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Biomedical subjects

B Costall

Publications and source records attributed to B Costall.

At least 199 records · Page 11Linked to original sources
PubMed1981

Dopamine antagonist properties of atypical neuroleptics may be revealed following mesolimbic denervation.

A mesolimbic denervation, caused by bilateral intra-accumbens 6-hydroxydopamine, increased the potency of apomorphine in two behavioural tests of dopamine agonist activity, climbing behaviour and circling (combinations of the accumbens denervation with unilateral electrolesion of the striatum). Of a number of neuroleptics tested, haloperidol, fluphenazine, sultopride, tiapride, sulpiride and thioridazine, only the latter two showed greater effectiveness than normal to antagonize the apomorphine responses after mesolimbic denervation. Sulpiride and thioridazine cause remarkably little change in 'normal' tests for antipsychotic activity; their effectiveness in the clinic may reflect a more unique ability to act on dopamine receptor mechanisms of changed sensitivity.

Animals↗
PubMed1980

The mesolimbic system, denervation and the climbing response in the mouse.

Bilateral intra-accumbens 6-OHDA (2 micrograms in the presence of DMI and tranylcypromine, 14th postoperative day) enhanced the climbing responses of mice to apomorphine and 2-(N,N-dipropyl)amino-5,6-dihydroxytetralin causing parallel shifts of the normal log dose-response curves to the left. The enhancement of the apomorphine response was shown to be dependent on the dose of 6-OHDA, 0.5 micrograms being threshold and 2 micrograms maximum. Increased climbing was apparent by the 5th postoperative day, maximum by the 10th day, and was then maintained throughout the experimental period (6-8 weeks). 0.25-2 micrograms intra-accumbens 6-OHDA caused dose-related decreases in the dopamine content of mesolimbic areas (nucleus accumbens and tuberculum olfactorium) without causing significant changes in mesolimbic noradrenaline or striatal dopamine. In the absence of DMI/tranylcypromine, 2 and 4 micrograms 6-OHDA also decreased mesolimbic noradrenaline and striatal dopamine content. 16 micrograms 6-OHDA injected into the striatum (after DMI/tranylcypromine) decreased the striatal dopamine content by 85% (without altering mesolimbic dopamine or noradrenaline content) but this treatment failed to modify apomorphine climbing (2nd-12th postoperative days). Haloperiod, sulpiride, thioridazine, clozapine ad metoclopramide each caused a dose-dependent decrease in apomorphine climbing in both normal and 6-OHDA-treated mice. Haloperidol and metoclopramide were approximately equipotent in both groups of animals whilst sulpiride and thioridazine were approximately 4x more potent in the 6-OHDA-treated mice (the development of muscular hypotonia made an interpretation of clozapine effects difficult). The data indicate that an important role for the mesolimbic nucleus accumbens in the mediation of apomorphine climbing, and indicate that the antagonism by sulpiride and thioridazine may be specifically increased when mesolimbic mechanisms are rendered 'supersensitive'.

Animals↗
PubMed1980

(-)N-(chloroethyl)norapomorphine inhibits striatal dopamine function via irreversible receptor binding.

beta-Haloalkylamine derivatives such as phenoxybenzamine are thought to irreversibly inactivate noradrenaline receptors by a process involving the formation of a reactive ethyleneimmonium cation which is followed by ring scission yielding the reactive carbonium ion which can then react further with a nucleophilic centre located on the receptor. Further study of catecholamine function has awaited the development of similar agents which can alkylate the dopamine receptor. We report here on the structure (Fig. 1) and evaluation of one agent with such potential, (--)N-(chloroethyl)norapomorphine [(--)NCA], and that this compound may be of significant value as a pharmacological and biochemical probe of the dopamine receptor.

Animals↗
PubMed1980

Congeners of the beta conformer of dopamine derived from cis- and trans-octahydrobenzo[f]quinoline and trans-octahydrobenzo[g]quinoline.

The so-called beta conformer of dopamine has been proposed to be involved in agonist--receptor interactions at several sites in the dopaminergic nervous system. Further to evaluate this proposal, rigid congeners of the beta conformer derived from linearly and angularly annelated octahydrobenzoquinolines have been synthesized. Certain N-alkylated trans-angularly annelated systems exhibited unusually potent and highly selective dopamine-like effects in an assay on a cardioaccelerator nerve preparation in the cat, but these compounds were inactive in a variety of assays for CNS effects. These compounds present a clear separation of CNS effects from some potent peripheral effects.

Animals↗
PubMed1979

A study of the changes in motor behaviour caused by TRH on intracerebral injection.

20 microgram TRH injected bilaterally into the caudate-putamen, tuberculum olfactorium, nucleus accumbens, amygdala, lateral ventricles, midbrain or cerebral cortex failed to induce any increase in locomotor activity (measured using photocells), although other behavioural changes were observed after each injection, and included body shakes, limb tremor, repetitive head and limb movements, biting, scratching and an alert appearance. These behavioural changes could result in positive readings from equipment used to measure locomotor activity, but careful investigations focussing on the nucleus accumbens used photocell boxes, activity wheels and Animex recorders to emphasise the inability of intracerebral TRH (10--40 microgram) to enhance locomotor activity. Intraaccumbens TRH also failed to enhance amphetamine hyperactivity or reduce the motor depression caused by haloperidol and analeptic drugs. The data do not support a central locomotor stimulant action of TRH.

Animals↗
PubMed1979

Rigid congeners of dopamine based on octahydrobenzo[f]quinoline: peripheral and central effects.

A series of cis- and trans-dihydroxycotahydrobenzo[f]quinoline congeners of dopamine has been prepared, in which the N substitutent is H, ethyl, or n-propyl. The trans isomers include the dopamine moiety held rigidly in an antiperiplanar diposition which is believed to be necessary for certian central and peripheral dopaminergic effects. The cis isomers are flexible molecules; the dopamine moiety lacks conformational integrity and it can exist in a conformation which is believed not to favor dopaminergic activity. The trans series of compounds was shown to possess a high level of central and peripheral dopaminergic effects, whereas the cis series was of low activity or was inert. These data further support previous proposals concerning stereochemical requirements for certain dopaminergic agonist activity.

Animals↗
PubMed1979

N-Alkyl derivatives of (+/-)-alpha-methyldopamine.

A series of N-alkylated alpha-methyldopamine derivatives has been prepared for comparison of their biological effects with those of semirigid dopamine congeners derived from 2-aminotetralin systems. All of the alpha-methyldopamine derivatives were inert as dopaminergic agonists in a variety of animal assays, both centrally and peripherally, although certain compounds produced powerful and prolonged locomotor hyperactivity on intra-accumbens injection in mice, by indirect mechanism(s). A rationalization, based upon conformational analysis, is presented for the lack of direct dopaminergic agonist activity of alpha-methyldopamine derivatives.

Animals↗