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Microinjection of noradrenaline and clonidine into lateral medullary pressor area (LMPA) of chloralose anaesthetized cats produced dose dependent decrease in blood pressure without affecting heart rate, while phenylephrine did not elicit any cardiovascular response. Selective alpha 2-adrenoceptor antagonists idazoxan and piperoxan, microinjected locally, blocked the effects of the agonists but prazosin and phenoxybenzamine, which are relatively selective for alpha 1-adrenoceptors, failed to do so. Clonidine did not elicit any response in guanethidine pretreated cats but noradrenaline microinjected into LMPA of these animals induced a pressor response which was blocked by prazosin pretreatment. It is concluded that catecholaminergic fibres impinging upon this area inhibit the activity of the inhibitory second order baroreceptor neurone by activating alpha 1-adrenoceptors while alpha 2-adrenoceptors situated presynaptically on these inhibitory catecholaminergic nerve terminals are responsible for the manifestation of the hypotensive effect of clonidine and exogenously administered noradrenaline.

The neuropil surrounding sympathetic preganglionic neurons (SPNs) receives an abundant catecholaminergic innervation originating from the brain stem. The effect of catecholamines (CA) released at this spinal level on the activity of SPNs is still controversial as is the extent to which this particular CA transmission is affected by central antihypertensive drugs, such as clonidine and alpha-methyldopa. The present study was initiated, therefore, to determine the effects of iontophoretic applications of CAs and clonidine on the discharges of identified SPNs and to determine the type of receptor mediating the action of these compounds. Extracellular recordings were made with five- or six-barrel electrodes in 20 pigeons anesthetized with urethane, artificially ventilated, and immobilized. Data were obtained on 83 SPNs localized in the three first thoracic segments and identified on the basis of constancy of antidromic activation latency and collision. All of the cells sampled were inhibited by the application of low iontophoretic currents of clonidine and by a series of CAs, including alpha-methylnorepinephrine, epinephrine, and phenylephrine. For each compound, the amount of charge necessary to decrease the level of cell firing to 50% of control was calculated. Using this value as an index of drug potency, the following rank order could be determined: clonidine greater than alpha-methylnorepinephrine greater than epinephrine greater than norepinephrine greater than phenylephrine. The inhibitory effects of both clonidine and norepinephrine were antagonized by iontophoretic applications of the alpha antagonists, yohimbine, piperoxan, and phentolamine. In contrast, the beta antagonist, sotalol, and the alpha 1 antagonist, prazosin, were found ineffective when similarly applied. It is concluded that CAs and clonidine are inhibitory to the maintained activity of SPNs and that an alpha2-adrenergic receptor may be involved in the action of these compounds.

The ratio (expressed in log10 units) of the equieffective concentrations of (+)- and (—)-noradrenaline has been measured in a variety of isolated tissues in the presence of cocaine (1 times 10−5m), tropolone (3 times 10−5m) and (±)-propranolol (5 times 10−7 to 5 times 10−5m). The values obtained fall into 3 distinct and statistically different groups. Firstly, a high group comprising (mean ± s.e.) mouse vas deferens (2·78 ± 0·04), rabbit duodenum (2·91 ± 0·07) and ileum (2·86 ± 0·05). Secondly a middle group comprising rabbit vas deferens (2·54 ± 0·04), bladder neck muscle (2·56 ± 0·07) and spleen (2·50 ± 0·02), guinea-pig vas deferens (2·55 ± 0·10) and bladder neck muscle (2·48 ± 0·13) and rat deferens (2·40 ± 0·08) and thirdly, a low group comprising the bladder detrusor muscle from both the rabbit (2·08 ± 0·08) and the guinea-pig (2·07 ± 0·04). Under the same conditions measurement of pA2 values for phentolamine and piperoxan against noradrenaline gave the following values in rat vas deferens (8·22 ± 0·07 and 6·72 ± 0·03 respectively) and mouse vas deferens (8·31 ± 0·05 and 6·53 ± 0·07 respectively). The results are discussed in relation to other findings concerning the nature of the α-adrenoceptor in these tissues. In spite of the absence of any significant difference between the potency of the α-adrenoceptor blocking agents in the two species it is suggested that α-adrenoceptors may not belong to a single homogeneous population but may vary in their characteristics from tissue to tissue.

The recent discoveries of the benzodiazepine receptor and of antagonist compounds, such as beta-CCE, have advanced our understanding of the neurochemistry of anxiety. In this review we summarize the evidence implicating the benzodiazepine receptor in anxiety and relate this model to other models of anxiety.

Intracerebroventricular administration of adrenaline, noradrenaline phenylephrine, clonidine and histamine produced a significant rise in plasma cortisol concentration whereas isoprenaline had no effect. alpha-Adrenoceptor blockers (yohimbine or piperoxon) per se did not alter the plasma cortisol level. Central pretreatment with yohimbine or piperoxin, blocked the rise in plasma cortisol level induced by icv noradrenaline, phenylephrine and clonidine. In another set of experiments, both H1 and H2 receptor antagonists (mepyramine, and metiamide) per se had not significant effect on plasma cortisol concentration. Central histamine induced rise in plasma cortisol concentration was significantly blocked by icv pretreatment with both H1 and H2 receptor blockers. Furthermore, yohimbine also significantly prevented the rise of plasma cortisol level induced by icv histamine.

A wide variety of phenylethylamine derivatives were injected bilaterally into the nucleus accumbens of rat following a nialamide pretreatment and hyperactivity was recorded. 2-Phenylethylamine was shown to induce a low intensity hyperactivity but the introduction of hydroxyl functions on to the phenyl ring at the 3- and/or 4-positions enhanced activity and m- and p-tyramine and dopamine each caused marked hyperactivity in the 3.4-25 mug dosage range. Methylation of one hydroxyl function reduced activity (3-methoxy-4-hydroxy- and 3-hydroxy-4-methoxy-phenylethylamine); 2(3,4-methylenedioxyphenyl) ethylamine was inactive. Agents with substitution of the side chain, such as noradreline, d-amphetamine and alpha-methyldopamine, were all shown to induce marked hyperactivity at doses of 1.6-25 mug. Alterations in the chain length markedly reduced activity (4-(3,4-dihydroxyphenyl) butylamine, 3,4-dihydroxybenzylamine). A variety of N-substituted compounds were shown to be potent inducers of hyperactivity from the nucleus accumbens (adrenaline, epinine, N-ethyldopamine, N-isopropyl-dopamine, isoprenaline) (0.2-25 mug). However, N-methyl-N-isopropyldopamine showed only weak activity and N,N-dimethyldopamine was inactive. All hyperactivity effects were shown to be dose-dependent. The hyperactivities induced by dopamine, noradrenaline and isoprenaline were each inhibited in a dose-dependent manner by subsequent injections of fluphenazine (1.25-25 mug) into the nucleus accumbens, although no reductions were recorded following similar injections of saline, solvent, 2% procaine, 50 mug propranolol or 50 mug piperoxan.

The effects of RU24722 (14,15-dihydro-20,21-di-noreburnamine-14-ol) on tyrosine hydroxylase in central catecholaminergic neurons were studied in rats treated with different quantities of the molecule, and a time course was done for the minimal dose that gave the maximal effect. RU24722 induced increases in tyrosine hydroxylase activities and specific protein content in noradrenergic cells of the locus ceruleus and decreased all these parameters in dopaminergic neurons of the substantia nigra and ventral tegmental area. The results pointed out that the specific activity of newly synthesized tyrosine hydroxylase in the loci cerulei was potentially greater but was not expressed “in vivo” except 7 days after injection. The phenotypic specificity and the time course pattern of the action could be considered as a consequence of an induction mechanism. The comparison of long-term change in tyrosine hydroxylase values after pipe-roxane, RU24722, clonidine, and combined RU24722-clon-idine treatment demonstrated that an activation during a few hours did not induce tyrosine hydroxylase in central noradrenergic neurons. Clonidine antagonized the activating effect of RU24722 following its injection but did not affect its long-term induction properties.

Strips of the main pulmonary artery of the rabbit were preincubated with [ 3 H]noradrenaline and then superfused and electrically stimulated transmurally. Yohimbine, dihydroergotamine and tolazoline at low concentrations enhanced the stimulation-evoked overflow of tritium; up to one hundred times higher concentrations were needed in order to reduce stimulation-evoked contractions. Piperoxan and mianserin enhanced the evoked overflow and reduced the evoked contractions at identical concentrations. Phentolamine, azapetine, clozapine and phenoxybenzamine at low concentrations diminished the contractile response; up to thirty times higher concentrations were needed to increase the evoked overflow of tritium. At high concentrations, all drugs accelerated basal tritium outflow. Separation of individual [ 3 H]-compounds revealed that a high concentration of piperoxan markedly accelerated the basal outflow of [ 3 H]3,4-dihydroxyphenylglycol. Lower concentrations of piperoxan and yohimbine that did not affect the basal efflux of [ 3 H]-compounds greatly increased the evoked overflow of [ 3 H]noradrenaline as well as of [ 3 H]3,4-dihydroxyphenylglycol and [ 3 H]normetanephrine. The pulmonary artery contains postsynaptic α-adrenoceptors which mediate smooth muscle contractions. Its noradrenergic neurones possess presynaptic α-receptors which mediate inhibition of the per pulse release of noradrenaline by a negative feedback mechanism. α-Adrenolytic drugs vary widely in their relative pre- and postsynaptic effects. Yohimbine, dihydroergotamine and tolazoline preferentially block presynaptic α-receptors and at low concentrations selectively facilitate noradrenaline release. Phentolamine, azapetine, clozapine and phenoxybenzamine preferentially block postsynaptic α-receptors and at low concentrations selectively antagonize the contractile response. Piperoxan and mianserin occupy an intermediate position. In a given tissue, pre- and postsynaptic α-receptors may differ in their structure.

The influence of mianserin and cyproheptadine on the response of the rat stomach fundus in vitro to Ach (acetylcholine), 5-HT (serotonin) and tryptamine in the presence of the α-adrenolytic, piperoxan, were compared. Cyproheptadine and mianserin competitively antagonized the Ach-induced contractions, but cyproheptadine was more effective. Mianserin, a recognized antagonist of 5-HT on rat uterus and on bronchospasm of the guinea pig, did not affect 5-HT- and tryptamine-induced contractions of the isolated rate stomach fundus in concentrations up to 10−6 M, while cyproheptadine proved highly effective. Higher doses of mianserin contracted the organ. A closed piperazine ring seems to be essential for such action. Although no anti-5-HT action could be found with mianserin on the rat fundus, it protected 5-HT-induced contractions against inhibition by phenoxybenzamine, cyproheptadine or methysergide. The α-adrenolytic piperoxan was more effective in protecting the response to 5-HT than to Ach against inhibition by phenoxybenzamine. It is concluded that differences might exist between D-tryptamine receptors in different organs and that the receptor protection by mianserin and pieperoxan towards the 5-HT-induced contractions may be related to an ability to interact at Ca2+-binding sites of the smooth muscle cell membrane. However, the possibility that piperoxan might in some way interfere with an inhibitory action of mianserin towards tryptamine receptors is not ruled out. Although both the response to 5-HT and tryptamine are affected by cyproheptadine, the 5-HT-induced contractions were more susceptible to inhibition by cyproheptadine than those of tryptamine. This possibly indicated a subsidiary action of tryptamine on other than the D-tryptamine receptors.

The effect of intracisternal (i.c.m.) injection of clonidine, noradrenaline, and piperoxane on the pressor response to electrical stimulation of a peripheral somatic afferent nerve was investigated using anaesthetized cats. It was found that noradrenaline caused a depression of the magnitude of the pressor response and this effect was antagonized by subsequent injection of piperoxane i.c.m. In contrast, clonidine had no significant effect on the magnitude of the somatic pressor reflex but caused a dose-dependent prolongation of the reflex after cessation of nerve stimulation. This prolongation was antagonized by piperoxane which also caused an increase in the magnitude of the reflex. Piperoxane alone had no significant effect on the magnitude or duration of the reflex. Neither magnitude nor duration of the somatic pressor reflex was influenced significantly by a reduction in resting blood pressure. It is suggested that clonidine and noradrenaline act at different sites within the central nervous system to produce qualitatively different changes in the efferent sympathetic discharge pattern modulating the somatic pressor reflex.

The paraventricular hypothalamic nucleus receives a dense noradrenergic innervation. Electrochemically treated carbon fibre electrodes were implanted in the paraventricular nucleus of anaesthetized rats and their locations were histologically controlled after each experiment. Differential normal pulse voltammograms showed an oxidation peak at +50 mV. This peak was mainly due to 3,4-dihydroxyphenylacetic acid synthesized by noradrenergic terminals since: (1) it appeared at the same oxidation potential as 3,4-dihydroxyphenylacetic acid in vitro ; (2) it was rapidly suppressed after inhibition of tyrosine hydroxylase byalpha-methyl- p -tyrosine or monoamine oxidase by pargyline; (3) blockade of dopamine-β-hydroxylase by FLA 63 induced a marked increase in this signal, whereas this drug was without effect in dopaminergic terminals fields (striatum, zona incerta); (4) stimulation of alpha 2 noradrenergic receptors by clonidine (50μg/kg) decreased the peak height and this effect was reversed by piperoxane (30 mg/kg). This oxidation peak corresponded to a 3,4-dihydroxyphenylacetic acid concentration of 2 μM. On the other hand, when recorded from rats which were treated with pargyline 3 h before recording, a small peak appeared at +100 mV. This signal was attributed to the oxidation of extracellular noradrenaline on the basis of the following arguments: (1) it appeared at the same potential as noradrenaline in vitro ; (2) desipramine (25 mg/kg) induced a 4-fold increase in this peak height; (3) piperoxan (2 mg/kg) enhanced this signal and reversed the decrease induced by clonidine (50 μ/Kg); (4) electrical stimulations (bipolar electrode, square pulses, 0.3 ms, 200 μA, 15 Hz for 40 s) in the rostral part of the Al group were followed by an immediate, short-lasting 4-fold increase in the signal.

The relationship between MHPG concentration in several brain areas, cisternal CSF and plasma was examined in 26 vervet monkeys. Free MHPG was measured by gas chromatography-mass spectrometry using deuterated MHPG as internal standard. In animals with or without treatment with drugs that alter norepinephrine metabolism, highly significant correlations were found in concentrations of MHPG between the various brain areas, between plasma and CSF, between plasma and brain areas and between CSF and brain areas. The concentration of MHPG in CSF was higher than in plasma and with the exception of occipital cortex, all brain regions contained a higher concentration of MHPG than CSF. This study supports the notion that free MHPG concentrations in plasma and cisternal CSF are useful indices of central noradrenergic activity.

Differential pulse voltammetry used in combination with electrochemically treated carbon fiber electrodes allowed us to detect catechols in the locus coeruleus (LC) of conscious freely moving rats. A micromanipulator cemented on the rat skull was designed in order to implant carbon fiber electrodes without anesthesia. Voltammograms were recorded every 2 min for 5 h. After the in vivo experiments electrodes were tested in 3,4-dihydroxyphenylacetic acid (DOPAC), 3,4-dihydroxyphenylglycol (DOPEG) and noradrenaline (NA) solutions. The catechol peak recorded from LC was suppressed by pargyline treatment and slightly reappeared after inhibition of the NA reuptake by desipramine (DMI). This reappearing signal was attributed to NA and estimated at a concentration 50 nM NA. Various drug treatments (piperoxane, haloperidol, clonidine, DMI and reserpine) allowed us to further support the conclusion of part I of this study: the catechol peak recorded from LC is mainly due to DOPAC synthesized by LC noradrenergic neurons. This DOPAC signal corresponded to a DOPAC concentration which reached 23 microM when the whole active part of the electrode was implanted in the LC. In addition to this pharmacological study, data from stress experiments pointed out a striking parallel between the variations of the DOPAC signal and those of the activity of LC noradrenergic neurons as revealed by reported electrophysiological studies.

The preferential alpha-2 noradrenergic agonists, clonidine (0.2--0.4 mg/kg), oxymetazoline (2.5--10.0 mg/kg) and UK 14,304 (0.6 mg/kg), when given i.p., reduce the severity of audiogenic seizures in 19- to 26-day-old DBA/2 mice. This protective effect can be diminished or reversed by alpha-2 noradrenergic antagonists such as yohimbine (2.5 mg/kg) or piperoxan (20--50 mg/kg) given i.p. or phentoalamine (100 micrograms) given intracerebroventricularly. It is not reversed by the preferential alpha-1 noradrenergic antagonist phenoxybenzamine (5 mg/kg) given i.p. Yohimbine, (1--2.5 mg/kg), piperoxan (20--50 mg/kg) or phenoxybenzamine (5 mg/kg) given i.p. alone did not change the severity of audiogenic seizure responses. Phentolamine (10--100 micrograms) or prazosin (10--50 micrograms) given intracerebroventricularly induced spontaneous limb myoclonus in some mice. Audiogenic seizure responses were unchanged after phentolamine (10--100 micrograms) but were reduced after prazosin (25--50 micrograms). Activation of a receptor pharmacologically similar to the peripheral alpha-2 noradrenergic receptor protects against seizures in this epilepsy model.

1 [3H]-prazosin binds specifically to a single class of alpha-adrenoceptors in rat cardiac membranes (KD25 degrees C = 0.2 nM). 2 That these receptors are of the alpha 1-type was indicated by competition studies, i.e. alpha 1-antagonists such as prazosin and (2-(2,6-dimethoxyphenoxyethyl) aminomethyl-1, 4-benzodioxane (WB 4101) were more potent than the alpha 2-antagonists, yohimbine and piperoxan in inhibiting [3H]-prazosin binding. 3 A comparative study of [3H]-prazosin binding and [3H]-dihydroergocryptine binding to cardiac membranes showed that both [3H]-prazosin and [3H]-dihydroergocryptine (at low concentrations) bind to alpha 2-adrenoceptors, while [3H]-dihydroergocryptine (at higher concentrations) also binds to another class of sites.

The effects of microinjection of histamine and its antagonists into mesencephalic nucleus dorsalis raphe, were investigated on mean arterial pressure and heart rate in cats to elucidate the nature and role of histaminergic receptors in cardiovascular regulation. Microinjection of histamine (5 and 10 μg) into nucleus dorsalis raphe elicited both inhibitory and excitatory cardiovascular responses respectively. On the other hand, microinjection of H2-receptor blocker, cimetidine (10 μg) resulted in hypertension and tachycardia while H1-receptor antagonist, mepyramine (10 μg) microinjection evoked hypotension and bradycardia. Furthermore, local pretreatment with cimetidine and mepyramine blocked the inhibitory and excitatory cardiovascular responses of graded doses of histamine microinjection. These H1 and H2 receptors are localized in nucleus dorsalis raphe since microinjection of histamine into adjoining neural structures did not evoke any cardiovascular change. Furthermore, both the inhibitory and excitatory cardiovascular responses to histamine microinjection could not be observed in animals with spinal cord transection and in animals pretreated with p-chlorophenylalanine while they could be observed in bilateral cervical vagotomized animals. Thus, it appears that these cardiovascular responses to microinjection of histamine into nucleus dorsalis raphe, are due to modulation of serotonergic bulbospinal influence on sympathetic preganglionic neurones in the spinal cord. Moreover, the excitatory cardiovascular responses of high dose of histamine (10 μg) seem to result from a local release of noradrenaline since they were blocked by prior microinjection of guanethidine and piperoxan into nucleus dorsalis raphe. A release of noradrenaline in turn, modulates the activity of the neurones of the nucleus by acting on α adrenoceptors and thereby alters the activity of sympathetic preganglionic neurones. These α adrenoceptors appear to be of α1 type (Saxena et al. 1985, 1987) since phenylephrine microinjection evoked excitatory cardiovascular responses could be blocked by piperoxan.

1. Cats were anaesthetized with pentobarbitone sodium. The hypothalamus was superfused with drugs through a push-pull cannula and electrically stimulated with the non-insulated tip of the cannula. In another series of experiments, the hypothalamus was stimulated with a monopolar electrode and the nucleus of the solitary tract superfused with drugs through a push-pull cannula. 2. Superfusion of the hypothalamus with alpha-adrenoreceptor blocking agents (piperoxan or tolazoline) decreased the pressor responses to hypothalamic stimulation. Superfusion with low concentrations of clonidine increased, whereas superfusion with higher concentrations of this drug diminished, the rise of blood pressure during hypothalamic stimulation. Muscarinic agents (oxotremorine, muscarine or AHR 602) decreased the pressor responses to hypothalamic stimulation. The inhibitory effects of the muscarinic compounds were abolished by superfusing the hypothalamus with methylatropine. Superfusion with nicotinic agents (1,1-dimethyl-4-phenylpiperazinium, or carbachol) enhanced the pressor responses to hypothalamic stimulation. The enhancement of the pressor responses by these drugs was completely inhibited by superfusion of the hypothalamus with hexamethonium. 3. Superfusion of the nucleus of the solitary tract with tolazoline enhanced the pressor responses to hypothalamic stimulation. The pressor responses were reduced during superfusion of the nucleus of the solitary tract with clonidine.

Depression of self-stimulation by clonidine has been ascribed to continuous direct stimulation of α-adrenoceptors with consequent disruption of reinforcement signals thought to be conveyed by noradrenergic pathways. This suggestion was tested by administration of α-receptor blocking agents (piperoxane, phentolamine and phenoxybenzamine, PBZ) differing in their affinity for pre- and post-synaptic receptor sites. Piperoxane in low doses (0.55–5.0 mg/kg) previously reported to cause specific blockade of pre-synaptic receptors implicated in negative feedback circuits, caused a significant increase in self-stimulation rate and strongly antagonized the depression of self-stimulation by clonidine (0.15 mg/kg). A larger dose of piperoxane (45 mg/kg) and graded doses of phentolamine and PBZ, affecting both pre- and post-synaptic receptors, depressed self-stimulation, and did not antagonize clonidine-induced depression of self-stimulation. It is concluded that depression of self-stimulation by clonidine may depend on clonidine-induced inhibition of NA release exerted via presynaptic receptors, and that the effect of clonidine is not necessarily evidence that noncontingent adrenergic stimulation disrupts reinforecement.

The effects of alpha adrenoceptor agonists and antagonists have been examined at pre- and post-synaptically located alpha-adrenoceptors in the pithed rat. The presynaptic receptors were those located at the cardiac sympathetic nerve terminals and the postsynaptic receptors were those present in vascular smooth muscle. Clonidine was approximately equipotent at pre- and post-synaptic alpha-adrenoceptors, whilst LSD and BAY-1470 were more active at the pre- than at post-synaptic sites. Oxymetazoline, naphazoline, methoxamine and phenylephrine were all much more active at the postsynaptic alpha-adrenoceptors. Phentolamine was the most potent antagonist at both pre- and post-synaptic alpha-adrenoceptors. Piperoxan, yohimbine and tolazoline were about 3-7X less potent than phentolamine at both sites. Thymoxamine was about 10X less potent than phentolamine at postsynaptic alpha-adrenoceptors but about 1000X less active at the presynaptic receptors. The differential actions of both agonsists and antagonists at pre- and post-synaptic alpha-adrenoceptors suggest that the receptors may be of different types.

The synthesis and in vitro alpha- and beta-adrenergic blocking potency of 1-[1-(2-benzodiaxanylmethyl)-4-piperidyl]amino-3-(1-naphthoxy-2-pr opanol (I) are described. Thus, N-benzyl-4piperidone was protected and debenzylated to the carbamate (V), which upon alkaline hydrolysis and acylation gave benzodioxanic amide (IX). Reduction of the amide group, deprotection of the ketone function of (X), and reductive amination gave the 4-aminopiperidine (XIII), which was finally condensed with the appropriate epoxide to yield the aminopropanol (I). Compound (I) is formally derived from a combination of piperoxan (II) and propranolol (III), and was approximately 10 times less potent than each one of these drugs, as an alpha- and beta-adrenergic blocker respectively.

In order to reinvestigate the role of brain alpha-adrenergic systems in the regulation of paradoxical sleep (PS), we recorded chronically implanted rats under the effect of various neuroactive substances. The functions describing the evolution of PS during sleep were calculated. The following substances were studied at different doses, alone and in various combinations: clonidine, phenoxybenzamine, chlorpromazine, yohimbine, piperoxane and desipramine. Chlorpromazine, yohimbine, piperoxane and desipramine were also studied after pretreatment with alpha-methylparatyrosine. The results are discussed in terms of the known pharmacological properties of these compounds, and indicate that brain alpha-adrenergic systems, probably mainly noradrenergic systems, are positively involved in the maintenance of PS. However, the activity of these systems is controlled by powerful regulatory mechanisms: inhibitory control of transmitter release at the effector site, collateral inhibition within the locus coeruleus and control of transmitter release at the site of collateral inhibition.

The effects of serotonin (5-HT) receptor agonists and antagonists on sympathetic nervous discharge (SND) recorded from the external carotid and splanchnic nerves were studied in baroreceptor-denervated cats. Intravenous administration of the 5-HT antagonists methysergide (0.025-1.6 mg/kg), metergoline (0.01-0.32 mg/kg), cyproheptadine (0.05-1.6 mg/kg) and cinanserin (0.2-6.4 mg/Kg) was associated with a prolonged dose-related inhibition of SND. Maximum reductions in SND produced by methysergide, metergoline, cyproheptadine and cinanserin were 90, 72, 71 and 50%, respectively. In contrast, a progressive increase in SND was observed in vehicle control animals. Methysergide, metergoline and cyproheptadine failed to reduce SND in cats pretreated with the 5-HT synthesis inhibitor p-chlorophenylalanine. Clonidine (20 micrograms/kg i.v.) significantly inhibited SND (-73%) in p-chlorophenylalanine-treated cats. The selective 5-HT agonists 5-methoxydimethyltryptamine and lisuride also reduced SND in a dose-dependent manner. The time course of the depressor effects of 5-methoxydimethyltryptamine and lisuride correlate well to their ability to inhibit 5-HT cell firing. These data indicate that 5-HT agonists which act presynaptically to inhibit 5-HT cell firing and antagonists which act postsynaptically to block the effect of synaptically released 5-HT both mediate a central reduction in SND. It is concluded that central 5-HT neurons facilitate transmission in central sympathetic pathways.

1 In rat isolated vas deferens, the isotonic contractile responses to low doses of noradrenaline or adrenaline were antagonized, and those to high doses were potentiated, by yohimbine, piperoxan, phentolamine and tolazoline. Effects due to intermediate doses were not affected, or were potentiated within about 30 min, following an initial inhibition. 2 The alpha-adrenoceptor blockers thus caused a shift to the right and an increase of the maximum height of log dose-response curves of alpha-adrenoceptor stimulants. For a given dose of antagonist, the onset was slower for the potentiating than for the blocking effect. 3 The shift to the right induced by piperoxan and yohimbine on dose-response curves of noradrenaline and adrenaline was analysed with the Schild plot, and the slopes obtained, around 0.3, were lower than expected from receptor theory. When cocaine was used to block neuronal uptake, the slopes were close to 1.0. 4 The increase in maximum response to noradrenaline and adrenaline induced by alpha-adrenoceptor blockers was dependent on the time of incubation, on the dose of antagonist, and on the initial height of responses to the agonist. A less pronounced potentiation was also obtained when acetylcholine was used as agonist. 5 The findings are explained in terms of receptor theory as being due to a dual effect of alpha-adrenoceptor antagonists; competitive antagonism proper, which may be disclosed after blockade of neuronal uptake, and an interaction at a different locus, which results in potentiation of the effects of noradrenaline and adrenaline.

The effects of intracerebroventricular (i.c.v.) injections of adrenaline on the blood pressure and heart rate of spontaneous hypertensive (SH) rats have been investigated. Adrenaline induced dose-related falls in blood pressure and heart rate in both conscious and urethane anaesthetised rats. In conscious rats, the hypotension and metoprolol, but were unaffected by pretreatment with phentolamine, piperoxan, fluphenazine or methysergide. However, in urethane-anaesthetised rats, the hypotension and bradycardia induced by i.c.v. adrenaline was not significantly affected by i.c.v. pretreatment with propranolol or oxprenolol, while metoprolol significantly antagonised only the bradycardia. Piperoxan, fluphenazine and methysergide were also without effect. Pretreatment with mecamylamine (i.p.) abolished the cardiovascular depressor effects of i.c.v. adrenaline in both conscious and urethane anaesthetised SH rats. It is concluded that the cardiovascular depressor effects of i.c.v. adrenaline are mediated by central adrenoceptors in SH rats and that, in conscious rats, these depressor effects may be mediated by central beta-adrenoceptors rather than alpha-adrenoceptors.

Various types of autonomic receptors were studied in isolated, 2 X 10 mm-size strips from the protruding part of human Graafian follicles obtained shortly before ovulation. The strip was mounted in an organ bath for recording of mechanical activity in the presence of different agonists and specific antagonists. The potency rank for sympathomimetics in their contractile effect (norepinephrine > epinephrine > penylephrine > isoproterenol) and the inhibition produced by phenoxybenzamine and piperoxan suggested the presence of a-receptors. The dissociation constant for their complex with norepinephrine (KA) was 1.68 X 10’M, and with piperoxan (KB) 7.90 X

Intravenous administration of erythro-1-(1-[2-(1,4-benzodioxan-2-yl)-2-OH-Et]-4-piperidyl)-2-benzimidazolinone (R-28935) (25--100 microgram/kg) produced a dose-related decrease in spontaneous electrical activity recorded in the splanchnic and renal nerves. Reductions in sympathetic nerve activity were paralleled by hypotension and bradycardia. R 28935-induced depressor responses were not affected by baroreceptor denervation, piperoxan, yohimbine or phentolamine. Results support the idea that R-28935 decreased resting blood pressure and heart rate through a reduction in central sympathetic outflow which does not involve alpha-adrenergic receptor activation.

Methodology has been developed to allow biochemical analysis of monoamine metabolites as well as histological analysis of brain tissue in a single sample. The levels of the major metabolites of norepinephrine (NE), dopamine (DA) and serotonin (5-HT) have been compared in specific brain regions of control rats and rats perfused with 10% formalin. No significant differences in metabolite levels were found. Secondly, control and formalin-perfused animals were treated with piperoxan, haloperidol or tryptophan, all compounds known to increase the concentrations of these metabolites in brain. Thirdly, NE metabolite levels were measured in ipsilateral and contralateral cerebral cortex hemispheres of contol and perfused locus coeruleus-stimulated rats. Pharmacological treatments and electrophysiological stimulation increased metabolite levels to the same magnitude in both controls and formalin-perfused animals. Finally, levels of NE metabolite in rat cortex were compared in control, formalin-perfused and gluteraldehyde/formalin-perfused animals. Again no significant differences were found. This method facilitates microdissection and the performance of microassays on selected regions of the brain.

The interaction of the catecholamines epinephrine (E) and norepinephrine (NE) (1.0-100 microM) and excitatory amino acids on motoneurons of the isolated superfused frog spinal cord was investigated by sucrose gap recordings from ventral roots. Exposure of the cord to E or NE 30 sec prior to application of L-aspartate or L-glutamate reduced the motoneuron depolarizations produced by the amino acids. The reduction of responses to the mixed receptor agonists L-glutamate and L-aspartate may be the result of opposite actions of the catecholamines on the activation of specific excitatory receptors by the amino acids. Thus, E and NE facilitated depolarizations caused by application of N-methyl-D-aspartate (NMDA) and depressed those produced by quisqualate. The effect on NMDA responses appeared to be beta-adrenoceptor mediated because it was mimicked by the beta-agonist isoproterenol and blocked by propranolol. The effect on quisqualate depolarizations appeared to require activation of alpha 2-adrenoceptors; it was mimicked by the alpha 2-agonists clonidine and alpha-methylnorepinephrine and antagonized by yohimbine and piperoxan. These results are important in understanding the actions of catecholamines on reflex transmission in spinal pathways which use excitatory amino acids as transmitters.

1 The presynaptic alpha-adrenoceptors located on the terminals of the cholinergic nerves of the guineapig myenteric plexus have been characterized according to their sensitivities to alpha-adrenoceptor agonists and antagonists.2 Electrical stimulation of the cholinergic nerves supplying the longitudinal muscle of the guinea-pig ileum caused a twitch response. Clonidine caused a concentration-dependent inhibition of the twitch response; the maximum inhibition obtained was 80 to 95% of the twitch response. Oxymetazoline and xylazine were qualitatively similar to clonidine but were about 5 times less potent. Phenylephrine and methoxamine also inhibited the twitch response but were at least 10,000 times less potent than clonidine.3 The twitch-inhibitory effects of clonidine, oxymetazoline and xylazine, but not those of phenylephrine or methoxamine, were reversed by piperoxan (0.3 to 1.0 mug/ml).4 Lysergic acid diethylamide (LSD) inhibited the twitch response, but also increased the basal tone of the ileum. Mepyramine prevented the increase in tone but did not affect the inhibitory action of LSD. Piperoxan or phentolamine only partially antagonized the inhibitory effect of LSD.5 Phentolamine, yohimbine, piperoxan and tolazoline were potent, competitive antagonists of the inhibitory effect of clonidine with pA(2) values of 8.51, 7.78, 7.64 and 6.57 respectively.6 Thymoxamine was a weak antagonist of clonidine; it also antagonized the twitch-inhibitory effect of morphine. Thus, its effect against clonidine is probably not mediated specifically at presynaptic alpha-adrenoceptors.7 Labetalol, itself, depressed the twitch response but did not antagonize the inhibitory effect of clonidine on the residual twitch.8 The results demonstrate that the presynaptic alpha-adrenoceptors in the guinea-pig ileum are of the same type as those located presynaptically in sympathetically innervated tissues. They are alpha(2)-adrenoceptors and are different from those located postsynaptically.

1 The selectivity and specificity of RX 781094 [2-(2-(1,4 benzodioxanyl))2-imidazoline HCl] for alpha-adrenoceptors have been examined in peripheral tissues. 2 In isolated tissue experiments RX 781094 was a competitive antagonist at prejunctional alpha 2-adrenoceptors situated on the sympathetic nerve terminals of the rat (pA2 = 8.56) and mouse (pA2 = 7.93) vas deferens and on the parasympathetic nerve terminals of the guinea-pig ileum (pA2 = 8.55). 3 Although RX 781094 was also a competitive antagonist at the postjunctional alpha 1-adrenoceptors of the rat anococcygeus muscle (pA2 = 6.10) its affinity for these receptors was markedly less than that displayed for prejunctional sites. From pA2 values obtained in the rat vas deferens and anococcygeus muscle the calculated alpha 2/alpha 1-adrenoceptor selectivity ratio for RX 781094 was 288. 4 The rank order of alpha 2/alpha 1-adrenoceptor selectivities for the antagonists studied was RX 781094 greater than RS 21361 greater than yohimbine greater than piperoxan greater than phentolamine greater than WB 4101 greater than prazosin. 5 RX 781094 had extremely low affinity for beta-adrenoceptors, histamine receptors, cholinoceptors, 5-hydroxytryptamine and opiate receptors in vitro. 6 In pithed rats, intravenous administration of RX 781094 antagonized the prejunctional alpha 2-adrenoceptor agonist effects of clonidine and guanabenz on electrically-induced contractions of the vas deferens and anococcygeus muscle respectively. 7 In the vas deferens the rank order of alpha 2-adrenoceptor antagonist potencies was RX 781094 greater than phentolamine greater than piperoxan greater than yohimbine greater than RS 21361 greater than WB 4101. Only RX 781094, yohimbine and RS 21361 were active against guanabenz in the anococcygeus muscle. 8 In the pithed rat, RX 781094 preferentially antagonized the pressor responses evoked by postjunctional alpha 2-adrenoceptor activation by UK 14,304 although higher doses also inhibited the effects of phenylephrine and cirazoline at postjunctional alpha 1-adrenoceptors. 9 RX 781094 had little effect on the cardiovascular responses to 5-hydroxytryptramine, angiotensin II, histamine, acetylcholine and isoprenaline in pithed rats and rats anaesthetized with pentobarbitone. 10 These results demonstrate that RX 781094 is a potent and selective alpha 2-adrenoceptor antagonist with a high degree of specificity for these receptors.

The rise in intraocular pressure (IOP) observed after the administration of clonidine into the carotid arteries was studied in anesthetized rats and cats. This increase of IOP proved to be blocked by the alpha-sympathicolytic agent piperoxane and by the muscle relaxants d-tubocurarine and gallamine. Our experiments suggest that the elevation of IOP after clonidine injection is due to contraction of the eyelids and extraocular muscles. In these tissues alpha-adrenoceptors seem to play a part.

In plexus containing preparations of the longitudinal muscle of the guinea-pig ileum, an inhibitory action of tetracyclines on twitch-responses to electrical field stimulation was found. Tetracycline, chlortetracycline, minocycline and doxycycline, but not oxytetracycline (0.02 to 1.6 mmol/l) caused a concentration-dependent presynaptic inhibition of acetylcholine release. The inhibitory effect of the tetracyclines was also obtained after ganglion block by hexamethonium (30 mumol/l). The inhibitory effect of the tetracyclines was not antagonized by piperoxan (2 mumol/l) or yohimbine (1 mumol/l) and was partly reduced by the presence of naloxone (1 to 50 nmol/l). After exposing the preparation the peptidase inhibitors, i.e., to the combination of bestatin (10 mumol/l), captopril (10 mumol/l) and thiorphan (0.3 mumol/l), the inhibitory effect of tetracyclines was significantly increased. From these results it would appear that twitch-inhibition caused by tetracycline, chlortetracycline, minocycline and doxycycline is mainly mediated via the release of endogenous opioids from the myenteric plexus.

(1) Yohimbine was administered to non-human primates (M. arctoides) in doses believed to preferentially inhibit alpha-2 receptors in the brain. Two and a half mg/kg of yohimbine was compared with 2·5 mg/kg piperoxane and with 1 mg/kg each of yohimbine or piperoxane. (2) The higher doses of yohimbine and piperoxane produced a rapid and significant (p < 0.01) increase in serum prolactin (PRL). (3) None of these treatments resulted in any significant change in serum growth hormone. (4) These data support the hypothesis that pharmacologically-defined alpha-2 receptors, stimulated by clonidine, epinephrine, and norepinephrine, and inhibited by yohimbine and piperoxane, are involved in the regulation of prolactin secretion. (5) These data are compatible with a noradrenergic mechanism which facilitates or an adrenergic mechanism which inhibits prolactin secretion.

M-7, 1 and 3 mg kg−1 s.c., elicits an antihypertensive response and bradycardia in conscious spontaneously hypertensive rats (SHR) and causes inhibition of stimulation-evoked pressor responses and tachycardia in pithed SHR. Metoclopramide (30 mg kg−1 i.p.), but not piperoxan (5 mg kg−1 i.p.), abolishes the antihypertensive effect and inhibition of stimulation-evoked pressor responses produced by M-7 (1 mg kg−1 s.c.) in SHR. Conversely, piperoxan, but not metoclopramide, reduces the bradycardia and inhibition of stimulation-evoked tachycardia produced by M-7. Metoclopramide (30 mg kg−1 i.p.) did not affect the cardiovascular responses elicited by intracerebroventricular administration of either clonidine (1 μg) or M-7 (3 μg). These results suggest that the antihypertensive effect of M-7 may be mediated by stimulation of presynaptic dopamine receptors on sympathetic nerves to the vasculature and is independent of the bradycardia, which is probably due to stimulation of presynaptic α2-adrenoceptors on cardiac sympathetic nerve endings.

A direct method for measuring the rate of production of neurotransmitter metabolites by the brain of awake monkeys is described. The method utilizes a coupling of a measure of cerebral blood flow with the determination of the difference in concentration of the metabolite under study in arterial and internal jugular bulb blood. A consistent veno-arterial difference for 3-methoxy-4-hydroxyphenethylenglycol (MHPG) has been found. The concentration of MHPG in blood obtained from the right and left venous outflows from brain were not significantly different indicating that blood from either the right or left internal jugular bulb may be used with this method. The rate of production of MHPG by the brain of thw awake monkey is estimated to be 24.1 ng/100 g brain/min. The rate of MHPG production by brain is increased by the administration of piperoxan and decreased by clonidine. Using the experimentally determined rate of production of MHPG by brain and extrapolating to the human it is suggested that a substantial fraction of the total body production of MHPG in man occurs in brain.

Dopamine concentration in rat heart is normally very low, only a few percent of the concentration of norepinephrine. After treatment of rats with a dopamine β-hydroxylase inhibitor, l-cyclohexyl-2-mercapto-imidazole (CHMI), there was a rapid increase in dopamine concentration even before norepinephrine concentration had decreased perceptibly. This accumulation of dopamine was readily measured by liquid chromatography with electrochemical detection. Since the percentage change in dopamine was much greater than the percentage change in norepinephrine, especially at early times, measurement of dopamine accumulation rather than norepinephrine decline was considered as a useful measure of norepinephrine turnover. Drugs that act on noradrenergic receptors and are known to alter norepinephrine turnover were found to alter the rate of dopamine accumulation. Clonidine and guanabenz decreased dopamine accumulation after CHMI, whereas piperoxan (but not prazosin) increased dopamine accumulation after CHMI. Pergolide, a dopamine agonist whose lowering of blood pressure and cardiac rate has been suggested to be due to suppression of neurogenic release of norepinephrine, also decreased dopamine accumulation after CHMI. The results suggest that measuring dopamine accumulation may have advantages over measuring norepinephrine disappearance after dopamine β-hydroxylase inhibition as an indicator of norepinephrine turnover in heart.

Experiments were performed to determine the effects of yohimbine, piperoxan, and mianserin on the flash-evoked afterdischarge (FEAD) in rat. All three drugs are alpha-adrenergic antagonists, which block the inhibition of norepinephrine-release mediated by presynaptic (alpha 2) receptors. It was predicted that these drugs would exert dose-dependent biphasic effects on FEAD: at low doses, which act presynaptically, the FEAD would be suppressed; while at higher doses, which also block postsynaptic (alpha 1) receptors, the FEAD would be disinhibited. The dose response curves for yohimbine and piperoxan were, in fact, biphasic with low doses decreasing the amount of FEAD, while higher doses returned the amount of FEAD to baseline. No biphasic effect was seen with mianserin. These observations are consistent with the fact that yohimbine and piperoxan are more potent antagonists at alpha 2- than at alpha 1-receptors, whereas the affinities of mianserin for the two receptor types is comparable. The results of these experiments support the hypothesis that norepinephrine modulates FEAD.

The putative autoreceptor-selective dopamine (DA) agonist B-HT 920 was tested using electrophysiological and behavioral models thought to reflect actions at postsynaptic D2 DA receptors. Direct iontophoretic application of B-HT 920 onto nucleus accumbens neurons caused a current-dependent inhibition of firing which could be attenuated by pretreatment with alpha-methyl-p-tyrosine (to deplete DA) and reinstated (enabled) by concurrent administration of the selective D1 DA receptor agonist SKF 38393. These findings suggest that, like other selective D2 DA receptor agonists, the postsynaptic effects of B-HT 920 require concurrent stimulation of D1 DA receptors. Behavioral indices of postsynaptic D2 DA receptor stimulation (stereotyped sniffing and rearing) were also evident following combined treatment with B-HT 920 and SKF 38393. Moreover, similar "low-level" stereotyped behaviors were also observed when B-HT 920 was administered alone following pretreatment with the alpha-2 adrenoceptor antagonists idazoxane and piperoxane, suggesting that alpha-2 agonist actions of B-HT 920, in some way, mask the expression of D2 receptor-mediated stereotyped responses. When B-HT 920 was combined with SKF 38393 following pretreatment with idazoxane, both the intensity and form (continual licking and gnawing) of stereotyped behavior was enhanced. Taken together, these electrophysiological and behavioral findings indicate that B-HT 920 possesses the properties of a selective D2 DA receptor agonist and cannot be considered as a DA autoreceptor-selective compound.

The interactions between α-adrenoceptors agonists and antagonists on the twitch response of the rat isolated vas deferens to low frequency motor nerve stimulation have been examined. Oxymetazoline, clonidine, naphazoline and BAY-1470 caused a concentration-dependent inhibition of the twitch response at concentrations lower than those causing smooth muscle stimulation. The twitch-inhibitory effect of these compounds us thought to result from stimulation of presynaptically located α-adrenoceptors. In contrast, phenylephrine and methoxyamine exerted little inhibitory effect at concentrations less than those which produced postsynaptic stimulation. The inhibitory effect of clonidine was antagonised by phentolamine, piperoxan, yohimbine and tolazoline, but not by thymoxamine. These results characterise the presynaptic α-adrenoceptors in the rat vas deferens as being of the same type as those present in the rabbit pulmonary artery and rat heart, but different from those located postsynaptically in sympathetically innervated tissues.

Seven alpha 2-adrenoceptor antagonists with diverse chemical structures have been examined for their effects at alpha 2-adrenoceptors in the vas deferens and central nervous system of the rat. Antagonist potency assessed against the presynaptic alpha 2-adrenoceptor agonist action of clonidine in the isolated vas deferens (RX 781094 greater than Wy 26703 greater than yohimbine greater than rauwolscine greater than piperoxan greater than mianserin greater than RS 21361) was highly correlated with the ability of these drugs to displace saturable [3H]-RX 781094 binding from cerebral cortex membranes. Similarly, antagonist potency in the vas deferens was highly correlated with antagonist activity in reversing the centrally-mediated mydriasis induced by the selective alpha 2-adrenoceptor agonist, guanoxabenz, in pentobarbitone-anaesthetized rats. The results indicate that the presynaptic alpha 2-adrenoceptors in the vas deferens are pharmacologically similar to characterized these alpha 2-adrenoceptors in the central nervous system of the rat.

In pentobarbital-treated dogs clonidine (10 micrograms/kg) reduced the increase in heart rate caused by electrical stimulation of the cardiac nerve (1-10 Hz). We studied the actions of six alpha-adrenoceptor blocking drugs. Yohimbine (0.3 mg/kg) and phentolamine (1 mg/kg) potentiated the effects of nerve stimulation and antagonized the inhibitory effects of clonidine. Piperoxan (1 mg/kg) increased the response to nerve stimulation but antagonized the effects of clonidine only at the lowest frequency of stimulation. Thymoxamine (1 mg/kg) and prazosin at high doses (1 mg/kg) also antagonized the effects of clonidine but failed to increase the positive chronotropic response to stimulation of the cardiac nerve. AR-C239, a new and potent alpha-adrenoceptor blocking agent, changed neither the response to nerve stimulation nor the inhibitory effect of clonidine. The effects of all these drugs were observed at doses which reduced or reversed the pressor response to adrenaline. Therefore, our results afford further evidence for a dissimilarity between postsynaptic and presynaptic alpha-adrenoceptors in the dog. In addition, they show that the failure of an alpha-adrenoceptor blocking compound to increase the response to nerve stimulation does not necessarily indicate a lack of presynaptic alpha-adrenoceptor blockade.

1. A study was made of the effects of centrally administered alpha-adrenoceptor agonist drugs on the pressure changes elicited by somatic afferent nerve stimulation using chloralose-anaesthetized cats with autoperfused hindlimb circulations. 2. Clonidine, noradrenaline and adrenaline, given intracisternally, differed in their effects on the magnitude and duration of the systemic component of the somatic pressor reflex. None of these drugs significantly affected the hindlimb component of this reflex. 3. The selectivity of these drugs for the different reflex components may be explained by the different haemodynamic characteristics of the systemic and hindlimb circulations. 4. Intracisternal injection of the alpha-adrenoceptor antagonist piperoxan after the agonist drugs resulted in a complex pattern of responses affecting both the systemic and hindlimb reflex components. This suggests that the central pharmacological mechanisms involved may modulate more subtle changes in cardiovascular function than might be indicated by observations made in intact animals.

Yohimbine and some stereoisomeric alkaloids inhibited the binding of 3H-clonidine and 3H-WB-4101 to rat cerebral cortex membranes. Rauwolscine and yohimbine had much higher affinity to the 3H-clonidine than to the 3H-WB-4101 site, whereas the reverse was true for corynanthine. The results indicate that the 3H-clonidine site is an alpha 2-adrenoceptor and not an agonist-selective site whereas the 3H-WB-4101 site is an alpha 1-andrenoceptor and not an antagonist-selective site.

There is evidence that the noradrenergic neurons of the locus coeruleus (LC) possess α-adrenoreceptors in the vicinity of their cell bodies. To further characterize this receptor, we studied the responses of LC neurons to a series of catecholamine agonist and antagonist drugs using the techniques of single-unit recording and microiontophoresis. The spontaneous firing of LC neurons was inhibited by microiontophoretic application of norepinephrine, epinephrine, the α-adrenoreceptor agonist clonidine and the β-agonist isoproterenol. These inhibitions were blocked by the α-adrenergic antagonist piperoxane but not by the β-antagonist sotalol. In addition these cells were strongly inhibited by dopamine or α-methylnorepinephrine, but only weakly inhibited by phenylephrine or the dopamine agonist apomorphine. The dopamine antagonist trifluoperazine was ineffective in blocking the inhibitions of LC neurons by both dopamine and norepinephrine. The rank order of potencies of agonist drugs in inhibiting LC neurons was clonidine > > α-methylnorepinephrine ⩾ epinephrine = norepinephrine > > phenylephrine. In this respect the LC α-receptor is similar to ‘presynaptic’ or ‘α2’ receptors or peripheral sympathetic nerves and differs from the classical postsynaptic α-receptor. The noradrenergic neurons of the LC thus appear to possess catecholamine receptors on or near their cell bodies which have pharmacological characteristics of ‘presynaptic’ α-adrenergic receptors. The LC receptors are distinct from central dopamine receptors and from norepinephrine receptors areas of the brain receiving their noradrenergic iput fom the LC.

The recent contributions in the selectivity of ligands acting at the adrenergic alpha-receptor toward pre- and post-synaptic receptors (i.e. alpha 1 and alpha 2-receptors) are reviewed. Furthermore, tissue differences and possible sub-classification of pre- and post-synaptic alpha-receptor types are discussed.

The effect of ergotamine on the isolated rat stomach and its influence on the response to ACh and 5-HT were investigated. The log dose-response curve of ergotamine was bell-shaped. Extension of the incubation time of ergotamine resulted in a parallel shift to the left of the curve. The response to ergotamine was inhibited by methyserigide and piperoxan. Incubation with ergotamine resulted in a decrease of the pD2-value of 5-HT together with a marked suppression of the maximum of the 5-HT curve. The response to ACh was affected in accordance with the prediction of an action of ACh and ergotamine on different receptors. The prolonged receptor stimulation by 5-HT or ACh resulted in a decrease of the apparent affinity towards their receptors. Incubation with ACh resulted in a parallel shift to the right of the 5-HT curve. However no inconsistency with the theoretical prediction of an action on separate receptors was observed with the ACh curve in the presence of 5-HT. It is concluded that ergotamine is a partial agonist on the D-tryptamine receptors of tbe isolated rat stomach. The marked decrease of the maximum of the 5-HT curve by ergotamine is probably caused by the slowly reversible character of its antagonism. The parallel shift to the left of the ergotamine curve with the extension of the incubation time and the persistence of its antagonism both are probably caused by a slow diffusion into and from the biophase.