Assessment of anti-migraine potential of a novel alpha-adrenoceptor agonist S19014: effects on porcine carotid and regional haemodynamics and human coronary artery.

Taking into account the drawbacks associated with the use of triptans, attempts are being made to explore other avenues for the treatment of migraine. Recently, it has been shown that both alpha1- and alpha2-adrenoceptors mediate the constriction of porcine carotid arteriovenous anastomoses, which has effectively served as an experimental model predictive of anti-migraine activity. The present study investigated the effects of a novel alpha-adrenoceptor agonist S19014 (spiro[(1,3-diazacyclopent-1-ene)-5 : 2'-(4',5'-dimethylindane)] fumarate) on carotid and systemic haemodynamics in anaesthetized pigs, and on human isolated coronary arteries. Increasing doses of S19014 (1-30 micro g/kg, i.v.) produced a dose-dependent initial short-lasting vasopressor response and a decrease of total carotid blood flow and conductance. The carotid blood flow and conductance changes were exclusively due to constriction of carotid arteriovenous anastomoses (capillary blood flow increased) and were accompanied by an increase in arterio-jugular venous oxygen saturation difference. Whereas prazosin (100 micro g/kg, i.v.) was ineffective, rauwolscine (300 micro g/kg, i.v.) attenuated the responses to S19014. The compound did not much affect the distribution of cardiac output to peripheral organs when compared with the vehicle group. Furthermore, S19014 only slightly contracted the human isolated coronary artery and its contractions, contrary to those of sumatriptan, were not increased in blood vessels pre-contracted with U46619. These results suggest that (i) the systemic and carotid vascular effects of S19014 are mainly mediated by alpha2-adrenoceptors, and (ii) S19014 could be effective in the treatment of migraine with an improved cardiovascular tolerance.

In vivo analysis of adrenergic and serotoninergic constrictions of the rabbit saphenous vein.

We aimed to develop a model to study in vivo the rabbit saphenous vein pharmacology and to investigate constrictions mediated by adrenoceptor and 5-HT receptor subtypes. We used the technique of high precision ultrasonic echo-tracking for direct measurement of saphenous vein diameters in pentobarbital anesthetized rabbits. Saphenous vein constrictions induced in rabbits by the alpha(1)-adrenoceptor agonist L-phenylephrine and the 5-HT(1B) receptor agonist sumatriptan were comparable with those induced in dogs but those induced by the 5-HT(1B) and 5-HT(7) receptor agonist 5-carboxamidotryptamine failed to appear in dogs. Dose-related constrictions of rabbit veins were obtained with L-phenylephrine and the alpha(2)-adrenoceptor agonist dexmedetomidine. Frequency-related constrictions of rabbit veins induced by nerve stimulation were partially inhibited by an alpha(1)-adrenoceptor or a postsynaptic alpha(2)-adrenoceptor antagonist (prazosin and SKF 104,078) but not affected by the pre- and post-synaptic alpha(2)-adrenoceptor antagonists BRL 44408 or rauwolscine. Constrictions of rabbit veins to sumatriptan and 5-CT were inhibited by GR 127935 and those induced by quipazine, a 5-HT(2) receptor agonist were prevented by ritanserin. The initial constrictions induced by 5-CT were followed by dilatations which were inhibited by the 5-HT(7) receptor antagonist mesulergine. These data indicate that rabbit saphenous veins, in vivo and at rest, respond to activation of 5-HT(1B) and 5-HT(2) receptors, alpha(1)- and alpha(2)-adrenoceptors and nerve stimulation; the dilator effect mediated by 5-HT(7) receptor activation was also detected. The data validate a new animal model to study superficial vein reactivity and its pharmacological sensitivity.

(S)-spiro[(1,3-diazacyclopent-1-ene)-5,2'-(7'-methyl-1',2',3',4'- tetrahydronaphthalene)]: resolution, stereospecific synthesis, and preliminary pharmacological characterization as a partial alpha-adrenergic agonist.

Recently, we reported on the design, synthesis, and structure-activity relationships of a series of spiroimidazolines endowed with alpha-adrenergic agonist activities. Among the compounds described, (R,S)-spiro(1,3-diazacyclopent-1-ene)-[5,2'](7'-methyl-1'2',3', 4',-tetrahydronaphthalene) fumarate (5RS) was chosen for further development as a venotonic agent. The resolution of this compound, as well as the pharmacological characterization of the enantiomers, stereospecific synthesis of eutomer (5S, S 18149), and determination of absolute configuration by single-crystal X-ray diffraction analysis, are described.

The central sympatho-inhibitory effect of 5,6-dihydroxy-2-dimethylaminotetralin (M7) is mediated by alpha 2-adrenoceptors.

M7 (5,6-dihydroxy-2-dimethylaminotetralin) produces in anesthetized rats a hypotensive response previously attributed to peripheral dopaminergic mechanisms. We re-examined the effects of this drug on arterial blood pressure, heart rate and sympathetic nerve activity in anesthetized rats and dogs. M7 (1-100 micrograms/kg i.v.) produced in the rats transient dose-dependent pressor effects, with bradycardia and sympatho-inhibition, followed by long-lasting dose-dependent hypotension, bradycardia and sympatho-inhibition. The sympatho-inhibitory and hypotensive effects were comparable in baroreceptor-denervated rats and were reversed by idazoxan (0.1 mg/kg i.v.). The sympatho-inhibitory response induced by M7 (1-100 micrograms/kg) was prevented by treatment with the specific alpha 2-adrenoceptor antagonist, 2-methoxy-idazoxan (0.03 mg/kg i.v.). This central effect of M7 was not altered by treatment with the alpha 1-adrenoceptor antagonist, prazosin (0.1 mg/kg i.v.), and was reduced by treatment with the alpha 2-adrenoceptor antagonists, yohimbine (1 mg/kg i.v.) or idazoxan (0.3 mg/kg i.v.), and the dopaminergic antagonists, haloperidol (0.5 mg/kg i.v.) or sulpiride (3 mg/kg i.v.). Bilateral microinjections of M7 (0.3-3 nmol) into the rostroventral medulla in the rat produced dose-dependent hypotension, bradycardia and sympathetic nerve inhibition which were reversed and prevented by bilateral microinjection of 2-methoxy-idazoxan (1 nmol) into the same sites. Microinjections of 2-methoxy-idazoxan into the rostroventral medulla also inhibited the central effects of M7 at 0.03 mg/kg i.v. In anesthetized dogs, M7 administered into the cisterna magna (1-10 micrograms/kg) reduced arterial blood pressure, heart rate and sympathetic nerve activity; these effects were reversed by administration of 2-methoxy-idazoxan (0.03 mg/kg i.v.). In conclusion, M7, a rigid catecholamine, produces a potent central sympatho-inhibitory and hypotensive effect by activation of alpha 2-adrenoceptors.

Central integration of the Bezold-Jarish reflex in the cat.

The medullary structures involved in the central Bezold-Jarisch reflex pathway were studied by recording unit activity of sympatho-excitatory (SE) or inhibitory (SI) cardiovascular neurons in pentobarbital-anesthetized cats. The neurons were selected based upon their spontaneous activity and upon their sensitivity to baroreceptor reflex activation by L-phenylephrine. The Bezold-Jarisch reflex was induced by i.v. injection of chlorophenylbiguanide 10 micrograms/kg which produced a short-lasting decrease in blood pressure, heart rate and renal nerve activity. 76 neurons were studied. In 10 out of 12 SE neurons of the rostral ventrolateral medulla the activity was inhibited by chlorophenylbiguanide whereas in 10 out of 11 SI neurons and 6 out of 6 baroreflex-insensitive cells of the caudal ventrolateral medulla it was activated. The others cells were insensitive. Three types of neurons: excitatory, inhibitory or non-barosensitive, were recorded in the lateral tegmental field (27 cells) and the medullary raphe (20 cells). These neurons were either activated, inhibited or insensitive to Bezold-Jarisch reflex activation. Microinjection of the glutamate receptor antagonist kynurenic acid (2.5 nmol/site) or the GABAergic agonist muscimol (1 nmol/site) into the nucleus tractus solitarii abolished the effects of both L-phenylephrine and chlorophenyl-biguanide on heart rate and renal nerve activity. These results indicate that the cardiovascular neurons (sympatho-excitatory and sympatho-inhibitory) located in the medullary areas, involved in cardiovascular and baroreflex mechanisms, are implicated in the central Bezold-Jarish reflex pathway.

Recording of the saphenous vein compliance by an ultrasonic echo-tracking device in the dog: effects of S 18149.

1. Saphenous vein reactivity was recorded in the anaesthetized dog by use of an ultrasonic echo-tracking device to measure the internal diameter of the vein and to calculate the venous compliance. This method was used to investigate the effects of a new partial alpha1/alpha2-adrenoceptor agonist, S 18149, on the canine saphenous vein in vivo after intravenous (i.v.) or oral administration. 2. Venoconstrictions induced by i.v. or local administration of compounds were evaluated by continuous recording of the internal diameter of the saphenous vein with the echo-tracking method. Venous compliance was calculated in two ways: (1) as the slope of the diameter-pressure curve obtained by increasing the venous pressure with an inflatable cuff and (2) in veins in which pressure was higher than 12 mmHg, pulsatile variations in the venous diameter and venous pressure were detected and used to calculate the pulsatile compliance of the vein. 3. S 18149 administered i.v. at 0.5 microg kg(-1) min(-1) for 10 min induced a decrease in the saphenous vein diameter (-15+/-3%) and blood flow (-72+/-6%) associated with an increase in saphenous vein resistance; at the dose used, S 18149 did not modify venous pressure and caused only a weak increase in arterial pressure (+7+/-2 mmHg). 4. The pulsatile compliance of the saphenous vein averaged 8.65+/-1.37 mm2 x 100 mmHg(-1) in control dogs and was significantly decreased to 5.13+/-0.68 mm2 x 100 mmHg(-1) in the same animals after treatment with S 18149 at 100 microg kg(-1) per os (n=10). The saphenous vein compliance calculated with the increased external pressure method averaged 24.90+/-1.49 microm mmHg(-1) in control dogs and was significantly reduced in the same animals after treatment with S 18149 at 100 microg kg(-1) per os to 9.06+/-3.42 microm mmHg(-1) (n=5). When constrictions of the vein were induced with increasing doses of (-)-phenylephrine, injected locally at 1, 3 or 6 microg min(-1), only the responses obtained with the lower dose of (-)-phenylephrine were increased in dogs treated with S 18149 100 microg kg(-1) per os (-16+/-4% versus -4+/-3%, n=5). 5. These results show that the high resolution echo-tracking device previously used for arterial compliance measurements, allows the detection of pulsatile changes in the canine saphenous vein and thus permits calculation of both the pulsatile and the static compliance of superficial veins in vivo. Using this technique, we have demonstrated that the novel alpha-adrenoceptor agonist S 18149 constricts the canine saphenous vein in vivo and decreases the saphenous vein compliance after oral administration.

A comparative study of the reversal by different alpha 2-adrenoceptor antagonists of the central sympatho-inhibitory effect of clonidine.

1. The recovery of the clonidine-induced hypotension, bradycardia and sympatho-inhibition produced by several putative alpha 2-adrenoceptor antagonists was investigated in pentobarbitone anaesthetized rats. The activity of four substances containing an imidazoline structure: idazoxan, methoxy-idazoxan, BRL44408 and atipamezole was compared with the effect of fluparoxan, yohimbine and L-657,743; in addition the effect of the alpha 1-adrenoceptor antagonist, prazosin, was also studied. 2. Prazosin (0.03-1 mg kg-1, i.v.) failed to alter the sympatho-inhibitory and hypotensive effects of clonidine (10 micrograms kg-1, i.v.). L-657,743 (0.01-1 mg kg-1, i.v.) induced a recovery of blood pressure, heart rate and renal sympathetic nerve activity. Yohimbine (0.03-3 mg kg-1, i.v.) completely reversed the sympatho-inhibitory effect of clonidine but did not alter its hypotensive effect. 3. The four imidazoline drugs: idazoxan (10-300 micrograms kg-1, i.v.), methoxy-idazoxan (1-100 micrograms kg-1, i.v.), BRL44408 (0.1-3 mg kg-1, i.v.) and atipamezole (0.03-1 mg kg-1, i.v.) and fluparoxan (10-300 micrograms kg-1, i.v.) reversed the clonidine-induced hypotension but produced only a partial recovery of the renal sympathetic nerve activity and of the heart rate. After pretreatment with prazosin (0.1 mg kg-1, i.v.), the recovery of the sympathetic nerve activity elicited by these compounds was significantly higher. In hexamethonium (10 mg kg-1, i.v.) pretreated rats, these five drugs induced dose-related hypertension which was reduced by pretreatment with prazosin (0.1 mg kg-1, i.v.). 4. Our results indicate that the putative alpha 2-adrenoceptor antagonists idazoxan, methoxy-idazoxan, BRL44408, atipamezole and fluparoxan also have a peripheral hypertensive effect which is mediated through activation of vascular alpha 1-adrenoceptors; this property of the compounds may be partly responsible for the reversal of the hypotensive action of clonidine. Considering the structure and the affinities of the drugs tested, our data indirectly suggest that alpha 2A-adrenoceptors may be implicated in the central sympatho-inhibitory effects of clonidine.

Evidence against the involvement of the nucleus tractus solitarii in the sympatholytic effect of 8-hydroxy-2-(di-n-propylamino)tetralin in the cat.

In different animal species, microinjections of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) into the nucleus tractus solitarii failed to alter arterial blood pressure and sympathetic nerve activity; however, the cardiovascular effects (hypotension, bradycardia, reduction in sympathetic nerve activity) of intravenous administration of 8-OH-DPAT were significantly reduced after blockade of the nucleus tractus solitarii by kainic acid as well as after blockade of the lateral tegmental field by kainic acid. The aim of the present study was to clarify these conflicting results. In the anesthetized cat, inhibition of neurotransmission in the nucleus tractus solitarii by bilateral microinjections of either muscimol (1 nmol in 50 nl) or kynurenic acid (2.5 nmol in 50 nl) suppressed the baroreceptor reflex and abolished the synchronism between the renal sympathetic bursts; however, these procedures did not alter the dose-related hypotension, bradycardia and sympatho-inhibition elicited by cumulative doses of 8-OH-DPAT (1-30 micrograms/kg i.v.). Moreover complete electrolytic destruction of the nucleus tractus solitarii, assessed by a complete loss of the baroreceptor reflex and the cardiac-related bursts of the sympathetic nerves, failed to alter the inhibitory effects of i.v. 8-OH-DPAT. Bilateral microinjections of muscimol into the lateral tegmental field induced a decrease of mean arterial blood pressure, heart rate and renal nerve activity (by respectively -35 +/- 13 mm Hg, -30 +/- 16 beats/min and -53 +/- 14%) and greatly reduced the effects of subsequent i.v. administration of 8-OH-DPAT. The present data indicate that the nucleus tractus solitarii does not play a dominant role in the central action of 8-OH-DPAT whereas they confirm our previous results showing that the lateral tegmental field is involved in this action and in the mecanisms regulating sympathetic tone. The results also suggest that kainic acid lesions are not restricted to the region in which the neurotoxic agent is injected.

Design, synthesis, and structure-activity relationships of a new series of alpha-adrenergic agonists: spiro[(1,3-diazacyclopent-1-ene)-5,2'-(1',2',3',4'- tetrahydronaphthalene)].

The contractions induced by a partial alpha 1-adrenoceptor agonist in cutaneous veins, such as the saphenous vein, show a particular sensitivity to changes in local temperature: the contractility to a partial alpha 1-adrenoceptor agonist increases when the temperature is raised, a response that contrasts to that noted with full alpha 1- and alpha 2-adrenoceptor agonists. This observation may be of importance for the treatment of the symptoms of venous insuffiency, favored during warm summer days. A new series of full and partial alpha-adrenergic agonists was designed and synthesized, the spiro[(1,3-diazacyclopent-1-ene)-5,2'-(1',2',3',4'- tetrahydronaphthalene)] 7a-kk or spiro-imidazolines. Using in vitro (femoral artery and saphenous vein) and in vivo (pithed rat) biological evaluations, structure-activity relationships could be defined which allowed the discovery of a full alpha 2-agonist (34b), a full alpha 1-agonist (7s), and a nonselective partial alpha 1/alpha 2-agonist (7aa) endowed with an outstanding veinotonic selectivity as compared to its effect on mean arterial pressure. The latter compound is presently undergoing extensive pharmacological and toxicological evaluations, as a clinical candidate.

Role of the nucleus tractus solitarii and the rostral depressive area in the sympatholytic effect of 8-hydroxy-2-(di-n-propylamino)tetralin in the cat.

Bilateral microinjections of kainic acid (500 ng/site) into the nucleus tractus solitarii produced hypertension, tachycardia and sympatho-excitation in anesthetized cats. The cardiac-related component of renal sympathetic nerve activity was abolished as well as the sympatho-inhibitory effects that accompany the phenylephrine (5-10 micrograms/kg i.v.)-induced hypertension. About 60 min after kainic acid microinjections into the nucleus tractus solitarii, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) administered in cumulative doses (1-100 micrograms/kg i.v.) failed to alter mean blood pressure, heart rate or renal sympathetic nerve activity. In addition, bilateral microinjections of 8-OH-DPAT (2 nmol in 40 nl) into the nucleus tractus solitarii did not change mean blood pressure, heart rate or renal sympathetic nerve activity. Microinjections of kainic acid into the rostral vasodepressive area produced hypotension, bradycardia and renal sympatho-inhibition followed by persistent increases in blood pressure, heart rate and renal sympathetic nerve activity. These effects were also associated with an inhibition of the baroreceptor reflex elicited by phenylephrine and by the disappearance of the synchronism between the renal sympathetic bursts and cardiac rhythm. Subsequent i.v. 8-OH-DPAT (1-100 micrograms/kg) elicited decreases in mean blood pressure, heart rate and in renal sympathetic nerve activity. Central baroreceptor denervation by kainic acid lesions of the lateral tegmental field largely attenuated the hypotensive, bradycardiac and sympatho-inhibitory effects elicited by 8-OH-DPAT applied to the ventral surface of the rostral ventrolateral medulla.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of the lateral tegmental field in the central sympatho-inhibitory effect of 8-hydroxy-2-(di-n-propylamino)tetralin in the cat.

Cardiovascular neurones with sympathetic nerve and cardiac related activity have been detected in the lateral tegmental field and have been classified depending on their response to baroreceptor activation. Baroreflex activation decreased and increased the firing rate of sympatho-excitatory neurones and sympatho-inhibitory neurones respectively. Intravenous (i.v.) administration of 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) (1 to 30 micrograms/kg) produced a dose-dependent decrease in the firing rate of sympatho-excitatory neurones in conjunction with a decrease in renal sympathetic nerve activity. 8-OH-DPAT had a variable effect (excitation or inhibition) on the firing rate of sympatho-inhibitory lateral tegmental field neurones. Both the excitatory and the inhibitory effects of 8-OH-DPAT were reversed by spiperone (1 mg/kg i.v.). Microinjection of 8-OH-DPAT (2 nmol/site) into the lateral tegmental field decreased blood pressure and renal sympathetic nerve activity. Compared with the effects elicited by microinjection of 8-OH-DPAT into the rostral ventrolateral medulla, the renal sympatho-inhibitory response elicited by 8-OH-DPAT injected into the lateral tegmental field appeared smaller. Chemical lesions of the lateral tegmental field neurones with kainic acid produced hypertension and sympatho-excitation. The correlation between renal sympathetic nerve activity and the R wave of the electrocardiogram disappeared after treatment with kainic acid. Subsequent i.v. 8-OH-DPAT (1 to 100 micrograms/kg) failed to alter blood pressure and renal sympathetic activity. In contrast clonidine (1 to 10 micrograms/kg) still decreased blood pressure, heart rate and renal sympathetic nerve activity in kainic acid-lesioned animals and these effects were reversed by the alpha 2-adrenoceptor antagonist, methoxy-idazoxan (10 micrograms/kg i.v.). The data described indicate that the lateral tegmental field plays a role in the central cardiovascular effects of 8-OH-DPAT and that the integrity of this area is necessary for the expression of the sympatho-inhibitory effects of the drug.

Cardiovascular effects of microinjections of quipazine into nuclei of the medulla oblongata in anaesthetized cats: comparison with L-glutamate.

Unilateral microinjections of quipazine (0.9 micrograms in 50 nl) into the subretrofacial nucleus produced hypertension and a slight tachycardia associated with an increase in renal sympathetic nerve activity. Microinjections of quipazine lateral, caudal or rostral to this nucleus failed to alter blood pressure and heart rate. Similarly, microinjections of l-glutamate (3 nmol in 15 nl) into the subretrofacial nucleus elicited hypertension, tachycardia and renal sympatho-excitation. The magnitude of the pressor response to quipazine was smaller than the response elicited by l-glutamate but its duration was longer. Microinjections of quipazine into the lateral tegmental field at l-glutamate hypertensive sites failed to alter arterial blood pressure and heart rate. In contrast, microinjections of quipazine into the caudal ventrolateral medulla or into the nucleus tractus solitarii produced hypotension and sympatho-inhibition. These effects were prevented by microinjections of the 5-HT2 receptor antagonists, LY 53857 or BW 501C. The present results indicate that stimulation of 5-HT2 receptors of the subretrofacial nucleus produces hypertension and sympatho-excitation whereas stimulation of 5-HT2 receptors in the caudal ventrolateral medulla and in the nucleus tractus solitarii produces hypotension and sympatho-inhibition.

Quipazine-induced hypertension in anaesthetized cats is mediated by central and peripheral 5-HT2 receptors: role of the ventrolateral pressor area.

Quipazine (0.5 mg/kg i.v.) produced a sustained pressor response and an increase in splanchnic nerve activity in intact as well as in baroreceptor-denervated cats without causing a significant change in heart rate. These effects were prevented by the 5-HT2 receptor antagonists, ritanserin (0.5 mg/kg i.v.) or BW 501 C (0.5 mg/kg i.v.). Quipazine induced an hypertensive response and an increase in splanchnic discharge in cats pretreated with prazosin (0.1 mg/kg) or hexamethonium (10 mg/kg i.v.). Bilateral application of quipazine (25 micrograms/side) to the ventrolateral pressor area produced a rapid increase in mean blood pressure and in splanchnic discharge. Pretreatment with prazosin (0.1 mg/kg i.v.) abolished the hypertension but not the sympatho-excitatory effects of quipazine. Local application of the 5-HT2 receptor antagonists, LY53857 (10 micrograms/side) or cyproheptadine (10 micrograms/side), had no effects on blood pressure and splanchnic nerve activity but prevented or reversed the actions of locally applied quipazine. LY 53857 (10 micrograms/side) antagonized the sympatho-excitatory effects of systemically administered quipazine. These results indicate that the cardiovascular changes induced by quipazine in anaesthetized cats are mediated by central 5-HT2 receptors located in the ventrolateral pressor area and by peripheral vascular 5-HT2 receptors.

The cardiovascular effects of quipazine are mediated by peripheral 5-HT2 and 5-HT3 receptors in anaesthetized rats.

Quipazine (0.5-2 mg/kg i.v.) produced transient hypotension and bradycardia followed by sustained hypertension and variable effects on heart rate in anaesthetized rats. The hypotension, bradycardia and sympatho-inhibitory effects of quipazine were attenuated by bivagotomy. In bivagotomized rats, the hypertension produced by quipazine was not modified by hexamethonium or prazosin but was abolished by ritanserin (1 mg/kg i.v.). In ritanserin-treated rats, section of the carotid sinus nerves and vagus nerves or ICS 205.930 (0.1 mg/kg i.v.) abolished the hypotensive, bradycardic and sympatho-inhibitory effects of quipazine; the action of quipazine was not reproducible in these rats. Quipazine also inhibited the Bezold-Jarish reflex elicited by 5-HT (20 micrograms/kg i.v.). In ICS 205.930-treated rats, the hypertension evoked by quipazine was associated with a reduction in splanchnic nerve activity due to stimulation of baroreceptors. The renin-angiotensin system is not involved in the hypertensive response. The increase in heart rate produced by quipazine in bivagotomized rats was reduced by ritanserin and tertatolol (0.1 mg/kg i.v.) and abolished by a combination of both drugs. We conclude that the bradycardic and sympatho-inhibitory effects of quipazine result from activation of 5-HT3 receptors located in the cardiopulmonary area and of carotid body chemoreceptors. The hypertension and tachycardia are mediated by vascular and myocardial 5-HT2 receptors. No evidence was obtained for a central sympatho-excitatory effect.

Taste as a highly discriminative system: a hamster intrapapillar single unit study with 18 compounds.

Seventy-nine single units were recorded with glass micropipettes applied onto taste pores of the anterior portion of the tongue in anesthetized hamsters. The receptive field of each recorded unit was located by iontophoretic stimulation applying either anodal or cathodal current (1-20 microA) to a non-stimulating solution of sodium cyclamate (5 mM). Different kinds of responses to iontophoretic stimulation were described. Eighteen chemical stimuli including sweet and bitter tastants for humans, and amino acids were locally applied to one papilla of the receptive field of 63 of these units. Stimulations were applied in a continuous flow (30 ml/min) in a small chamber. Response criterion was chosen as 2 S.D. above the mean activity recorded during the minute preceding the stimulus arrival. The low amplitude of single unit responses to chemicals is discussed by reference to the recording and stimulating techniques and compared to results of control experiments on whole nerve recordings and psychophysical experiments on human subjects. The importance of a high flow rate during continuous flow stimulation was demonstrated. The possible necessity of mechanical stimulation to facilitate taste responses was outlined. The sensitivity of units to stimuli applied either chemically or iontophoretically was not identical. Contrary to authors expectations, localized sensitivities for a few specific chemicals were disclosed. The response reproducibility to chemical stimulation was 84% (S.D. = 1.6%). chi 2 calculation, correspondence analysis and hierarchical clustering showed small distances between the two profiles representing the same stimulus or the two profiles representing the same unit, but great distances between profiles representing either different stimuli or different units. All stimuli are different from one another. Only 6 pairs of similar units were found among 63 units. Unit clusters could be found only if a few stimuli were considered but they vanished when all 18 stimuli were used in the calculation. The breadth of tuning of units ranged from 0.25 to 0.92 with a mean of 0.68. We show that the peripheral taste system is highly discriminative. Each stimulus evokes a distinct sensory image. At least 8 independent factors are needed to describe the peripheral taste space, setting a lower limit to the number of different peripheral information channels (putative acceptors) involved.

[Evidence for sensory convergences in rat entorhinal cortex]. / Mise en évidence de convergences sensorielles dans le cortex entorhinal du rat.

Unit neuronal activity was investigated in the Rat lateral entorhinal cortex. Neurons were found which reacted to various sensory stimulations, auditory, visual, somesthetic, gustative and olfactory. This cortex is thus a site of convergence of sensory information which could be relayed further to the hippocampus.

[Demonstration of olfactory projections and responses within the entorhinal cortex in rats]. / Mise en évidence de projections et de réponses olfactives au sein du cortex entorhinal du rat.

An electrophysiological study was performed in rat entorhinal cortex. The results confirmed anatomical data on its connections with olfactory structures. Unit analysis has shown that neurons respond to odours. This area thus appears as an important structure for olfactory projections, possibly relaying these informations to the hippocampus.