Biomedical subjects

P Delagrange

Publications and source records attributed to P Delagrange.

87 records · Page 5Linked to original sources

PubMed1996

Effects of both a melatonin agonist and antagonist on seasonal changes in body mass and energy intake in the garden dormouse.

BACKGROUND: Many physiological functions including nycthemeral rhythm, reproductive cycles, body temperature and body mass are controlled by photoperiodic changes in different species. In the hibernating garden dormouse, both energy intake and body mass increase with the duration of the night. This seasonal mass gain is spontaneous and reversible. AIM: We have studied the occurrence of the increase of body mass by taking into account the endogenous variations of melatonin due to changing photoperiod or to pharmacological treatment. RESULTS: A single daily administration of either a melatonin agonist or antagonist just before night mimics the short day and long day effects, respectively. Compared to the control animals (natural photoperiod), the mass gain was greater and occurred earlier in animals under short days (6 h light (L)/18 h dark (D)) and in those receiving the melatonin agonist (S 20304). The animals treated with the antagonist (S 20928) during the same period exhibited no mass gain and their response was similar to that of the long-day group (16L/8D). Solely agonist treatment acted on metabolic rate. CONCLUSION: These results demonstrate that the duration of melatonin-receptor exposure per day determines the onset of seasonal obesity in garden dormice and, on the other hand, that restriction of melatonin-receptor exposure by pharmacological treatment prevents it.

Animals↗

PubMed1995

Design and synthesis of new naphthalenic derivatives as ligands for 2-[125I]iodomelatonin binding sites.

New melatonin-like agents were designed from the frameworks of 2,5-dimethoxyphenethylamine, an important structural moiety for the 5-HT receptor, and (2-methoxynaphthyl)-ethylamine. The compounds were synthesized by classical methods and evaluated in binding assays with chicken brain membranes using 2-[125I]iodomelatonin as the radioligand. Preliminary studies on the series of N-acyl-disubstituted phenethylamines showed the favorable role of the methoxy group in the ortho position of the side chain on the affinity for the receptor (Ki = 8 +/- 0.2 nM) for N-[2-(2-methoxy-5-bromophenyl)ethyl]propionamide (3o). This effect was confirmed in a series of the naphthalene derivatives, a bioisosteric moiety of the indole ring, and several potent ligands for melatonin binding sites were prepared such as N-[2-(2-methoxynaphthyl)ethyl]propionamide (4b) (Ki = 0.67 +/- 0.05 nM) and N-[2-(2,7-dimethoxynaphthyl)ethyl]cyclopropylformamide (Ki = 0.05 +/- 0.004 nM) (4k). Structure-activity relationships are discussed with regard to melatonin and bioisosteric naphthalenic compound 2. The Ki value for 4b was affected to a similar extent to that of melatonin by GTP-gamma-S or Mn2+ in competition experiments, suggesting an agonist profile for this compound.

Animals↗

PubMed1995

Dose dependent effects of S-20098, a melatonin agonist, on direction of re-entrainment of rat circadian activity rhythms.

The chronobiotic properties of melatonin are well documented. For example, following an 8-h phase advance of the light-dark cycle daily injections of melatonin administered at the pre-shift dark onset alter the direction of re-entrainment of rat activity rhythms. Using this 8-h phase advance paradigm, the effects of the melatonin agonist S-20098 (1 mg/kg and 3 mg/kg) on the rat circadian system were compared with those of melatonin. S-20098 altered the direction of re-entrainment in the same manner as melatonin. A study using lower doses of S-20098 showed that the effect on direction of re-entrainment was dose-dependent, with 100% of rats responding at a dose of 100 micrograms/kg. S-20098 may, therefore, have therapeutic potential as a chronobiotic in the treatment of circadian disorders in humans.

Acetamides↗

PubMed1994

Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands.

A series of N-naphthylethyl amide derivatives were synthesized and evaluated as melatonin receptor ligands. The affinity of each compound for the melatonin receptor was determined by binding studies using [2-125I]iodomelatonin on ovine pars tuberalis membrane homogenates. Structure-activity relationships led to the conclusion that naphthalene is a bioisostere of the indole moiety of melatonin. Moreover it appears that the affinity is strongly affected by the size of the substituent of the nitrogen of the amidic function. Many of these ligands give biphasic dose-response curves which suggests that there may be two melatonin receptor subtypes within the ovine pars tuberalis cells. The replacement of naphthalene by benzofuran or benzothiophene did not strongly alter the affinity for the melatonin receptor. In contrast, the benzimidazole analogue was a poor ligand. Compound 7, the naphthalenic analogue of melatonin, a selective ligand of the melatonin receptor and an agonist derivative, has been selected for clinical development.

Acetamides↗

PubMed1993

Effects of locus coeruleus lesions on vigilance and attentive behaviour in cat.

Previous data have suggested that in the cat, expectancy behaviour (waiting for a target to appear) and associated electrocortical, focal, synchronized activity ('mu' rhythms) are modulated by a noradrenergic system possibly originating from the locus coeruleus (LC). To test the latter hypothesis, we have examined the behavioural and ECoG changes induced after bilateral LC lesions. Our results demonstrated that destruction of the anterior 3/4th of the LC (A6 noradrenergic cell group) resulted in a considerable increase of mu rhythms and expectancy behaviour, without episodes of drowsiness that normally occur. Destruction of the posterior fourth of LC (A4 noradrenergic group) only increased the duration of slow sleep. Extending the A6 lesion to include the dorsal ascending noradrenergic bundle also increased the expectancy behaviour and mu rhythms. Finally, when the nucleus subcoeruleus was also involved, the duration of slow sleep and the frequency of paradoxical sleep episodes increased. These findings indicate that the LC exerts an inhibitory effect on structures involved in the induction and persistence of expectancy behaviour with accompanying mu rhythms.

Animals↗

PubMed1991

Noradrenaline-like terminals in the cat nucleus ventralis posterior of the thalamus.

Noradrenaline-like immunoreactivity in the cat nucleus ventralis posterior of the thalamus was investigated using an indirect immunocytochemical technique. Specific antinoradrenaline antibodies, raised in rabbits, were used. It was first verified that these antibodies recognize noradrenaline cells bodies of the locus coeruleus and their ascending axons in the ascending noradrenergic tract. In the nucleus ventralis posterior itself, noradrenaline-like fibers were observed. They were either randomly distributed or grouped around nonlabeled cell bodies. These neurons were generally oblong and measured 60-80 microns. With electron microscopy, preliminary results showed immunoreactive fibers in close apposition to unlabeled cell bodies or dendrites. The precise nature of these profiles was sometimes difficult to ascertain, since experiments were done in presence of detergent. In some cases symmetric synapses might be observed between immunoreactive axon terminals and unlabeled dendrites. The specificity of the reaction is discussed in the light of several control experiments.

Animals↗

PubMed1990

Action of tianeptine on focalization of attention in cat.

Tianeptine, an antidepressant substance devoid of sedative action, was investigated for its effects on focalization of attention in cats, using combined behavioural and electrocorticographic (ECoG) observations. The ECoG index was the presence of 40 Hz frontoparietal rhythmic cortical activities, developing while the animal displayed a behaviour suggesting focused attention. Cats were observed in two conditions: a "neutral" one, with no specific target, and another one, "of focused attention" where a live mouse placed in a transparent box was present in the recording room, each test lasting for 90 min. After treatment the animals displayed increased attention even in the neutral situation, where the cat, instead of sleeping like during control sessions, payed sustained attention to its environment. Conversely, at corresponding doses, amitriptyline, another antidepressant drug chosen as a reference, induced uninterrupted slow sleep even in the situation of focused attention.

Amitriptyline↗

PubMed1989

Effect of DSP4, a neurotoxic agent, on attentive behaviour and related electrocortical activity in cat.

Six behaving cats were administered N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) (i.p. 10 mg/kg), a neurotoxic agent known to destroy noradrenergic endings in the CNS. They were placed, both before (control) and after treatment in 3 different situations, each time for 90 min: (1) a 'neutral' one (N) with no significant stimuli; (2) another one eliciting focused attention (F); (3) a third one, creating a situation of 'expectancy of an event to occur' (E), with the animal usually displaying a posture of quiet waking. Simultaneously, the electrocorticogram (ECoG) was recorded from the sensorimotor and parietal cortex through implanted electrodes. We already knew and were able to confirm that the normal animals (i.e. before treatment) displayed distinct behavioural patterns depending on the situation and distinct accompanying parietofrontal ECoG activities, with a dominance of drowsiness and sleep during N, that of a 36-Hz 'beta' rhythms in condition F, and of 14-Hz 'mu' rhythms in condition E. It was shown that the prevailing attitude of the animals after treatment was now, in all 3 situations, that of 'quiet waking and/or expectancy-like watching', with a large if not exclusive dominance of only one ECoG pattern, namely mu. These changes were considered as due to a release of the mu system from a noradrenergic modulatory blockade, in accordance with some of our previous data. An immunohistochemical study with anti-tyrosine hydroxylase antibody was also performed; it confirmed that after DSP4 treatment there were substantial alterations in the immunoreactivity of locus coeruleus cells, the structure which is likely to be involved in this NAergic control of the mu rhythms and of its concomitant behaviour.

Animals↗

PubMed1989

[Regulation pathways of expectancy behavior in the cat: histologic study].

In the behaving cat, motion expectancy of an event to occur (for a prey to appear) is accompanied by the development of 14 Hz electrocortical mu rhythms in the hand subarea of cortical somatic area SI. Our first aim here was to identify subcortical sites projecting to this cortical mu focus, using localised retrograde HRP marking. The only site thus labelled was the thalamic zone well known to project to the cortical mu area, and to act as a generator for the mu rhythms (ventral posterior nucleus, VP); no other deep structure could be identified, that could have been considered as a putative zone for control of cortical mu. We then injected minute amounts of HRP into the thalamic mu zone; labelled neurones were located (apart from those expected in the relays of the somatic pathway) in locus coeruleus (bilaterally) and ipsilaterally in the thalamic nuclei anteroventralis and laterodorsalis. In brief then, it seems that the regulation of the VP-SI mu channel (that we could previously demonstrate), by other deep structures is exerted upon the thalamic side.

Animals↗

PubMed1988

[DSP 4, a neurotoxic agent that destroys noradrenergic endings, selectively increases "expectancy" in the cat].

Cats were treated with DSP 4, a neurotoxic agent known to destroy central noradrenergic endings. A significant increase was subsequently noticed in the amount of time spent by the treated animals in an attitude of "expectancy", i.e. of motionless waiting for an "event to occur". They even developed this attitude when no such real situation existed. Concomitantly, an increase was noticed in the power of the 14 Hz electrocortical rhythms recorded over the somatic sensory cortex. These patterns, designated as "mu" rhythms, had previously been shown to characterize this particular type of attentive state. The present data tends to confirm our previous hypothesis, that immobile expectancy and its accompanying electrocortical pattern are under a noradrenergic inhibitory control.

Animals↗

PubMed1987

[Unit activity of neurons of the posterior ventral nucleus of the thalamus for various waking stages in the normal cat].

Using the electrocortical activity in the sensorimotor cortex as an index, three distinct levels of motionless waking can be identified in the cat, all three different from active waking and from slow sleep (attentive waking, quiet waking and drowsiness). It has now been shown that spontaneous and evoked single unit activities in n. ventralis posterior of the thalamus undergo significant changes when passing from one level of waking into another one.

Animals↗

PubMedDate not supplied

Effects of a novel melatonin analog on circadian rhythms of body temperature and activity in young, middle-aged, and old rats.

Circadian rhythms of body temperature and activity were recorded in young, middle-aged, and old rats. A new melatonin analog, S20242, was administered daily around the onset of darkness for a 2-week period. Compared to the young animals, there was a significant age-related reduction in the amplitude and stability of body temperature and activity in both the middle-aged and old rats. In these two groups there was an improvement of the circadian rhythm of body temperature as a result of daily application of the melatonin analog.

Aging↗

PubMedDate not supplied

Reentrainment of the spontaneous locomotor activity rhythm to a daylight reversal in C57BL/6 and C3H/He mice: implication of melatonin.

The adaptation of the locomotor activity rhythm to a daylight reversal was previously found to be faster in C57BL/6 mice, which present a low level of melatonin, than in C3H/He mice, which exhibit a large nocturnal melatonin peak. Because pinealectomy has been shown to accelerate resynchronisation time in rats after a daylight reversal, we investigated the involvement of melatonin in the resynchronisation rate of locomotor activity rhythm in C57BL/6 and C3H/He strains. We first tested the effects of melatonin, administered at zeitgeber time (ZT) 20 (with ZT0 corresponding to light onset) for the 3 days preceding the daylight reversal, on the reentrainment of locomotor activity rhythm in both strains. Second, the effects of S-22153, a melatonin receptor antagonist, on the reentrainment of locomotor activity rhythm in C3H/He mice were examined. S-22153 was administered for the 3 days preceding the daylight reversal either at ZT12 or at ZT20, i.e., when endogenous melatonin levels are respectively low and high. Melatonin significantly delayed the resynchronisation of locomotor activity rhythm in C57BL/6 mice without affecting this parameter in C3H/He mice. S-22153 significantly accelerated the resynchronisation in C3H/He mice when administered at ZT20, but had no effect when administered at ZT12. These results support the hypothesis that the differences between C3H/He and C57BL/6 in the reentrainment of their locomotor activity rhythm depend, at least in part, on the interstrain differences in melatonin synthesis.

Animals↗

PubMedDate not supplied

[Signaling by melatonin receptors].

Melatonin is a hormone involved in various physiological processes such as the circadian cycle, hormone release and immune response. High-affinity melatonin receptors are classified in two pharmacologically distinct groups: Mel1 and Mel2. These receptors have first been localized in different organs and brain structures and some subtypes have since been cloned. Inhibition of adenylyl cyclase by Mel1 receptors is the best investigated signalling pathway but cannot be entirely responsible for the diversity of melatonin-induced phenomena. Phospholipase C, potassium ion channels and guanylyl cyclases have also been reported to be modulated by melatonin. This review updates present knowledge of the characterization and signalization of melatonin receptors.

Adenylyl Cyclase Inhibitors↗

PubMedDate not supplied

[Melatonin and regulation of the cardiovascular system].

Evidence from the last 10 years suggests that melatonin may influence the cardiovascular system. Vascular melatoninergic receptors/sites have been demonstrated and are functionally linked with vasoconstrictor or vasodilatory effects of low (10(-9)-10(-7) M) and high (10(-6)-10(-3) M) melatonin concentrations respectively. Furthermore several other properties of the neurohormone (e.g. sympathetic inhibition) could contribute to cardioprotection. In vivo melatonin beneficially affects the rat cerebrovascular circulation and protects the rat heart following myocardial ischaemia. In this regard, preliminary clinical data report some alteration of the melatoninergic system in human stroke and coronary heart disease. Finally, the suprachiasmatic nucleus and possibly the melatoninergic system may modulate cardiovascular rhythmicity. Clinical cardiovascular data on melatonin treatment are very scarce; the effects of a therapy modulating the melatoninergic system on cardiovascular haemodynamics and rhythmicity under several physiopathological conditions need to be further explored together with the possible impact on cardiovascular morbidity and mortality.

Animals↗