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Biomedical subjects

R J Naylor

Publications and source records attributed to R J Naylor.

At least 235 records · Page 13Linked to original sources
PubMed1978

Preparation and biological actions of some symmetrically N,N-disubstituted dopamines.

The title compounds have been synthesized and evaluated for emetic effects in the dog, actions on the cardioaccelerator nerve in the cat, pecking in pigeons, and for behavioral effects following both peripheral and direct intracerebral injection into the nucleus accumbens and caudate-putamen of the rat. Generally, in the series studied, the N,N-diethyl and N,N-di-n-propyl congeners of dopamine displayed notably high degrees of activity. However, the test compounds exerted differing effects on peripheral and central dopamine receptors and in the area postrema. Differentiations of the activities of the different homologues within the brain were also shown.

Animals↗
PubMed1978

Dopamine antagonistic effects of a series of analogues of oxiperomide and spiroxatrine measured behaviourally in the rodent.

The activity spectra of oxiperomide, spiroxatrine and analogues were determined in two experimental models of abnormal peri-oral movements (induced by intrastriatal dopamine and subcutaneously administered 2-(NN-dipropyl)amino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene (NN-diPr-5,6-diOHATN) in the guinea-pig), and in a stereotypy test (induced by subcutaneous apomorphine in the guinea-pig); the ability of the test compounds to induce catalepsy or catatonia in the rat was also determined. The parent compounds oxiperomide and spiroxatrine possessed optimal activity in all tests, although responses to the series of compounds allowed clear differentiation between an ability to antagonize the peri-oral movements (dopamine- or NN-di Pr-5,6-diOHATN induced) and an ability to antagonize apomorphine stereotypy. However, all compounds that antagonized the abnormal peri-oral movements also caused catalepsy/catatonia. The results are considered in terms of the selection of suitable agent(s) for the treatment of peri-oral dyskinesias.

Animals↗
PubMed1977

Stereotyped behaviour patterns and hyperactivity induced by amphetamine and apomorphine after discrete 6-hydroxydopamine lesions of extrapyramidal and mesolimbic nuclei.

Changes in stereotyped sniffing, biting and hyperactivity induced by apomorphine and D-amphetamine in the rat were determined after bilateral 6-hydroxy-dopamine (6-OHDA) lesions (8-16 micron/4micron6) of the extrapyramidal caudate-putamen (CP) (anterior and centre), globus pallidus (GP) and substantia nigra (SN), the mesolimbic nucleus (ACB), tuberculum olfactorium (TUO) and central amygdaloid nucleus (ACE). Lesions were also induced in the medial forebrain bundle in the lateral hypothalamus (LH). The 6-OHDA lesions of the CP reduced amphetamine biting but not sniffing or hyperactivity. Centrally placed 6-OHDA failed to modify any response to apomorphine but anterior locations reduced apomorphine biting. Both lesion locations led to a 45-65% reduction in striatal dopamine (DA) content, but the anterior location also involved depletions of mesolimbic DA. 6-OHDA lesions of the GP reduced striatal DA by 62% but initially potentiated before reducing both apomorphine and amphetamine biting. These lesions also potentiated amphetamine hyperactivity but other parameters were unmodified. The LH and SN lesions reduced striatal and mesolimbic DA by 75-80% and potentiated apomorphine biting. The LH lesions reduced amphetamine biting and hyperactivity but the SN lesions initially potentiated these responses. 6-OHDA lesions of the ACB reduced the DA content of this nucleus by 72% but had little effect on the TUO: these lesions reduced the duration of amphetamine hyperactivity and potentiated apomorphine biting. In contrast, equally selective lesions of the TUO (80% DA depletion) enhanced the locomotor activity response to both apomorphine and amphetamine; apomorphine biting was also increased but other parameters were unmodified. Lesions of the ACE depleted amygdaloid DA by at least 80% and reduced or abolished apomorphine and amphetamine biting in the chronic stage. The results indicate that the sites for mediation of sterotyped sniffing, biting or hyperactivity are not the same for apomorphine and amphetamine, and that each behavioural state involves the functioning of more than one DA-containing area.

Amygdala↗
PubMed1977

Differential activation by some 2-aminotetralin derivatives of the receptor mechanisms in the nucleus accumbens of rats which mediate hyperactivity and stereotyped biting.

A series of 2-aminotetralin derivatives were injected into the nucleus accumbens of rat to assess the nature of the dopamine mechanisms in this nucleus which modulate hyperactivity and stereotyped behaviour. It was shown that (1) Derivatives with either 5,6- or 6,7-dihydroxy substitutions were each able to induce hyperactivity and stereotyped behaviour, but substitutions in the 5,6-positions conferred greater potency throughout the series. This differential was emphasised by the continued activity of 2-amino-5,6-dihydroxytetralin in the absence of nialamide whilst the action of 2-amino-6,7-dihydroxytetralin was greatly reduced. (2) The hydroxyl functions in both the 5,6- and 6,7-series were essential for activity: dimethyoxy derivatives were inactive. (3) Generally, substitution of the nitrogen atom with one or two methyl groups, or with a butyl group, reduced or abolished activity. However, N-ethyl and N-propyl substitution markedly enhanced stereotypic potential in the 5,6-dihydroxy series (but not in the 6,7-series). The N-isopropyl derivative in the 5,6-series reflected the activity of the N-propyl compound but a further substitution of the N atom with the methyl group (N-isopropyl-N-methyl) greatly reduced the stereotypic potential without modification of the hyperactivity response. In contrast, N,N-dipropyl substitution abolished the hyperactivity response whilst increasing sterotypic potential. (4) alpha and beta-adrenoceptor blocking agents and alpha-methyl-p-tyrosine failed to reduce the hyperactivity induced by 2-amino-5,6-dihydroxytetralin or the stereotyped behaviour induced by 2-(N,N-dipropyl)-amino-5,6-dihydroxytetralin. Both behaviours were, however, very sensitive to blockade by haloperidol, indicating that both the hyperactivity and stereotyped responses are dopamine-dependent. It is concluded that the dopamine mechanisms in the nucleus accumbens which mediate/regulate hyperactivity and stereotyped behaviour are different. Further, it is suggested that the 2-aminotetralins may be valuable tools in studies designed to assess the topography of cerebral dopamine systems.

2-Naphthylamine↗
PubMed1977

Aporphines, 21. (1,2) Dopaminergic activity of aporphine and benzylisoquinoline derivatives. Synthesis of 8-hydroxyaporphines and 1-(hydroxybenzyl)-2-n-propyl-1,2,3,4-tetrahydroisoquinolines.

The synthesis and physical properties of 8-hydroxyaporphine (3a) and 8-hydroxy-N-n-propylnoraporphine (3b) are described. The replacement of the rigid aporphine ring system by the more flexible benzyltetrahydroisoquinoline moiety, still containing all the necessary substitutents of the potent dopamine agonist N-n-propylnorapomorphine (1b) (NPA), resulted in the synthesis of 1-(3,4-dihydroxybenzyl)-2-propyl-1,2,3,4-tetrahydroisoquinoline (4). Analogous to 4,1-(4-hydroxybenzyl)-2-propyl-1,2,3,4-tetrahydroisoquinoline (5) was synthesized for a direct comparison with the biological activity of the corresponding 10-hydroxyaporphine (2). All compounds synthesized were evaluated as salts of their racemates. In animals with unilateral 6-OHDA lesion of the nigrostriatal pathway, (-)NPA and 2 caused dose-dependent contralateral circling behavior although activity was greatly reduced for the monohydroxylated aporphine 2. 3b,4, and 5 were inactive at doses of 0.25-4.0 mg/kg sc. Compounds 2 and 3b exhibited very weak activity in the stereotype tests in comparison to the response obtained with apomorphine and (-)-NPA. 4 and 5 failed to induce any sterotyped response. These compounds were also investigated for their ability to stimulate locomotor activity following direct injection into the nucleus accumbens. (-)-NPA induced a modest increase in activity but apomorphine completely failed to elicit a locomotor responses and antagonized the effect induced by dopamine. 2,3b, 4 and 5 neither enhanced locomotor activity on direct injection into the nucleus accumbens nor antagonized the hyperactivity response to intraacumbens dopamine when administered peripherally. On direct injection into the caudate-putamen only apomorphine induced stereotyped biting; (-)-NPA, 2, 3b, 4, and 5 were inactive. The differential activity of the aporphine derivatives in these tests strongly supports the possible existence of different types of dopamine receptors within the extrapyramidal and mesolimbic systems. The present studies confirm that the flexible benzylisoquinolines 4 and 5 do not adopt the active dopamine conformation and that the rigid aporphines, preferably containing hydroxyl functions at the 10 or 11 positions, are of greater importance in eliciting potent dopamine agonist activity.

Animals↗
PubMed1976

The relationship between striatal and mesolimbic dopamine dysfunction and the nature of circling responses following 6-hydroxydopamine and electrolytic lesions of the ascending dopamine systems of rat brain.

The importance of extrapyramidal and mesolimbic function for circling behaviour was investigated by placing 6-hydroxydopamine (6-OHDA) and electrolesions in the cell bodies, axons and terminals of each system. Circling behaviour was weak when 6-OHDA was placed at the centre of the substantia nigra (SN), but the characteristic contralateral/ipsilateral turning to apomorphine/amphetamine were recorded. Circling was more marked when 6-OHDA was placed anterior to the SN but was generally absent following injections posterior to the SN. However, 6-OHDA placed in the medial forebrain bundle in the lateral hypothalamus resulted in intense contralateral/ipsilateral turning to apomorphine/amphetamine. Generally, the intensity of circling responses was related to the degree of striatal dopamine (DA) depletion but the more effective lesions also caused reductions in mesolimbic DA content. However, circling was not observed following any 6-OHDA injection into the mesolimbic DA system and it is concluded that mesolimbic DA function is not essential for the initiation of circling. In contrast to the 6-OHDA lesions, rats circled ipsilateral to both apomorphine and amphetamine when the SN was damaged by electrocoagulation to cause marked depletion of striatal dopamine. Lesser depletions of striatal dopamine after electrocoagulation in different regions of the medial forebrain bundle were associated with a lower intensity of ipsilateral circling to both drugs. In general, the differences between 6-OHDA and electrolesions could not be explained by additional damage to ascending noradrenaline or 5-hydroxytryptamine pathways. Lower doses of apomorphine were effective in the 6-OHDA circling rats, and the ipsilateral striatum of such rats was more sensitive to directly applied DA. Higher doses of apomorphine were required to produce circling after chronic electrolesions which rendered the ipsilateral striatum insensitive to DA. The contralateral circling to apomorphine after 6-OHDA lesions was abolished by chronic but not by acute electrolesion of the SN. It is suggested that electrolesions of the SN cause different effects to 6-OHDA because they destroy neuronal pathways in addition to the dopaminergic nigrostriatal tract. These appear to be required for the expression of circling behaviour caused by stimulation of the denervated striatum. Whereas 6-OHDA lesions result in super-sensitivity of the denervated strital DA receptors, electrolesions may cause a hypo-sensitivity of the same receptor sites.

Afferent Pathways↗