Field stimulation-induced responses of circular smooth muscle from guinea-pig stomach. Characterisation of the receptor mechanisms involved.
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Animals↗
Biomedical subjects
R J Naylor
Publications and source records attributed to R J Naylor.
A comparison of the behavioural consequences of chronic stimulation of dopamine receptors in the nucleus accumbens of rat brain effected by a continuous infusion or by single daily injections.
Mesolimbic dopamine (DA) receptors of the rat were subject to a chronic (13 day) stimulation effected either by single, repeated daily injections or by infusion from osmotic minipumps of 1.56-50 micrograms DA bilaterally into the nucleus accumbens. Rats were preselected according to their responsiveness to the hyperactivity inducing effect of the DA agonist (--)N-n-propylnorapomorphine [(--)NPA], and the two groups categorised as 'high' and 'low' activity responders were used in the present studies. Whilst the stimulation of mesolimbic DA receptors by a single acute injection or by a 24 h infusion was ineffective to modify locomotor responding, the repetition of the daily injections or the continuation of the infusion caused dose-related increases in locomotor activity of both groups of rats. The spectrum of enhanced activity responding depended on the mechanism of stimulation, a 'biphasic' or 'monophasic' pattern resulting from the infusion or daily injections respectively. It was an important observation that a repetitive biting behaviour developed concomitant to the hyperactivity during daily DA injections, a response not observed during infusion, indicating that the nature of the receptor stimulation, continuous or pulsatile, can dictate the development of a motor response. The effects of discontinuing the chronic intra-accumbens stimulation on responsiveness to (--)NPA was the same whether the chronic stimulation was achieved by repeated injection or infusion. However, the consequences of DA withdrawal critically depended on the initial classification of rat activity according to (--)NPA. Thus, initially 'high' response animals developed a 'low' sensitivity whilst initially 'low' sensitive animals reversed to 'high' responsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Reduction in motor responding of the mouse by actions of dopamine agonists in the midbrain.
Mice were implanted stereotaxically with chronically indwelling bilateral guide cannulae to allow the intracerebral injection of dopamine or the dopamine agonist 2-di-n-propylamino-5,6-dihydroxytetralin into the centre of the substantia nigra, above the substantia nigra or anterior and posterior to the nigra. The intranigral injection of dopamine and the tetralin compound could be shown to dose-dependently reduce the spontaneous locomotor activity of mice. The effectiveness of dopamine decreased with a delayed onset when injections were made anterior or posterior to the substantia nigra; this spectrum of reduced and delayed responding was also apparent when dopamine and the tetralin compound were injected 1 or 2 mm above the nigra. The inhibitory action of dopamine on motor activity, when injected into the substantia nigra, was antagonised by a small dose of spiroperidol which did not influence spontaneous locomotor responding in its own right; prazosin and yohimbine were ineffective. It is suggested that the inhibitory actions of dopamine and 2-di-n-propylamino-5,6-dihydroxytetralin on motor activity may reflect an ability to stimulate dopamine "autoreceptors" in the midbrain area containing the dopamine cell bodies which innervate striatal and mesolimbic forebrain regions.
Animals↗
Does contralateral circling involve action of drugs on hyposensitive striatal dopamine receptors in the hemisphere contralateral to denervation?
Rats receiving unilateral intrastriatal injections of 6-hydroxydopamine (6-OHDA) (3 x 16 micrograms, in the presence of tranylcypromine and desmethylimipramine (DMI), resulting in 84% dopamine depletion) exhibited contralateral asymmetry and circling behaviour on peripheral challenge with apomorphine or on unilateral intrastriatal injection of dopamine (into the denervated striatum) (resulting in a stable response after 8 days). The denervated striatum was markedly more sensitive to the effects of dopamine than the normal striatum, although dopamine failed to elicit a response from an intact striatum opposite to a denervation by 6-OHDA. Following unilateral striatal electrolytic lesions (resulting in a stable response after 6-8 days) the rats exhibited ipsilateral asymmetry and circling after the apomorphine challenge. Again, the striata opposite to the lesion failed to mediate a response to dopamine. The contralateral responses to apomorphine observed in animals lesioned with 6-OHDA were not enhanced when an electrolytic lesion was subsequently placed in the intact striatum, nor were the ipsilateral responses of lesioned rats to apomorphine enhanced when 6-OHDA was subsequently injected into the opposite striatum. All asymmetric and circling responses were sensitive to neuroleptics. Thus, it is concluded that a unilateral striatal lesion produced by 6-OHDA or electrolytic lesion can cause reduced functional dopaminergic activity in the opposing striatum. This dopaminergic hyposensitivity would facilitate a contralateral response initiated by hypersensitive mechanisms in the denervated striatum.
Animals↗
Ascorbic acid and membrane ageing: critical determinants of the in-vitro binding of [3H]ADTN to rat striatal tissue.
Tritiated (+/-)-2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene [( 3H]ADTN), binding (0.125-4.0 nM) to rat striatal membranes was investigated using Tris-HCl buffer containing Na2EDTA, nialamide and varying concentrations of ascorbic acid. In the absence of ascorbic acid [3H]ADTN exhibited a high affinity (KD 1.26 nM) saturable binding (Bmax 138 fmol mg-1 protein) (Scatchard analysis). This was not modified by 10(-6) or 10(-5) M ascorbic acid used immediately or 60 min after preparation. However, 10(-4) M ascorbic acid added (within) 15 min after its preparation reduced the number of bindings sites and added 60 min after it also reduced affinity. Ascorbic acid 5.7 mM reduced affinity whether used within 15 min or 60 min of its preparation. When ascorbic acid 10(-4) M was used within 15 min of preparation, and membranes were used immediately, the binding of 2 nM [3H]ADTN was specifically displaceable by nM or sub-nM concentrations of dopamine agonists and antagonists. However, when membranes were used 1-2 h after their preparation there was an increasing loss of the high affinity binding sites displaceable by sub-nM concentrations of (+/-)-ADTN. Thus. [3H]ADTN can be shown to exhibit high affinity stereoselective binding to rat striatal membranes when these are freshly prepared and the assay is performed using Tris-HCl buffer containing nialamide. Na2EDTA and 10(-4) M ascorbic acid prepared within 15 min of use. The characteristics of this binding can be markedly modified if the concentration of ascorbic acid is increased, if its preparation time is extended, or if the membranes are allowed to 'age'.
Animals↗
Aminoalkylindoles: atypical dopamine antagonists.
The neuropharmacological profile of a series of aminoalkylindole compounds (AHR 1229-(3-[2-(3-indolyl)-ethyl]-butylamino-1-phenyl-pyrrolidine), AHR1771-(1-[2-(2-methyl-3-indolyl)ethyl]-4-phenyl-3,4-dehydropiperidine), AHR1806-(1-[2-(5-chloro-3-indolyl)-ethyl]-4-phenyl-3,4-dehydropiperidine), AHR1858-(1-[2-(3-indolyl)ethyl]-4-(4-fluorophenyl)-1,2,3, 6-tetrahydropyridine), AHR1709-(1-[2-(3-indolyl)ethyl]-4-phenyl-1,2,3,6-tetrahydropyridine) was determined in comparison with the classical neuroleptic agents haloperidol and oxypertine, the latter being of similar indole structure. The indole analogues were shown to antagonize amphetamine-induced toxicity in aggregated mice, to indicate a 'tranquillizing' action but, in contrast to haloperidol and oxypertine, showed weak or no activity in other classical behavioural tests for neuroleptic action, catalepsy induction and stereotypy antagonism. In further contrast to haloperidol or oxypertine, the indole derivatives failed to displace [3H]spiperone in radioligand binding assays and failed to increase prolactin levels. However, similarly to both typical and atypical neuroleptic agents, the indole derivatives were shown to inhibit the behavioural hyperactivity resulting from the intracerebral administration of dopamine into the mesolimbic nucleus accumbens of rat. The dissociation of an ability to antagonize a dopamine action in the mesolimbic system from classical neuroleptic actions involving other cerebral dopamine systems is the most important finding of the present study.
Amphetamine↗
Motor inhibition induced by aporphine derivatives in the mouse.
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Animals↗
Spontaneous climbing behaviour of mice, its measurement and dopaminergic involvement.
Measurement of spontaneous climbing behaviour of mice, made in Mouse Climbing Monitors which used photocell detection of vertical movements, was most reliable and intense when made over a 40 min period using two mice per cage and taking readings before 2:00 p.m. The climbing response was antagonised by low doses of the neuroleptics (-)-sulpiride and spiroperidol, and by low doses of the dopamine agonists apomorphine, N-n-propylbenzo(f)quinoline, N-n-propylbenzo(g)quinoline and 2-di-n-propylamino-5,6-dihydroxytetralin; N,N-dipropyldopamine was less effective. Higher doses of the dopamine agonists induced climbing. The inhibition afforded by apomorphine was partially antagonised by (-)-sulpiride and spiroperidol (at doses which do not in themselves modify spontaneous climbing) but not by prazosin or yohimbine. Bilateral electrolesions of the caudate-putamen, nucleus accumbens or tuberculum olfactorium attenuated spontaneous climbing for the first 5-9 postoperative days, the accumbens lesions being most effective. Thus, spontaneous climbing behaviour of mice can be precisely quantified, dopamine-containing forebrain areas are involved with its expression and it can be potently modified by dopamine agonists and antagonists.
Animals↗
Benzamide action at alpha 2-adrenoceptors modifies catecholamine-induced contraction and relaxation of circular smooth muscle from guinea-pig stomach.
Dopamine was shown to act on the circular smooth muscle of the stomach body to cause contraction at a yohimbine-sensitive site (alpha 2) and a relaxation at a prazosin-sensitive site (alpha 1). Metoclopramide and tiapride failed to modify either response, failed to antagonise a relaxation to phenylephrine at alpha 1 sites in the same tissue, and failed to modify the contractions caused by dopamine and phenylephrine at an alpha 1-adrenoceptor site in the pyloric sphincter. However, (+)- and (-)-sultopride and (+)-sulpiride antagonised the dopamine-induced contractions of the stomach body indicating an alpha 2-antagonist action. An ability to attenuate the relaxation of this tissue may reflect a displacement of the contraction curve to the right rather than an alpha 1-antagonist action since the response to phenylephrine was not antagonised either in this tissue or in the pyloric sphincter. Within the central nervous system the (-)-enantiomers of sultopride and sulpiride have a highly selective dopamine receptor blocking action. This contrasts with the present findings in the stomach musculature of a non-stereospecific antagonism at alpha 2-type adrenoceptors.
Animals↗
Apomorphine contracts and relaxes circular smooth muscle of guinea-pig stomach via action on adrenoceptor mechanisms.
Nanomolar concentrations of apomorphine caused contractions of the circular smooth muscle from the body region of the guinea-pig stomach, the response showing rapid tachyphylaxis. These contractions were antagonised by yohimbine but not by prazosin, haloperidol, propranolol or methysergide. Higher concentrations of apomorphine caused concentration-related relaxations of the stomach body which were not subject to tachyphylaxis. These were antagonised by propranolol but not by prazosin, yohimbine or haloperidol. Dopamine-induced contractions of the circular smooth muscle from the stomach body were antagonised by apomorphine in nanomolar concentrations; acetylcholine-induced contractions and isoprenaline-, dopamine- and phenylephrine-induced relaxations were unaffected by apomorphine. Thus, it is concluded that the contraction of circular smooth muscle from the stomach body to apomorphine is mediated via an adrenoceptor with characteristics of the alpha2-type, and that a partial agonist-antagonist action prevents subsequent contractile responses to apomorphine and dopamine. Relaxation caused only at higher concentrations of apomorphine is mediated via an adrenoceptor with characteristics of the beta-type.
Acetylcholine↗
Behavioural and biochemical consequences of persistent overstimulation of mesolimbic dopamine systems in the rat.
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Animals↗
Synthesis and dopaminergic properties of some exo- and endo-2-aminobenzonorbornenes designed as rigid analogue of dopamine.
Stereospecific syntheses of exo-2-amino-5,6-dihydroxybenzonorbornene (11f), exo-2-amino-6,7-dihydroxybenzonorbornene (11h), exo-2-amino-7,8-dihydroxybenzonorbornene (11g), and endo-2-amino-6,7-dihydroxybenzonorbornene (14d), rigid analogues of dopamine, are described. Compounds 11 h and 14d, their N-methyl (11i and 11j) and N,N-dimethyl (14i and 14j) derivatives, and compounds 11f and 11g were inactive as dopamine agonists when evaluated for dopaminergic activity by their ability to induce stereotyped behavior in mice after subcutaneous injection and by their ability to cause hyperactivity in rats after bilateral injection into the nucleus accumbens. However, compounds 11f, 11g, 11h, and the N-methyl derivatives 11i and 14d were all effective in displacing [3H]-2-amino-6,7-dihydroxytetralin ([3H]ADTN) and [3h[-N-n-propylnorapomorphine ([3H]NPA) from rat striatal membranes.
Animals↗
On the preferred rotameric conformation for dopamine agonist action: an illusory quest.
Putative dopamine agonists from the 2-aminotetrahydronaphthalene and trans-octahydrobenzo (f) and (g) quinoline series were shown to inhibit the spontaneous locomotor activity of mice. Marked potency differences were observed between the alpha-and beta-rotameric conformations, compounds having the alpha-rotameric conformation having the greater potency. Thus, 2-di-n-propylmino-5,6-dihydroxytetrahydronaphthalene was 339 times more potent than the 6, 7-dihydroxy isomer, and 2-n-propylamino-5,6-dihydroxy-compound was respectively 79 times and 179 times more than 6,7-hydroxy-and 7,8-dihydroxycompounds. trans-7,8-dihydroxy-1-n-propyl-1,2,3,4,a,9,10,10b-octahydrobenzo(f)quinoline was 11 times more potent than the beta-rotamer, the 6,7-dihydroxy compound, and within the trans-octahydrobenzo(g)quinoline series the alpha-rotameric N-propyl derivative was 467 times more potent than the beta-rotamer, and the alpha-rotameric greater than N-H analogue was 46 fold more potent than the beta-rotamer. Thus, the alpha-rotamer appears the more potent in causing the present functional dopaminergic change. The dopaminergic nature of the response was indicated by its sensitivity to spiroperidol but not to yohimbine or prazosin. The possibility that a difference in behavioural potency between the alpha- and beta-rotamers may reflect a differential metabolism by catechol-O-methyl transferase was assessed by administration of different agonists after pyrogallol pretreatment. This potentiated the activity of 2-di-n-propylamino-6,7-dihydroxytetrahydro-naphthalene but not that of the 5,6-dihydroxy analogue. However, changes in the effects of N-propyl derivatives of trans-octahydrobenzo (f) and (g)quinoline were not marked and, in all experiments, pyrogallol treatment failed by orders of magnitude to shift the dose-response curves of the beta-rotamers to indicate a comparable potency to the rotameric forms.
Animals↗
On the ability of domperidone to selectively inhibit catecholamine-induced relaxation of circular smooth muscle of guinea-pig stomach.
The effects of noradrenaline and dopamine, and their interactions with alpha- and beta-adrenoceptor antagonists and with domperidone, were studied on circular smooth muscle strips taken from the cardia, fundus, body and antrum of the guinea-pig stomach. Noradrenaline and dopamine caused relaxations of all tissues which were generally susceptible to antagonism by either propranolol or phentolamine in concentrations shown to antagonize the relaxations caused by isoprenaline or phenylephrine respectively. In addition, dopamine, in concentrations subthreshold for relaxation, caused contraction of the muscle strips which increased in intensity from the cardia to the antral region: these contractions were antagonized by phentolamine and yohimbine but were insensitive to prazosin: prazosin selectively inhibited the phenylephrine relaxations. With the exception of a modest reduction in the responses of the cardia to dopamine, all tissue responses to noradrenaline and dopamine were resistant to reserpine. Domperidone and haloperidol were found to selectively inhibit the phenylephrine- noradrenaline- and dopamine-induced relaxations of the stomach strips and to enhance the contractile component of dopamine's action: this ability of domperidone to facilitate a dopamine induced contraction, which was most marked in the body and antral regions, was prevented by phentolamine. It is thus concluded that domperidone antagonizes noradrenaline- and dopamine-induced relaxations at one adrenoceptor site having characteristics consistent with an alpha 1-adrenoceptor type whilst failing to antagonize at a further dopamine-sensitive adrenoceptor site involved in contraction of circular smooth muscle of the stomach and having characteristics consistent with an alpha 2-adrenoceptor.
Animals↗
Catecholamine-induced relaxation and contraction of the lower oesophageal and pyloric sphincters of guinea-pig stomach: modification by domperidone.
Catecholamine control of circular smooth muscle activity of the lower oesophageal (LOS) and pyloric sphincters (PS) of the guinea-pig was studied using alpha- and beta-adrenoceptor agonists and antagonists. In both sphincters dopamine (DA) and noradrenaline (NA) caused relaxation followed by contraction of the circular smooth muscle, although the ability of NA to contract the PS was weak and inconsistent. Isoprenaline relaxed both sphincter preparations but, whilst phenylephrine contracted the muscle of the PS, it caused a biphasic relaxation-contraction of the LOS. The use of the alpha- and beta-adrenoceptor antagonists, phentolamine and propranolol, indicated that contractions of both sphincters by NA and DA involved an alpha-type adrenoceptor whilst relaxation was mediated via a beta-adrenoceptor (PS) or via both alpha- and beta-adrenoceptors (LOS). Use of the alpha 1 and alpha 2 antagonists, prazosin and yohimbine, indicated that the alpha-adrenoceptor type involved with both the contractions and relaxation was alpha 1. Both domperidone and haloperidol antagonized the contractile responses of both tissues to DA (and partly the relaxation of the LOS) but were similarly effective against the contractions induced by NA and phenylephrine; an effect on alpha 1-adrenoceptors was therefore, concluded. In selectively antagonizing the contractile effects of DA in the PS, domperidone enhanced DA's ability to relax this sphincter.
Animals↗
Catecholamines act as alpha 2-adrenoceptors to cause contraction of circular smooth muscle of guinea-pig stomach.
Circular smooth muscle strips taken from the body region of the guinea-pig stomach responded to dopamine and noradrenaline with contraction at lower concentrations followed by relaxation at higher concentrations. A beta-adrenoceptor-mediated relaxation response was excluded by propranolol treatment and this allowed the remaining alpha-adrenoceptor involvement with relaxation and contraction to be incisively differentiated in terms of two distinct alpha-adrenoceptor mechanisms. Thus, the relaxation responses to the catecholamines were mimicked by phenylephrine and antagonized by prazosin, phentolamine but not by yohimbine or rauwolscine. In contrast, the catecholamine-induced contractions were mimicked by clonidine and antagonized by yohimbine and phentolamine but not by prazosin. It is therefore concluded that the alpha mechanisms via which dopamine and noradrenaline are able to relax and contract the circular smooth muscle from the body region of guinea-pig stomach are of the alpha 1- and alpha 2-type respectively.
Animals↗
Behavioural actions of neuroleptics are not reduced by hypophysectomy.
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Animals↗
Characterisation of the mechanisms by which purported dopamine agonists reduce spontaneous locomotor activity of mice.
The spontaneous locomotor activity of mice, recorded in the first 20 min period after placement in individual cages fitted with photocells, was reduced dose-dependently by apomorphine, (-)-N-n-propylnorapomorphine, 2-dimethylamino-5,6-dihydroxytetralin (M-7), 2-di-n-propylamino-5,6-dihydroxytetralin, (3,4-dihydroxyphenylamino)-2-imidazoline (DPI), N-n-propyl-benzo(f) and (g) quinolines, bromocriptine, N-n-propyl-3-(3-hydroxyphenyl)-piperidine (3-PPP) and by the N,N-dimethyl-, -diethyl-, -dipropyl- and -dibutyl-dopamines. SK&F 38393, in a wide dose range, failed to modify spontaneous locomotion. The inhibition of spontaneous locomotion caused by 2-di-n-propylamino-5,6-dihydroxytetralin was reversed by spiroperidol, haloperidol, benperidol and (-)-sulpiride, used in doses which did not in themselves modify spontaneous locomotion, but not by similarly selected doses of trifluperidol, fluphenazine, oxiperomide, molindone, thioridazine, prazosin, picrotoxin, methysergide, yohimbine, propranolol, phentolamine, atropine or SK&F 38393. Spiroperidol was also shown to reduce the actions of N,N-diethyl-, N,N-dipropyl- and N,N-dibutyl-dopamine, M-7, bromocriptine, apomorphine and, less markedly, 3-PPP and the (f) and (g)benzoquinolines, but not the actions of N,N-dimethyldopamine or DPI. Yohimbine reversed the action of DPI but ont that of any other purported dopamine agonist, whilst prazosin was ineffective throughout the experiments. The neuroleptic agents did not in themselves cause significant increase in spontaneous locomotor activity. Data is discussed in terms of a dopamine-neuroleptic sensitive mechanism for motor inhibition.
Animals↗