site of action above the level of transection.

Arecoline induced dissociation of the EEG in the hippocampus and neocortex in doses of 20–40 μg/kg in the rostral midbrain transected cat. Marked hippocampal slow “arousal” waves with no desynchronization of the neocortical EEG were seen. These effects of arecoline were blocked by atropine. In the caudal midbrain preparation, even after bilateral lesions of the midbrain reticular formation which blocked nicotine activation, arecoline (20–40 μg/kg) still induced hippocampal slow ‘arousal’ waves without neocortical desynchronization. With doses of 100 μg/kg of arecoline both neocortical and hippocampal EEG activation was noted.

It is concluded that the site of nicotine on the rostral forebrain activating system is located primarily in the midbrain reticular formation, whereas arecoline acts on the midbrain reticular formation as well as above the level of the mesencephalon.

In two tests of spontaneous activity, rats given d-amphetamine in doses of 1.0, 2.0 and 4.0 mg/kg became hyperactive. Chlorpromazine in doses of 0.5 and 1.0 mg/kg blocked this hyperactivity by increasing the periods of immobility, ambulation and grooming, as measured in an observation box and increasing the number of alleys entered in a Y-maze. In addition, the phenothiazine reduced head lifting, sniffing, head turning and rearing, which appeared in amphetamine treated rats. The most pronounced counter-effects on behaviour induced by 4 mg/kg d-amphetamine, were brought about by 1.0 mg/kg chlorpromazine, but the same ratio of 4: 1 at half these doses was less effective. The possible source of this behavioural antagonism of the two drugs, at a neuronal and a non-neuronal level, is discussed.

The effects on unit discharges of various doses of the compounds chlordiazepoxide, meprobamate, sodium pentobarbital, and diazepam were studied in the unanesthetized, unrestrained rat. Recordings of action potentials were made simultaneously in hippocampus, pre-optic region, and the reticular formation of the midbrain. The doses of chlordiazepoxide were 5, 10, 20 and 40 mg/kg; 5, 10 and 20 mg/kg of sodium pentobarbital; 80, 100 and 120 mg/kg of meprobamate, and finally 5, 10 and 20 mg/kg of diazepam.

In the hippocampus, chlordiazepoxide depressed spontaneous activity at every dose used. The reduction ranged from 30 to 50%, but in no case was there inhibition of all discharges. Diazepam also had substantial depressing effects on the activity in this region of the brain. In contrast, sodium pentobarbital had relatively minor effects in the lower dose range, but significant depressing effects at the higher doses. Meprobamate also had comparatively small effects in the hippocampus.

In the pre-optic area, chlordiazepoxide and meprobamate depressed spontaneous activity at the higher dose range. There were small effects in the lower dose range. Sodium pentobarbital also had minor depressing effects at all doses. Diazepam caused less depression even at the higher doses than either chlordiazepoxide or meprobamate, and these effects were transient.

In the midbrain reticular formation, meprobamate caused substantial depression of spontaneous activity even at the lower doses. Sodium pentobarbital similarly depressed activity, but the onset of effect was less delayed than with meprobamate. Chlordiazepoxide at low doses caused less depression of reticular midbrain neurons than of hippocampal or pre-optic region ones. At high doses, the effect was similar to that of meprobamate.

The data suggest the possibility of a mode of action of chlordiazepoxide and diazepam which implicates the hippocampus, whereas in the case of sodium pentobarbital and meprobamate, the mode of action appears to implicate the midbrain reticular area. Such a view is based upon comparison of effects at low doses on spontaneous activity of the three regions investigated.

1. A method is reported for the simultaneous study of the central and peripheral actions of drugs on the pressor response to electrical medullary stimulation in cats anaesthetized with chloralose.

2. Variations in the magnitude of the medullary vasopressor response were reduced by stabilization of the blood pressure using a reservoir of dextran solution connected to the venous circulation. Results were qualitatively the same with or without stabilization. Decreasing the body temperature over the range 39.5–32°C produced a linear and reversible decrease in the medullary vasopressor response. This response was slightly reduced by bilateral adrenalectomy.

3. Benactyzine, hydroxyzine and mebutamate depressed the medullary vasopressor response by a central action; perphenazine, prochlorperazine and atropine also reduced the vasopressor response but they did so by acting on the peripheral sympathetic outflow. Promazine and chlorpromazine reduced the medullary vasopressor response principally by a peripheral blocking action but there may be also a small central action component.

4. The importance of assessing the peripheral action of “centrally acting” drugs is emphasized.

5. The drugs benactyzine, hydroxyzine, mebutamate, chlorpromazine and promazine appear to exert a depressant action on the central sympathetic nervous system.

When repeated daily administrations of tetrabenazine were given 2 hr before daily injection of morphine in mice, the development of tolerance to morphine analgesia was markedly suppressed. This suppressive effect was antagonized by repeated administrations of DOPA. These findings suggest that catecholamines might be involved in the development of tolerance to morphine.

The results of earlier investigations pointed to a connection between a raised striatal excitability and the catatogenic effect of neuroleptic drugs. This paper describes experiments in which the caudate function in catatonic rats was blocked by means of local application of KCl solution.

It is demonstrated that a spreading depression (recorded electrographically) in the caudate nucleus inhibits the catatonic picture seen following neuroleptics (reserpine and SUM-3170, 2-chlor-11(4-methyl-1-piperazinyl)-dibenz[b,f][1,4]-oxazepine). During blockage of the caudate function (as seen in the EEG) the previously akinetic animals show an increased locomotor activity with snuffling and searching head movements; the rigor disappears and the animals show an intense desire to gnaw or lick. With return of the caudate activity (as seen in the EEG) the animals appear to freeze suddenly during movement; the typical catatonic position being resumed.

A cortical spreading depression is without effect on the catatonia arising after administration of neuroleptics. Only with the arrival of the inhibitory wave in the striatum, 4–5 min after induction of the spreading depression in the cortex, is the neuroleptic-induced catatonia inhibited. That is to say, blockage of the cortical afferent and efferent capsule fibres does not explain the effect of striatal spreading depression on the catatonia.