Barry Cox

Characterisation of Inhibitory 5-Hydroxytryptamine Receptors That Modulate Dopamine Release in the Striatum

Abstract: The effect of a series of indoleamines on the potassium‐evoked tritium release of previously accumulated [3H]dopamine from rat striatal slices has been investigated. The indoleamines 5‐hydroxytryptamine, 5‐methoxy‐tryptamine, 5‐methoxy‐N, N′‐dimethyltryptamine and tryptamine (10−7 to 10−3 M) all reduced potassium‐evoked release of tritium, to a maximum of 50%. The uptake of [3H]dopamine was unaffected by these compounds. A series of 5‐hydroxytryptamine antagonists were examined for their ability to reduce the inhibition of potassium‐evoked tritium release induced by 5‐methoxytryptamine. The relative order of antagonist potency obtained was methysergide > metergoline > methiothepin > cinanserin > cyproheptadine > mianserin, and was consistent with an action on 5‐hydroxytryptamine receptors. It is concluded that there are inhibitory 5‐hydroxytryptamine receptors located on the terminals of dopaminergic neurones in the striatum.

The relationship between tremor and change in brain acetylcholine concentration produced by injection of tremorine or oxotremorine in the rat

1 The relationship between tremor and change in brain acetylcholine concentration after the injection of tremorine or oxotremorine has been investigated in rats. 2 Tremorine produced a significant increase in whole brain acetylcholine and in tremor 5 min after injection. After this time tremor subsided but brain acetylcholine continued to increase. 3 Oxotremorine produced tremor within 30 sec. This became maximal within 5 min of injection and then declined rapidly. The brain acetylcholine concentration showed a significant increase 5 min after injection and continued to increase until 30 min afterwards.

A decision support system using judgmental modeling: a case of R&D in the pharmaceutical industry

The development of a computerized decision support system for R&D project ranking, monitoring and control in the pharmaceutical industry is described. Using a series of techniques based on a judgmental modeling approach, an overall system has been developed that covers several different aspects of the whole decision making process. Illustrative examples are given to show how the components of the model are used in practice, indicating their place in the overall management process. The results provide evidence supporting the value of such models which help reduce ambiguity by using structured approaches. >

Effects of drugs on tremor and increase in brain acetylcholine produced by oxotremorine in the rat

1 In rats the effect of drugs on oxotremorine tremor and oxotremorine‐induced increase in brain acetylcholine has been investigated. 2 Reserpine, (±)‐α‐methylmetatyrosine and diethyldithio‐carbamic acid, drugs which have in common the ability to decrease tissue noradrenaline concentration, inhibited oxotremorine tremor without preventing the oxotremorine‐induced increase in brain acetylcholine. 3 (±)‐p‐chlorophenylalanine, a depletor of tissue 5‐hydroxytryptamine, did not inhibit oxotremorine tremor. 4 Phenoxybenzamine and propranolol inhibited oxotremorine tremor, and propranolol was without effect on oxotremorine‐induced increase in brain acetylcholine. 5 The toxicity of oxotremorine was increased by reserpine and phenoxybenzamine. 6 The significance of these findings is discussed with regard to the mode of action of oxotremorine.

Suppressant effects of selective 5-HT2 antagonists on rapid eye movement sleep in rats

The effects of the novel, highly selective serotonin-2 (5-HT2) antagonists, ICI 169,369 and ICI 170,809, on 24 h EEG sleep-wake activity were studied in the rat. Both compounds caused a dose-related increase in the latency to rapid eye movement sleep (REMS) and significantly suppressed cumulative REMS time up to 12 h postinjection. In contrast, neither drug disrupted slow-wave sleep continuity in as much as the latency to non-REMS (NREMS) and cumulative NREMS time were unchanged. However, at the highest dose tested (20 mg/kg) ICI 170,809 did produce a significant increase in total NREMS time during the second half of the sleep-awake cycle. These results demonstrate effects of selective 5-HT2 antagonists on sleep in rats which appear to be specific for REMS behavior, suggesting that the priming influence of serotonin on REMS may involve 5-HT2 receptor subtypes. The relationship between the REMS suppressant actions of these compounds and their consideration as therapeutic agents in depression is discussed.

Effects of morphine and related drugs on core temperature of two strains of rat

The changes in core temperature induced by low (5 mg/kg) and high (40 mg/kg) doses of morphine were compared in Wistar and Sprague-Dawley rats. In Sprague-Dawley rats the low dose caused a hyperthermia and the high dose a hypothermia but in Wistar rats both doses caused a hyperthermia. In either case the change in core temperature was antagonized by naloxone (2 mg/kg). Tolerance to the effects of the high dose of morphine developed in both strains of rat. Dextromoramide (3.75 and 15 mg/kg) also had an effect on core temperature, but in this case the responses of the strains were opposite to those seen with morphine. Laevomoramide was relatively ineffective. Naloxone (2 mg/kg) had no effect on the ability of rats of either strain to withstand heat or cold stress, providing no evidence that endogenous morphine-like substances have a physiological role in thermoregulation.

The effect of psychoactive drugs on plasma corticosterone levels and behaviour in the bulbectomised rat

Abstract Bilateral olfactory bulbectomy (OB) in the rat produces a rise in circulating 11-hydroxycorticosterone (11-OHCS) to intermediate levels (40–50 μg/100 ml plasma). Following footshock extreme corticosterone elevation occurs (65–80 μg/100 ml plasma). Bulbectomy also produces behavioural changes which include hyper-reactivity and an acquisition deficit in a step-down passive avoidance test. Treatment of the bulbectomised rat with amitriptyline (5 and 10 mg/kg), mianserin (5 and 10 mg/kg) and viloxazine (2 and 5 mg/kg) administered IP for at least 7 days corrected the acquisition deficit, reduced the hyper-reactivity and the elevated corticosterone levels in a reproducible manner. This reduction in 11-OHCS concentrations occurred in bulbectomised rats with and without footshock. In contrast, the antidepressant drugs did not produce these changes in sham-operated controls (SO). The central stimulant, amphetamine (1 and 3 mg/kg/day for 7 days, IP), increased 11-OHCS concentrations in unstressed OB and SO rats. There was no further elevation in the 11-OHCS concentrations of stressed rats of both OB and SO groups. This drug further impaired the acquisition of both OB and SO rats and increased the reactivity scoring of both groups. The major tranquillizer, chlorpromazine (1 and 3 mg/kg IP for 7 days), reduced plasma 11-OHCS levels and the hyperreactivity of both OB and SO groups. It did not reduce the acquisition deficit exhibited by the OB rats. Chlordiazepoxide (5 and 15 mg/kg IP for 7 days), had a profile similar to that of chlorpromazine except that it impaired acquisition in the SO group. Thus using the techniques described above it is possible to separate the antidepressants from other major classes of psychotropic drugs.

An investigation of the tremorgenic actions of harmine in the rat

Abstract Antagonism of harmine tremor by drugs which interfere with adrenergic nervous function was investigated in rats. Reserpine, diethyldithiocarbamic acid and propranolol reduced the intensity of the tremor without abolishing it completely. Phenoxybenzamine, mebanazine and atropine were without effect. Harmine produced a small but significant decrease in the acetylcholine content of the brain. It induced tremor after stereotaxic injection into the area of the caudate nucleus and substantia nigra. It is concluded that harmine produces tremor by a central mechanism, not simply related to its monoamine oxidase inhibiting action, and without involving cholinergic mechanisms. The reduction of tremor by anti-adrenergic drugs was thought to be not necessarily occurring at the primary site of action of harmine but on a secondary pathway involving catecholamine neurones.

Characterization of 5-hydroxytryptaminergic autoreceptors in the rat hypothalamus

5‐hydroxytryptamine (5‐HT) (3 × 10−9 to 10−6 M) produced a concentration‐related inhibition of potassium‐evoked tritium release from slices of rat hypothalamus preloaded with [3H]‐5‐HT. The response to 5‐HT was unaffected by the presence of yohimbine (10−6 M), pimozide (10−7 M), domperidone (10−7 M) or tetrodotoxin (10−7 M), indicating that the response was not mediated via α1‐ or α2‐adrenoceptors or dopamine receptors and that the receptors that were involved were located directly on the 5‐HT nerve terminal. The 5‐HT antagonist metergoline (10−8 to 3 × 10−7 M) produced a parallel rightward shift in the concentration‐effect curve to 5‐HT with no reduction in the size of the maximum response. The pA10 value for metergoline was 6.82 and the slope of the Arunlakshana‐Schild plot was not significantly different from 1.0 indicating that it was a competitive antagonist. Methiothepin produced a similar effect to metergoline whilst cyproheptadine and methysergide were less potent as antagonists of 5‐HT and were not competitive. Cinanserin was inactive. Thus we have characterized the 5‐HT autoreceptor in the rat hypothalamus using a classical pharmacological approach and found that it has more in common with the autoreceptor which we have previously identified in the raphe nuclei of the rat than it has with the 5‐HT receptor located on dopamine neuroterminals in the striatum.

A comparison between a melanocyte-stimulating hormone inhibitory factor (MIF-I) and substances known to activate central dopamine receptors.

The tripeptide, prolyl-leucyl glycine amide, a melanocyte-stimulating hormone inhibitory factor (MIF-I), which has been reported to be effective in improving symptoms of Parkinsons disease, has been compared with drugs known to activate dopamine receptors in rat and mouse brain. Unlike apomorphine, amphetamine and amantadine it was incapable of producing sterotyped behaviour in the rat and unlike 1-dopa it was also ineffective in rats pretreated with the monoamineoxidase inhibitor mebanazine. Neither did it potentiate apomorphine nor amphetamine in this test. MIF-I did not antagonise chlorpromazine-induced loss of locomotor activity in mice, an effect which was antagonised by apomorphine, amphetamine and amantadine. Chlorpromazine hypothermia in the mouse was antagonised by 1-dopa but not by MIF-I; similar findings were obtained in reserpine-pretreated mice. These results suggest that the reported beneficial effect of MIF-I in Parkinsons disease is unlikely to be due to an interaction with dopamine systems in the brain.