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Biomedical subjects

R J Naylor

Publications and source records attributed to R J Naylor.

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

Use of the intracerebral injection technique to elucidate mechanisms of apomorphine climbing and its antagonism in the mouse.

Climbing behavior induced by peripherally administered apomorphine in the mouse was reduced by 0.25-10 microgram bilateral intra-accumbens fluphenazine, (+/-) and (-) sulpiride and by serotonin, but not by (+)sulpiride, dl-propranolol, phentolamine, atropine or methysergide. A specific antagonism of climbing could not be shown when fluphenazine was injected into the striatum, hypothalamus, thalamus, reticular formation, frontal cortex or cerebellum, but was apparent when a large dose of fluphenazine was placed below (but not above) the accumbens nucleus. 6-Hydroxydopamine denervation of the nucleus accumbens did not alter the climbing antagonism afforded by fluphenazine, although sulpiride was three-fold more effective following denervation. The data indicates an accumbens involvement in the climbing phenomenon, that sulpiride more effectively antagonises climbing after accumbens denervation and that the presumed dopamine agonist-antagonist interaction in the accumbens, which controls climbing, may also involve serotonergic function. The studies emphasise the value of the intra-cerebral injection technique to an analysis of drug action in the mouse.

Animals↗
PubMed1981

5,7-Dihydroxy-2-aminotetralin derivatives: synthesis and assessment of dopaminergic and adrenergic actions.

Replacement of the catechol 3,4-dihydroxylation pattern of certain adrenergic beta-phenethylamines by a resorcinol 3,5-dihydroxylation pattern has led to a greater selectivity of adrenergic agonist effects in certain molecules. This strategy has been applied to a series of dopaminergic agents derived from 2-aminotetralin, leading to a 5,7-dihydroxylation pattern. Traditional literature approaches to formation of a tetralin ring with this oxygenation pattern failed. A method was used which involved cyclization of 3,5-dimethoxybenzylsuccinic acid derivatives with pyridinium poly(HF) and subsequent modification of the tetralin ring. The resorcinol-derived 2-aminotetralins were less potent and less active dopaminergic agents than their catechol-derived isomers (5,6-dihydroxy and/or 6,7-dihydroxy). Certain of the subject compounds demonstrated alpha- and beta 1-adrenoceptor activating properties.

Animals↗
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↗
PubMed1980

Presynaptic effects of 2-aminotetralins on striatal dopaminergic neurons.

The present study evaluated whether 2-amino-5,6-dihydroxy-1,2,3,4,-tetrahydronaphthalene (A-5,6 DTN) and its 6,7-dihydroxy isomer (A-6,7 DTN) had effects on striatal dopaminergic terminals in addition to their well known action as agonists on postsynaptic dopamine (DA)-receptors. The presynaptic effects of 2-aminotetralins were evaluated on rat striatal tissue slices prelabeled with [3H]DA. Both, A-5,6 and A-6,7 DTN enhanced the basal efflux of radioactive products in a concentration-dependent fashion. Benztropine (1 microM) antagonized the releasing effects of low concentrations of both drugs (0.1-3.0 microM). Apomorphine and A-5,6 DTN (alpha rotamers, trans conformation) were 3 to 5 times more potent than A-6,7 DTN (beta rotamer, trans conformation) in inhibiting rat striatal monamine oxidase. This effect could account for the 50-fold greater potency of A-6,7 than A-5,6 DTN in enhancing the efflux of [3H]dihydroxyphenylacetic acid. A-5,6 DTN, A-6,7 DTN and apomorphine (0.3 microM each), reduced by 30% the depolarization elicited overflow of radioactive products. In summary, A-5,6 and A-6,7 DTN seem to enter DA-terminals and storage vesicles to accelerate the efflux of [3H]DA and 3H-dihydroxyphenylacetic acid and act upon presynapatic receptors to inhibit transmitter release. A greater selectivity for monamine oxidase inhibition was found with the alpha rotameric agents. The present study indicates that A-5,6 and A-6,7 DTN have marked presynaptic effects on rat striatal DA-containing neurons in addition to their well known effects as agonists on postsynaptic DA receptors.

2-Naphthylamine↗
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↗