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J Costentin

Publications and source records attributed to J Costentin.

At least 199 records · Page 11Linked to original sources
PubMed1984

Rat climbing behavior elicited by stimulation of cerebral dopamine receptors.

The experimental conditions allowing to elicit by administration of dopamine agonists a climbing behavior in rats, apparently analogous to the stereotyped cage climbing behavior previously described in mice (Protais et al. 1976), have been established. Among the various strains of rats studied i.e. Sprague-Dawley, Long Evans and Wistar, the latters were selected as the most responsive to the dopamine agonist apomorphine. However, even in the Wistar strain, only about 60% of animals responded to a test-dose of 0.4 mg/kg apomorphine by adopting in a sustained manner the typical upright position against the walls of a suitable experimental cage. Hence responsive rats were preselected 4 days before the experimental sessions and finally rated during a 60-min observation period. Increasing the test-dose of apomorphine led to a biphasic effect, the spontaneous climbing behavior being decreased at low dosage and, then, both the percentage of climbing animals and the duration of the behavior were progressively increased at higher dosages. A scoring system based on an all-or-none evaluation of the frequency of stereotyped climbing episodes over the 1 h observation period was finally adopted allowing to establish dose response curves to apomorphine and its more potent derivative N-propylnorapomorphine. Dexamphetamine (associated to L-Dopa) also produced the stereotyped climbing behavior. The latter was completely abolished in animals treated with the "atypical" antipsychotic sulpiride. The effects of lesioning various cerebral dopaminergic areas on the apomorphine-induced behavior were investigated. The response was not significantly altered following bilateral thermocoagulations of the striatum (restricted lesions), globus pallidus, nucleus interstitialis of the striae terminalis, amygdala, nucleus lateralis septi or nucleus accumbens.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Selection of dopamine antagonists discriminating various behavioral responses and radioligand binding sites.

In order to document the hypothesis that antipsychotics may interact with more than one class of cerebral dopamine receptors, the relative potencies of a series of compounds were compared in three behavioral tests and in binding studies with two radioligands. Apomorphine (0.6 mg/kg) simultaneously elicited in rat two kinds of facial stereotypies (sniffing and licking) and a stereotyped climbing behavior, allowing to compare in the same animals the relative potencies of various antipsychotics against the three behaviors. Only some substituted benzamides (Sulpiride, LUR 2366 and DAN 2163) antagonised at significantly lower dosages climbing than sniffing (or licking). The possibility that this discriminant potency might be related to a distinct affinity for two classes of dopamine receptors was investigated by binding studies on striatal membranes with 3H-apomorphine and 3H-domperidone. From lesion and subcellular fractionation studies, two classes of binding sites both labeled with 3H-domperidone but distinguished by apomorphine i.e. D-2 sites with nM affinity and D-4 sites with microM affinity for the dopamine agonist (according to the nomenclature of Sokoloff et al. 1980 b) appear to be differently localised in striatum. Thus D-2 sites, whose number decreases after kainate lesion, are not significantly modified following cortical lesions and preferentially sediment with heavy primary subcellular fractions. In contrast D-4 sites, less affected by kainate lesions, are significantly decreased following cortical lesions (-30%) and preferentially sediment with the light subcellular fractions. In addition the apparently heterogeneous recognition of total 3H-domperidone binding sites (i.e. the sum of D-2 and D-4 sites) by dopamine and apomorphine persists in the presence of guanosine-5'-triphosphate (pseudo-Hill coefficient of 0.60 instead of 0.55). This suggests that D-2 and D-4 sites cannot be considered as two discrete states of the same receptor strictly convertible one into the other by guanylnucleotides. Whereas most dopamine antagonists inhibited D-2 and D-4 site binding with similar affinities, the three benzamide derivatives with the largest selectivity in behavioral tests displayed 2-3-fold higher affinity for D-4 than for D-2 sites and the ratios of ID50 values of the whole series of antagonists against sniffing (or licking) and climbing behaviors were correlated (P less than 0.01) with the ratios of Ki values regarding D-2 and D-4 site binding. Also, sulpiride and LUR 2366 unlike haloperidol and metoclopramide, inhibited the total specific 3H-domperidone binding in a biphasic manner.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1983

Catatonic or hypotonic immobility induced in mice by intracerebroventricular injection of mu or kappa opioid receptor agonists as well as enkephalins or inhibitors of their degradation.

The intracerebroventricular injections in mice of the mu receptor agonists morphine and fentanyl induced an immobility state (the animals staying motionless with the head down on a 45 degree inclined plane) which was apparently hypertonic (catatonia ?) or at least enabled them to remain hanging on a horizontal wire with their forepaws. In similar conditions, injections of the kappa receptor agonists ketocyclazocine and bremazocine induced an immobility state which was hypotonic, in contrast with the preceding one. In a similar way to the mu agonists, Met-enkephalin or Leu-enkephalin injected i.c.v. in association with the inhibitor of enkephalinase thiorphan induced an apparently hypertonic immobility which was easily antagonized by naloxone. The association of thiorphan with bestatin (an inhibitor of aminopeptidases involved in enkephalins inactivation) produced similar results. In contrast, the hypotonic immobility induced by the kappa receptor agonists required relatively high doses of naloxone to be antagonized. The opiate antagonist MR 2266 antagonized equipotent doses of all the above mentioned agents with a similar efficacy. From these data it is suggested that enkephalins could induce an apparently tonic immobility by stimulating mu receptors and that endogenous enkephalins could be involved in a tonic mediation modulating the locomotor activity or regulating the muscular tone.

Animals↗
PubMed1983

Pharmacological characteristics of dopamine receptors involved in the dual effect of dopamine agonists on yawning behaviour in rats.

Increasing doses of apomorphine (APO) induced the dose-dependent appearance of yawns in rats at doses up to 0.1 mg X kg-1 and their disappearance from 0.1 to 0.6 mg X kg-1. A similar biphasic effect on yawning was observed with increasing doses of n-propyl norapomorphine, piribedil, S 584, bromocriptine, lergotrile, lisuride, CQ 32084 and L-DOPA. APO, n-propyl norapomorphine, piribedil and CQ 32084 had similar ED50 on the induction of sniffing and on the disappearance of yawns. All the neuroleptics tested antagonized the yawns induced by 0.1 mg X kg-1 APO. Increasing doses of haloperidol, chlorpromazine, mezilamine, metoclopramide and thioridazine made the yawns reappear in rats injected with 0.6 mg X kg-1 APO. The ID50 were similar to those for the antagonism of sniffing. On the other hand, increasing doses of clozapine, (+/-)- or (-)-sulpiride, veralipride and DAN 2163 did not make the yawns reappear in rats injected with 0.6 mg X kg-1 APO although sniffing was antagonized. These results are discussed in terms of the ability of sulpiride, veralipride and DAN 2163 to distinguish between the dopamine (DA) receptors involved in the appearance of yawns at low doses of DA agonists and in their disappearance at higher doses. The decreased APO-induced yawning observed concomitantly with increased sniffing in rats with 6-hydroxydopamine-lesioned olfactory tubercles suggests that yawning and sniffing could be mutually exclusive.

Animals↗
PubMed1983

Pharmacological evidence against the involvement of the D1 subtype of dopamine receptors in apomorphine-induced hypothermia.

In chloral anaesthetized rats, apomorphine, bromocriptine, lergotrile, piribedil and its presumed active metabolite S 584, induced a hypothermia antagonized, except for S 584, by stereotactically controlled microinjections of haloperidol into the preopticus medialis nucleus. Hypothermia was also produced by these dopamine agonists when they were injected directly into the preopticus medialis nucleus. Furthermore, apomorphine-induced hypothermia was antagonized by an infusion of sulpiride into the preopticus medialis nucleus. These data suggest that the dopamine receptors located in the preopticus medialis nucleus which are involved in dopamine agonists-induced hypothermia do not possess the same pharmacological characteristics as the D1 subtype.

Anesthesia, General↗
PubMed1983

Inhibition of enkephalin metabolism by, and antinociceptive activity of, bestatin, an aminopeptidase inhibitor.

In the presence of thiorphan an 'enkephalinase' inhibitor, bestatin an aminopeptidase inhibitor of bacterial origin potently inhibited the hydrolysis of [3H][Leu5]enkephalin by slices from rat striatum with an IC50 value of about 0.2 microM whereas puromycin was approximately 1000 times less potent on this preparation. In vivo bestatin or thiorphan (but not puromycin) significantly protected [3H][Met5]enkephalin administered intracerebroventricularly to mice from hydrolysis and co-administration of these two peptidase inhibitors resulted in a strong reduction in the appearance of hydrolysis products in brain. In a parallel fashion the antinociceptive activity of [Met5]enkephalin in the mouse hot-plate test was additively potentiated by bestatin and thiorphan but not by puromycin. Finally both bestatin and thiorphan themselves displayed antinociceptive properties on either the hot-plate jump test or the phenyl-benzo-quinone writhing test. It is concluded that a bestatin-sensitive aminopeptidase activity together with the 'enkephalinase' activity plays a critical role in the inactivation of both exogenous and endogenous enkephalins.

Aminopeptidases↗
PubMed1983

Pharmacological characterization of the receptors involved in the apomorphine-induced polyphasic modifications of locomotor activity in mice.

Increasing doses of apomorphine elicited polyphasic changes in locomotor activity in mice, consisting of: (i) hypokinesia with a peak effect at 25 micrograms/kg, which was not antagonized by various neuroleptics used at the highest doses not changing spontaneous locomotor activity, except for haloperidol; (ii) a relative restoration of locomotor activity at 75 micrograms/kg; this effect was antagonized by all the neuroleptics tested (except clozapine) and was hardly affected by domperidone and sulpiride; this apomorphine-induced effect was markedly increased 12 days after ICV 6-hydroxydopamine, (iii) a further hypokinetic effect with a peak effect at 150 micrograms/kg-1 (occurring simultaneously with hypothermia) which was antagonized by all the neuroleptics tested (including sulpiride at low doses) except levomepromazine and clozapine, and was again hardly affected by domperidone; this hypokinesia was reduced after prior (24 h) administration of 5 mg/kg apomorphine, (iv) finally another restoration of locomotor activity was observed at doses of apomorphine above 200 micrograms/kg.

Animals↗
PubMed1983

Pain control by endogenous enkephalins is mediated by mu opioid receptors.

The analgesic effects of bestatin and thiorphan, two enzymatic inhibitors protecting endogenous enkephalins from their degradation, and those of DAGO and deltakephalin, respectively mu and delta opioid peptides, are assessed on the electrical stimulation test of the mouse tail. The relative analgesic potency of DAGO and deltakephalin is in good agreement with their relative potency on mu pharmacological assays: inhibition of electrically-induced contractions of guinea-pig ileum, displacement of 3H DAGO on rat brain. Finally, the analgesic effects of DAGO, deltakephalin and bestatin + thiorphan, are antagonized by the mu antagonist naloxone with similar pA2, and they are not modified by the delta antagonist ICI 154, 129. We conclude that only mu and not delta receptors are involved in the analgesic effects of enkephalins.

Amino Acids, Sulfur↗
PubMed1983

New carboxyalkyl inhibitors of brain enkephalinase: synthesis, biological activity, and analgesic properties.

New carboxyalkyl compounds derived from Phe-Leu and Phe-Ala were synthesized and checked as inhibitors of "enkephalinase", a metalloendopeptidase cleaving the Gly3-Phe4 bond of enkephalins from mouse striatal membranes. Differential recognition of both brain enkephalinase and angiotensin-converting enzyme (ACE) catalytic sites by these carboxylalkyl compounds lead to potent (KI approximately 0.5 microM), competitive and selective inhibitors of the enkephalin-degrading enzyme. The most interesting compound, N-[(RS)-2-carboxy-3-phenylpropanoyl]-L-leucine (3, KI = 0.34 microM), is 10000 times more potent on enkephalinase than on ACE activities. Intracerebroventricular (icv) injection of 3 in mice leads to a high potentiation of the analgesic effect of the exogenously administered D-Ala2-Met-enkephalin, evidencing the in vivo inhibition of enkephalinase. Moreover, icv administration of 3 alone induces a dose-dependent analgesia in mice measured on both hot-plate and writhing tests. In the former assay, the ED50 was approximately 10 micrograms per animal, slightly higher than that of thiorphan. All the antinociceptive effects were antagonized by naloxone, demonstrating the involvement of enkephalins in analgesia and their in vivo protection from enkephalinase by 3. The described compounds can be considered as first examples of a new series of analgesics and potentially psychoactive agents.

Amino Acids↗
PubMed1983

Complete differentiation between enkephalinase and angiotensin-converting enzyme inhibition by retro-thiorphan.

Thiorphan, N-[(R,S)-3-mercapto-2-benzylpropanoyl]glycine is a highly potent inhibitor (Ki = 3.5 nM) of "enkephalinase," a metalloendopeptidase cleaving the Gly-Phe bond (positions 3 and 4) of enkephalins in brain tissue. In accordance with this property, thiorphan displays antinociceptive activity after systemic administration. However, thiorphan also inhibits to a lesser extent (Ki = 140 nM) the widely distributed angiotensin-converting enzyme, a carboxydipeptidase implicated in blood pressure regulation. Therefore, in view of an eventual clinical use of enkephalinase inhibitors, it was very important to develop fully specific compounds. Such derivatives were obtained taking into account that N-methylation of the ultimate amide bond of dipeptides strongly decreases enkephalinase affinity without affecting angiotension-converting enzyme recognition, whereas retro-inversion of the amide bond leads to the inverse effect. Thus, the retro-inverso dipeptide (R)-H2N-CH(CH2 phi)-NHCO-CH2-CO2H exhibits an inhibitory potency on enkephalinase (IC50 approximately equal to 12 muM) close to that of the natural dipeptide L-Phe-Gly (IC50 approximately equal to 3 muM). This result shows the topological analogy between the crucial components involved in enkephalinase recognition both in active dipeptides and structurally related retro-inverso isomers. Taking into account these observations, retro-thiorphan, (R,S)-HS-CH2-CH-(CH2 phi)-NHCO-CH2-COOH, was prepared. As compared to thiorphan, the retro isomer is 50% as potent (Ki = 6 nM) on enkephalinase but displays a drastic loss of potency on angiotension-converting enzyme (IC50 greater than 10,000 nM). This specificity was interpreted as a consequence of differences in the stereochemical constraints involving enzyme-inhibitor hydrogen bonding. This hypothesis is supported by reported crystallographic studies on related enzymes such as thermolysin and carboxypeptidase A. As expected, retro-thiorphan exhibits about the same analgesic potency as thiorphan on the hot plate and writhing tests in mice. Therefore, the topological concept of retro-inverso isomers could be extended to other enkephalinase inhibitors, allowing the design of potent and highly selective compounds occurring as new classes of analgesic and psychoactive agents.

Amino Acids, Sulfur↗
PubMed1983

Inhibition of the spontaneous climbing behavior elicited in mice by opiates.

The spontaneous climbing behavior (SCB) developed by naive mice when they are introduced into small individual cylindrical cages with walls of vertical bars is inhibited in a dose-dependent manner by all the tested opiates. Only nalorphine administered over a large scale of doses never completely inhibits the SCB; its maximal effect is only about 50% of total inhibition. The efficacy of opiates on this special component of the locomotor activity has been compared with that on the horizontal displacements measured with an actometer equipped with photoelectric cells. Whereas the drugs known as specific kappa agonists depress both the horizontal locomotor activity and the SCB, most of the other tested opiates inhibit the SCB at doses which do not modify the horizontal locomotion. The low efficacy of loperamide, an opiate agent crossing the blood-brain barrier with difficulty, as well as the strong efficacy of a morphine low dose injected i.c.v. suggest that the opiate-induced SCB inhibition is centrally mediated. Finally, the involvement of mu and kappa receptors is discussed from the observed interactions with various opiate agonists, partial agonist (nalorphine) and antagonists (naloxone and diprenorphine).

Animals↗
PubMed1983

Peptidases involved in the inactivation of exogenous and endogenous enkephalins.

Among the various cerebral enzyme activities able to hydrolyse the enkephalins into inactive fragments only two seem responsible for the metabolism of the endogenous opioid peptides: a dipeptidylcarboxypeptidase ("enkephalinase"), and a bestatin-sensitive aminopeptidase. Their inhibition by thiorphan and bestatin results in an antinociceptive effect observed in tests in which the nociceptive stimulation is probably accompanied by a concomittent release of enkephalins.

Aminopeptidases↗
PubMed1982

Antagonism of the apomorphine-induced yawning by "atypical" neuroleptics.

In relatively small doses, the four "atypical" neuroleptics, sulpiride, clozapine, thoiridazine and mezilamine were effective antagonists of apomorphine-induced yawning in rats. Of the four drugs, used in doses which inhibited apomorphine-induced yawning almost completely, only clozapine also antagonized yawning induced by physostigmine. Therefore it appears that the antagonism of this effect of apomorphine, already reported for classical neuroleptic agents, is also shown by "atypical" ones. By combining apomorphine- and physostigmine-induced yawning, it is possible to assess the anticholinergic component in the antagonism of this effect of apomorphine and this may be of value for the understanding of the mechanisms underlying the "atypical" character.

Animals↗
PubMed1982

Histamine-induced rise in core temperature of chloral-anaesthetized rats: mediation by H2-receptors located in the preopticus area of hypothalamus.

Intracerebroventricular (i.c.v.) administration of histamine in chloral anaesthetized rats exposed to an ambient temperature of 22 C elicited a rise in their colonic temperature associated with a shivering. This effect was shared by the H2 receptor agonists dimaprit and impromidine. Impromidine is, in this respect, a partial agonist with an ED50 much lower than histamine. The histamine-induced rise in core temperature was antagonized by cimetidine administered either centrally (in doses of 25-40 micrograms, i.c.v.) or peripherally (large doses greater than or equal to 50 mg/kg i.p.) This constitutes an indication for the crossing of the blood-brain barrier by cimetidine. The H2 histamine receptors involved in this effect seem to be located mainly in the preopticus medialis nucleus (p.o.m.n.) of the hypothalamus since bilateral microinjections of histamine (5 ng) into this nucleus induced the effect, whereas cimetidine injected into the p.o.m.n., antagonised the relative hyperthermia elicited by an intracerebroventricular administration of histamine.

Animals↗
PubMed1982

Enkephalin metabolism in brain and its inhibition.

Various cerebral peptidases are able to hydrolyse the enkephalins into inactive fragments. Among these enzymes enkephalin-dipeptidylcarboxypeptidase ("enkephalinase") inhibited by thiorphan and a bestatin-sensitive aminopeptidase activity seem to play a key-role as "inactivating neuropeptidases". Their inhibition, in vitro as well as in vivo, leads to a protection of endogenous enkephalins and to antinociceptive effects.

Aminopeptidases↗