30 results on '"Girardon, S."'
Search Results
2. Wood and plywood as eco-materials for sustainable mobility: A review
- Author
-
Castanié, B., Peignon, A., Marc, C., Eyma, F., Cantarel, A., Serra, J., Curti, R., Hadiji, H., Denaud, L., Girardon, S., and Marcon, B.
- Published
- 2024
- Full Text
- View/download PDF
3. 5-HT2C receptors are involved in the discriminative stimulus effects of citalopram in rats
- Author
-
Millan, M. J., Girardon, S., and Dekeyne, A.
- Published
- 1999
- Full Text
- View/download PDF
4. DISCRIMINATIVE STIMULUS (DS) PROPERTIES OF THE NOVEL AND POTENT SEROTONIN (5-HT)2C RECEPTOR AGONIST, RO 60–0175, IN RATS
- Author
-
Dekeyne, A., Brocco, M., Girardon, S., Monneyron, S., Veiga, S., and Millan, M. J.
- Published
- 1998
5. Stereospecific blockade of marble-burying behaviour in mice by selective, non-peptidergic neurokinin 1 (NK 1) receptor antagonists
- Author
-
Millan, M.J., Girardon, S., Mullot, J., Brocco, M., and Dekeyne, A.
- Published
- 2002
- Full Text
- View/download PDF
6. P.1.01 Time-dependent progression of tauopathy and disruption of synaptic proteins in the PS19 P301S transgenic mouse
- Author
-
Francois, A., Dores, G. Das, Billiras, R., Pasteau, V., Iop, F., Girardon, S., Liard, C., Dumas, N., Lliopis, K., Gobert, A., Millan, M.J., and Jeggo, R.
- Published
- 2019
- Full Text
- View/download PDF
7. Stereospecific blockade of marble-burying behaviour in mice by selective, non-peptidergic neurokinin1 (NK1) receptor antagonists
- Author
-
Millan, M.J., Girardon, S., Mullot, J., Brocco, M., and Dekeyne, A.
- Subjects
- *
SEROTONIN uptake inhibitors , *ANIMAL behavior , *LABORATORY mice - Abstract
By analogy with the selective serotonin reuptake inhibitor, fluvoxamine, and the tricyclic agent, clomipramine, the novel, selective, non-peptidergic NK1 receptor antagonist, GR205,171, dose-dependently and completely blocked marble-burying behaviour in mice: Inhibitory Dose50s (ID50s), 4.5, 4.8 and 7.6 mg/kg, respectively. In contrast to GR205,171, its isomer, GR226,206, which displays substantially lower affinity for NK1 receptors, was inactive (> 40.0 mg/kg). By analogy with GR205,171, a further, selective NK1 antagonist, RP67,580, abolished marble-burying behaviour with an ID50 of 11.9 mg/kg. At doses significantly reducing marble-burying behaviour, GR205,171 and RP67,580 little influenced motor behaviour. In conclusion, like fluvoxamine and clomipramine, selective, non-peptidergic NK1 receptor antagonists block marble-burying in mice. Although the biological bases of this behaviour remain unclear, these observations underpin the contention that NK1 receptors may be implicated in affective disorders. [Copyright &y& Elsevier]
- Published
- 2002
- Full Text
- View/download PDF
8. Antinociceptive profiles of non-peptidergic neurokinin1 and neurokinin2 receptor antagonists: a comparison to other classes of antinociceptive agent.
- Author
-
Seguin, L, Le Marouille-Girardon, S, and Millan, M J
- Published
- 1995
- Full Text
- View/download PDF
9. 5-HT[sub 2C] receptors are involved in the discriminative stimulus effects of citalopram in rats.
- Author
-
Millan, M. J., Girardon, S., and Dekeyne, A.
- Subjects
SEROTONIN ,SEROTONIN uptake inhibitors ,RAT physiology - Abstract
Abstract Rats were trained on a fixed ratio 10, food-reinforced schedule to recognize a discriminative stimulus (DS) elicited by the selective serotonin (5-HT) reuptake inhibitor (SSRI), citalopram (2.5 mg/kg, IP). The preferential, high efficacy agonist at 5-HT[sub 2C] receptors, Ro60-0175, dose-dependently generalized to citalopram with an ED[sub 50] of 0.3 mg/kg, IP. Further, the selective 5HT[sub 2C] receptor antagonist, SB242,084, dose-dependently (ED[sub 50] = 0.1 mg/kg, IP) blocked the citalopram DS. These data suggest that 5-HT[sub 2C] receptors are involved in the DS properties of the SSRI, citalopram, in rats. They do not, however, exclude a potential role of other 5-HT receptor types. [ABSTRACT FROM AUTHOR]
- Published
- 1999
- Full Text
- View/download PDF
10. The differential reinforcement of low-rate (DRL) 72 model for characterization of antidepressant agents: Noradrenaline, but not serotonin or dopamine, uptake inhibitors mimic the actions of imipramine
- Author
-
Dekeyne, A., Adhumeau-Auclair, A., Girardon, S., and Millan, M.J.
- Published
- 2000
- Full Text
- View/download PDF
11. Antinociceptive profiles of non-peptidergic neurokinin 1 and neurokinin 2 receptor antagonists: a comparison to other classes of antinociceptive agent
- Author
-
Seguin, L., Le Marouille-Girardon, S., and Millan, M.J.
- Published
- 1995
- Full Text
- View/download PDF
12. ChemInform Abstract: Characterization of Potent and Selective Antagonists at Postsynaptic 5- HT1A Receptors in a Series of N4-Substituted Arylpiperazines.
- Author
-
PEGLION, J.-L., CANTON, H., BERVOETS, K., AUDINOT, V., BROCCO, M., GOBERT, A., LE MAROUILLE-GIRARDON, S., and MILLAN, M. J.
- Published
- 1996
- Full Text
- View/download PDF
13. A microfluidic approach for investigating multicomponent system thermodynamics at high pressures and temperatures.
- Author
-
Pinho B, Girardon S, Bazer-Bachi F, Bergeot G, Marre S, and Aymonier C
- Abstract
In this work, we present a novel microfluidic-based approach for investigating the thermodynamics of multicomponent systems at high pressures and temperatures, such as determining miscibility diagrams and critical coordinates of complex mixtures. The developed method is primarily based on (i) bubble and dew point detection through optical characterization and (ii) the use of a so-called dynamic stop-flow measurement mode for fast screening of the diagram parameters, mainly P, T and composition. Our strategy was validated through the studies of model binary CO2-alkane mixtures. The obtained results were then compared to PREOS-calculated and literature data. We later applied this strategy for determining ternary and quaternary mixtures critical coordinates. This approach has equal accuracy compared to conventional high-pressure optical cell methods but allows for a much faster phase diagram determination, taking advantage of improved heat and mass transfers on the microscale and of the dynamic stop-flow approach.
- Published
- 2014
- Full Text
- View/download PDF
14. Enhancement of social novelty discrimination by positive allosteric modulators at metabotropic glutamate 5 receptors: adolescent administration prevents adult-onset deficits induced by neonatal treatment with phencyclidine.
- Author
-
Clifton NE, Morisot N, Girardon S, Millan MJ, and Loiseau F
- Subjects
- Aging drug effects, Aging metabolism, Allosteric Regulation, Animals, Animals, Newborn, Benzamides pharmacology, Brain drug effects, Brain growth & development, Brain metabolism, Dizocilpine Maleate pharmacology, Dose-Response Relationship, Drug, Male, Microinjections, Oxadiazoles pharmacology, Piperidines pharmacology, Pyrazoles pharmacology, Rats, Rats, Wistar, Receptor, Metabotropic Glutamate 5, Receptors, Metabotropic Glutamate antagonists & inhibitors, Receptors, N-Methyl-D-Aspartate antagonists & inhibitors, Receptors, N-Methyl-D-Aspartate metabolism, Schizophrenia chemically induced, Schizophrenia metabolism, Schizophrenia prevention & control, Aging psychology, Behavior, Animal drug effects, Discrimination, Psychological drug effects, Phencyclidine pharmacology, Receptors, Metabotropic Glutamate metabolism, Social Behavior
- Abstract
Metabotropic glutamate-5 receptors (mGluR5), which physically and functionally interact with N-methyl-D-Aspartate (NMDA) receptors, likewise control cognitive processes and have been proposed as targets for novel classes of antipsychotic agent. Since social cognition is impaired in schizophrenia and disrupted by NMDA receptor antagonists like dizocilpine, we evaluated its potential modulation by mGluR5. Acute administration (0.63-40 mg/kg) of the mGluR5 positive allosteric modulators (PAMs), 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) and ADX47273, reversed a delay-induced impairment in social novelty discrimination (SND) in adult rats. The action of CDPPB was blocked by the mGluR5 antagonist, 2-methyl-6-(phenylethynyl)-pyridine (2.5-10 mg/kg), and was also expressed upon microinjection into frontal cortex (0.63-10 μg/side), but not striatum. Supporting an interrelationship between mGluR5 and NMDA receptors, enhancement of SND by CDPPB was blocked by dizocilpine (0.08 mg/kg) while, reciprocally, dizocilpine-induced impairment in SND was attenuated by CDPPB (10 mg/kg). The SND deficit elicited by post-natal administration of phencyclidine (10 mg/kg, days 7-11) was reversed by CDPPB or ADX47273 in adults at week 8. This phencyclidine-induced impairment in cognition emerged in adult rats from week 7 on, and chronic, pre-symptomatic treatment of adolescent rats with CDPPB over weeks 5-6 (10 mg/kg per day) prevented the appearance of SND deficits in adults until at least week 13. In conclusion, as evaluated by a SND procedure, mGluR5 PAMs promote social cognition via actions expressed in interaction with NMDA receptors and exerted in frontal cortex. MGluR5 PAMs not only reverse but also (when given during adolescence) prevent the emergence of cognitive impairment associated with a developmental model of schizophrenia.
- Published
- 2013
- Full Text
- View/download PDF
15. Cellular and behavioural profile of the novel, selective neurokinin1 receptor antagonist, vestipitant: a comparison to other agents.
- Author
-
Brocco M, Dekeyne A, Mannoury la Cour C, Touzard M, Girardon S, Veiga S, de Nanteuil G, deJong TR, Olivier B, and Millan MJ
- Subjects
- Animals, Dose-Response Relationship, Drug, Enzyme Activation drug effects, Extracellular Signal-Regulated MAP Kinases metabolism, Fear drug effects, Female, Fluorobenzenes, Gerbillinae, Interpersonal Relations, Locomotion drug effects, Male, Mice, Motor Activity drug effects, Piperidines pharmacology, Protein Binding drug effects, Psychomotor Performance drug effects, Rats, Rats, Wistar, Substance P metabolism, Vocalization, Animal drug effects, Behavior, Animal drug effects, Binding, Competitive drug effects, Neurokinin-1 Receptor Antagonists, Substance P pharmacology
- Abstract
This study characterized the novel neurokinin (NK)(1) antagonist, vestipitant, under clinical evaluation for treatment of anxiety and depression. Vestipitant possessed high affinity for human NK(1) receptors (pK(i), 9.4), and potently blocked Substance P-mediated phosphorylation of Extracellular-Regulated-Kinase. In vivo, it occupied central NK(1) receptors in gerbils (Inhibitory Dose(50), 0.11 mg/kg). At similar doses, it abrogated nociception elicited by formalin in gerbils, and blocked foot-tapping and locomotion elicited by the NK(1) agonist, GR73632, in gerbils and guinea pigs, respectively. Further, vestipitant attenuated fear-induced foot-tapping in gerbils, separation-induced distress-vocalizations in guinea pigs, marble-burying behaviour in mice, and displayed anxiolytic actions in Vogel conflict and fear-induced ultrasonic vocalization procedures in rats. These actions were mimicked by CP99,994, L733,060 and GR205,171 which acted stereoselectively vs its less active isomer, GR226,206. In conclusion, vestipitant is a potent NK(1) receptor antagonist: its actions support the utility of NK(1) receptor blockade in the alleviation of anxiety and, possibly, depression.
- Published
- 2008
- Full Text
- View/download PDF
16. S33138 [N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]-benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide], a preferential dopamine D3 versus D2 receptor antagonist and potential antipsychotic agent. II. A neurochemical, electrophysiological and behavioral characterization in vivo.
- Author
-
Millan MJ, Svenningsson P, Ashby CR Jr, Hill M, Egeland M, Dekeyne A, Brocco M, Di Cara B, Lejeune F, Thomasson N, Munoz C, Mocaër E, Crossman A, Cistarelli L, Girardon S, Iob L, Veiga S, and Gobert A
- Subjects
- Animals, Antipsychotic Agents chemistry, Antipsychotic Agents metabolism, Callithrix, Corpus Striatum drug effects, Corpus Striatum metabolism, Dopamine Antagonists chemistry, Dopamine Antagonists metabolism, Dopamine D2 Receptor Antagonists, Electrophysiology, Guinea Pigs, Male, Mice, Mice, Inbred C57BL, Motor Activity physiology, Rats, Rats, Sprague-Dawley, Rats, Wistar, Receptors, Dopamine D3 antagonists & inhibitors, Antipsychotic Agents pharmacology, Dopamine Antagonists pharmacology, Motor Activity drug effects, Receptors, Dopamine D2 physiology, Receptors, Dopamine D3 physiology
- Abstract
The novel benzopyranopyrrolidine, S33138 [N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide], is a preferential antagonist of cloned human D(3) versus D(2L) and D(2S) receptors. In mice, S33138 (0.04-2.5 mg/kg i.p.) increased levels of mRNA encoding c-fos in D(3) receptor-rich Isles of Calleja and nucleus accumbens more potently than in D(2) receptor-rich striatum. Furthermore, chronic (3 weeks) administration of S33138 to rats reduced the number of spontaneously active dopaminergic neurones in the ventral tegmental area (0.16-10.0 p.o.) more potently than in the substantia nigra (10.0). In primates treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, antiparkinson actions of the D(3)/D(2) agonist, ropinirole, were potentiated by low doses of S33138 (0.01-0.16 p.o.) but diminished by a high dose (2.5). Consistent with antagonism of postsynaptic D(3)/D(2) sites, S33138 attenuated hypothermia and yawns elicited by the D(3)/D(2) agonist 7-OH-DPAT [(+)-7-dihydroxy-2-(di-n-propylamino)-tetralin] in rats, and it blocked (0.01-0.63, s.c.) discriminative properties of PD128,907 [(+)-(4aR,10bR)-3,4, 4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin-9-ol; trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl]cyclohexyl]-4-quinolininecarboxamide]. Suggesting antagonist properties at D(3)/D(2) autoreceptors, S33138 prevented (0.16-2.5 s.c.) the inhibitory influence of PD128,907 upon dopamine release in frontal cortex, nucleus accumbens, and striatum and abolished (0.004-0.25 i.v.) its inhibition of ventral tegmental dopaminergic neuron firing. At higher doses, antagonist actions of S33138 (0.5-4.0 i.v.) at alpha(2C)-adrenoceptors were revealed by an increased firing rate of adrenergic perikarya. Finally, antagonism of 5-hydroxytryptamine (5-HT(2A) and 5-HT(7)) receptors was shown by blockade of 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane-induced head twitches (0.63-10.0 s.c.) and 5-carboxytryptamine-induced hypothermia (2.5-20.0 i.p.), respectively. In conclusion, S33138 displays modest antagonist properties at central alpha(2C)-adrenoceptors, 5-HT(2A) and 5-HT(7) receptors. Furthermore, in line with its in vitro actions, it more potently blocks cerebral populations of D(3) versus D(2) receptors.
- Published
- 2008
- Full Text
- View/download PDF
17. Blockade of serotonin 5-HT1B and 5-HT2A receptors suppresses the induction of locomotor activity by 5-HT reuptake inhibitors, citalopram and fluvoxamine, in NMRI mice exposed to a novel environment: a comparison to other 5-HT receptor subtypes.
- Author
-
Millan MJ, Veiga S, Girardon S, and Brocco M
- Subjects
- Animals, Environment Design, Injections, Subcutaneous, Male, Mice, Receptor, Serotonin, 5-HT1B drug effects, Receptor, Serotonin, 5-HT1B physiology, Receptor, Serotonin, 5-HT2B drug effects, Receptor, Serotonin, 5-HT2B physiology, Citalopram pharmacology, Fluvoxamine pharmacology, Motor Activity drug effects, Movement Disorders prevention & control, Receptors, Serotonin classification, Serotonin 5-HT1 Receptor Antagonists, Serotonin 5-HT2 Receptor Antagonists, Selective Serotonin Reuptake Inhibitors pharmacology
- Abstract
Rationale: Though 5-HT plays an important role in the modulation of motor function, which is perturbed in depressive states, little is known concerning the influence of serotonin reuptake inhibitors (SSRIs) on locomotor activity (LA). Recently, we demonstrated that SSRIs, such as citalopram, enhance LA in mice exposed to a novel environment., Objectives: This study examined the role of multiple classes of 5-HT receptor in citalopram-induced LA., Methods: The most selective antagonists currently available were used., Results: Citalopram-induced LA was dose-dependently attenuated by the 5-HT1B/1D receptor antagonists, S18127, GR125,743 and GR127,935, and by the selective 5-HT1B antagonist, SB224,289, but unaffected by the selective 5-HT1A antagonist, WAY100,635. The selective antagonists at 5-HT2A receptors, MDL100,907 and SR46,349 also dose-dependently attenuated induction of locomotion by citalopram, whereas the 5-HT2B antagonist, SB204,741, and the 5-HT2B/2C antagonist, SB206,553 were ineffective. Further, the selective 5-HT2C antagonist, SB242,084, potentiated the response to citalopram. Selective antagonists at 5-HT3 (ondansetron), 5-HT4 (GR125,487), 5-HT6 (SB271,046) and 5-HT7 (SB269,970) receptors did not significantly modify the action of citalopram. Underpinning these findings, SB224,289, GR125,743, MDL100,907 and SR46,349 likewise attenuated induction of locomotion by a further SSRI, fluvoxamine., Conclusions: The locomotor response to SSRIs of mice exposed to a novel environment is mediated via 5-HT1B and 5-HT2A receptors. In view of the importance of motor function to the etiology and treatment of depression, the significance of these observations to the clinical actions of SSRIs will be of interest to elucidate.
- Published
- 2003
- Full Text
- View/download PDF
18. Differential modulation of efficiency in a food-rewarded "differential reinforcement of low-rate" 72-s schedule in rats by norepinephrine and serotonin reuptake inhibitors.
- Author
-
Dekeyne A, Gobert A, Auclair A, Girardon S, and Millan MJ
- Subjects
- Animals, Brain metabolism, Conditioning, Operant drug effects, Differential Threshold drug effects, Dopamine metabolism, Dose-Response Relationship, Drug, Eating drug effects, Locomotion drug effects, Male, Norepinephrine metabolism, Rats, Rats, Wistar, Reinforcement Schedule, Serotonin metabolism, Adrenergic Uptake Inhibitors pharmacology, Antidepressive Agents, Tricyclic pharmacology, Dopamine Uptake Inhibitors pharmacology, Selective Serotonin Reuptake Inhibitors pharmacology
- Abstract
Rationale: The differential reinforcement of low-rate 72-s (DRL 72-s) schedule, in which rats must withhold a response for at least 72 s to obtain a reward (generally water), is an attractive procedure for the characterisation of potential antidepressant agents. Indeed, several antidepressants have been shown to improve efficiency (ratio of reinforcement rate to response rate) in this model, either by decreasing response rates and/or by increasing reinforcement rates., Objective: Herein, we compared the actions of antidepressants known to inhibit serotonin (5-HT), norepinephrine (NE) and/or dopamine (DA) reuptake in a food-rewarded DRL 72-s schedule., Methods: Rats trained in a food-rewarded DRL 72-s schedule and showing stable baseline performance were administered with drugs i.p. once a week. In independent experiments, the influence of drugs on food intake, spontaneous locomotor activity and extracellular levels of monoamines in the frontal cortex was evaluated., Results: In confirmation of previous studies, the tricyclic agent imipramine (10.0 mg/kg) and the "atypical" agent mianserin (40.0 mg/kg) significantly increased efficiency. In analogy, the selective NE reuptake inhibitors (NARIs) desipramine (20.0 mg/kg), nortriptyline (2.5 mg/kg) and reboxetine (0.63 mg/kg) all displayed marked enhancements in efficiency. In contrast, the selective 5-HT reuptake inhibitors (SSRIs) citalopram (10.0 mg/kg), fluvoxamine (10.0 mg/kg) and paroxetine (10.0 mg/kg) all significantly decreased efficiency. The mixed 5-HT/NE reuptake inhibitors (SNRIs) venlafaxine (2.5 mg/kg, 10.0 mg/kg) and S33005 (0.16-10.0 mg/kg), likewise, did not increase efficiency. Further, the DA reuptake inhibitors (DARIs) bupropion (0.16-10.0 mg/kg) and GBR12935 (0.63-10.0 mg/kg) had no effect on DRL 72-s performance. All drug classes exerted a similar, mild inhibitory influence on food intake and locomotor behaviour. Imipramine, mianserin and NARIs markedly increased extracellular levels of NE, and SSRIs elevated levels of 5-HT, while SSRIs augmented levels of both., Conclusions: The present experimental procedure demonstrates, in analogy to imipramine and mianserin, robust and consistent increases in efficiency with NARIs. Their effects may be distinguished from a decrease in efficiency elicited by SSRIs, and a lack of activity of SNRIs and DARIs. While the reasons underlying the ineffectiveness of SSRIs (in contrast to previous studies) remain to be clarified, these data underline the importance of adrenergic mechanisms in the control of behaviour under conditions of delayed responding. Further, they support the interest of DRL 72-s procedures for the characterisation of diverse classes of antidepressant agent.
- Published
- 2002
- Full Text
- View/download PDF
19. Induction of hyperlocomotion in mice exposed to a novel environment by inhibition of serotonin reuptake. A pharmacological characterization of diverse classes of antidepressant agents.
- Author
-
Brocco M, Dekeyne A, Veiga S, Girardon S, and Millan MJ
- Subjects
- Adrenergic Uptake Inhibitors pharmacology, Animals, Antidepressive Agents, Tricyclic pharmacology, Ataxia chemically induced, Ataxia psychology, Citalopram pharmacology, Cyclohexanols pharmacology, Dose-Response Relationship, Drug, Environment, Hyperkinesis psychology, Mice, Motor Activity drug effects, Receptors, Adrenergic, alpha-2 drug effects, Venlafaxine Hydrochloride, Antidepressive Agents pharmacology, Hyperkinesis chemically induced, Selective Serotonin Reuptake Inhibitors pharmacology
- Abstract
This study characterized the influence of acute administration of diverse classes of antidepressant agent upon the spontaneous locomotor activity (LA) of mice in a novel, open-field environment. The selective serotonin (5-HT) reuptake inhibitors (SSRIs), citalopram, fluoxetine, paroxetine, fluvoxamine, litoxetine and zimelidine, dose-dependently enhanced LA. Their actions were mimicked by the mixed 5-HT/noradrenaline (NA) reuptake inhibitors (SNRIs), venlafaxine, duloxetine and S33005. In contrast, clomipramine only slightly elevated LA and two further tricyclics, imipramine and amitriptyline, were inactive. Further, the selective NA vs. 5-HT reuptake inhibitors (NARIs), reboxetine, desipramine, maprotiline, nisoxetine and nortriptyline all failed to increase LA. The "atypical antidepressants," mianserin and mirtazapine, neither of which modify 5-HT reuptake, as well as the mixed SSRI/5-HT(2) antagonists, nefazodone and trazodone, also failed to increase LA. Doses of SSRI and SNRI which increased LA did not modify motor performance in the rotarod test. Further, they did not enhance LA in rats, suggesting that this response is characteristic of mice. Finally, upon prehabituation of mice to the activity chamber, the SSRI, citalopram, and the SNRI, venlafaxine, failed to increase LA. In conclusion, in mice exposed to a novel environment, inhibition of 5-HT reuptake by SSRIs and SNRIs enhances spontaneous LA in the absence of a generalized influence upon motor function. This response provides a simple parameter for characterization of SSRIs and SNRIs, and differentiates them from other classes of antidepressant agent. Although an influence upon arousal and/or anxiety is likely related to the increase in LA, the functional significance of this response requires additional elucidation.
- Published
- 2002
- Full Text
- View/download PDF
20. S18616, a highly potent, spiroimidazoline agonist at alpha(2)-adrenoceptors: I. Receptor profile, antinociceptive and hypothermic actions in comparison with dexmedetomidine and clonidine.
- Author
-
Millan MJ, Dekeyne A, Newman-Tancredi A, Cussac D, Audinot V, Milligan G, Duqueyroix D, Girardon S, Mullot J, Boutin JA, Nicolas JP, Renouard-Try A, Lacoste JM, and Cordi A
- Subjects
- Animals, CHO Cells, Cricetinae, Humans, Imidazoles pharmacology, Imidazoline Receptors, Male, Mice, Rats, Rats, Wistar, Receptors, Drug metabolism, Adrenergic alpha-2 Receptor Agonists, Adrenergic alpha-Agonists pharmacology, Analgesics, Non-Narcotic pharmacology, Body Temperature drug effects, Clonidine pharmacology, Dexmedetomidine pharmacology, Oxazoles pharmacology
- Abstract
S18616 ((S)-spiro[(1-oxa-2-amino-3-azacyclopent-2-ene)-4, 2'-(8'-chloro-1',2',3',4'-tetrahydronaphthalene)]) displayed high affinity at native rat alpha(2)-adrenoceptors (AR)s (pK(i), 9.8), native human (h)alpha(2A)-ARs (9.6), and cloned halpha(2A)- (9.5), halpha(2B)- (9.2), and halpha(2C)- (9.0) ARs. It showed 40-fold lower affinity for halpha(1A)-ARs (8.4) and >/=100-fold lower affinity for rat alpha(1)-ARs (7.1), halpha(1B)-ARs (7.7), halpha(1D)-ARs (7.6), imidazoline(1) (7.4), and imidazoline(2) (7.4) sites and >100-fold lower affinity for all other (>50) sites. At halpha(2A)-ARs, in guanosine-5'-O-(3-[(35)S]thio)triphosphate binding studies, S18616 was a potent (partial) agonist: log effective concentration (pEC(50)), 9.3/maximal effect, 51%. This observation was corroborated employing a halpha(2A)-Gi1alpha fusion protein/GTPase assay (9.0/40%) in which the actions of S18616 were blocked by pertussis toxin. Employing guanosine-5'-O-(3-[(35)S]thio)triphosphate binding assays, S18616 was also a partial agonist at halpha(2C)-ARs (8.2/63%) but a full agonist (8.4/124%) at halpha(2B)-ARs. At halpha(2A)-, halpha(2B)-, and halpha(2C)-ARs, the selective alpha(2)-AR antagonist, atipamezole, abolished the actions of S18616: pK(b) values of 9.1, 9. 1, and 9.4, respectively. As determined by depletion of membrane-bound [(3)H]phosphatidyl inositols, S18616 behaved as a (less potent) agonist (7.8/79%) at halpha(1A)-ARs, an action abolished by prazosin (pK(b), 8.9). Reflecting alpha(2)-AR agonist properties, S18616 potently (>/=1 microg/kg, s.c.) and dose dependently elicited hypothermia and antinociception (nine diverse models) in rodents. These actions were dose dependently inhibited by chemically diverse alpha(2)- versus alpha(1)-AR antagonists, atipamezole, idazoxan, RX821,002, and BRL44418 (a preferential alpha(2A)-AR ligand). In contrast, the actions of S18616 were unaffected by the alpha(1)-AR antagonists, ARC239 and prazosin (which preferentially block alpha(2B/2C)- versus alpha(2A)-ARs). Although the affinity of dexmedetomidine at alpha(2)-ARs was lower than S18616; it displayed a similar receptor and functional profile. Clonidine displayed lower efficacy than S18616, was substantially less potent, and had marked affinity for imidazoline(1) sites and alpha(1)-ARs. In conclusion, S18616 is a novel, selective, and highly potent agonist at alpha(2)-ARs.
- Published
- 2000
21. Discriminative stimulus properties of the dopamine D3 receptor agonists, PD128,907 and 7-OH-DPAT: a comparative characterization with novel ligands at D3 versus D2 receptors.
- Author
-
Millan MJ, Girardon S, Monneyron S, and Dekeyne A
- Subjects
- 2-Naphthylamine analogs & derivatives, 2-Naphthylamine pharmacology, Animals, Dioxins pharmacology, Discrimination Learning physiology, Dopamine D2 Receptor Antagonists, Furans pharmacology, Generalization, Psychological, Humans, Indoles pharmacology, Ligands, Male, Piperazines pharmacology, Piperidines pharmacology, Rats, Rats, Wistar, Receptors, Dopamine D2 agonists, Receptors, Dopamine D3, Receptors, Dopamine D4, Stereoisomerism, Benzopyrans pharmacology, Discrimination Learning drug effects, Dopamine Agonists pharmacology, Oxazines pharmacology, Receptors, Dopamine D2 metabolism, Tetrahydronaphthalenes pharmacology
- Abstract
Rats were trained to recognize a discriminative stimulus (DS) elicited by the preferential dopamine D3 receptor agonists, PD128,907 (0.16 mg/kg, i.p.) and 7-OH-DPAT (0.16 mg/kg, i.p.). PD128,907 and 7-OH-DPAT showed "full" (> or = 80%) and mutual generalization. Chemically-diverse, preferential D3 versus D2 agonists, quinelorane, CGS15855A, pramipexole, ropinirole and piribedil, generalized to PD128,907 (and 7-OH-DPAT) in this order of potency, which correlated more strongly with affinity/activity at cloned human (h)D3 (r=0.68/0.81, n=7) than hD2 (0.27/0.64, n=7) receptors. Further, generalization potency strongly correlated with potency for suppression of response rates (0.86), induction of hypothermia (0.92), reduction of striatal dopamine turnover (0.92) and diminution of immobility in a forced-swim procedure (0.97). Nafadotride, UH232 and AJ76, which show a mild preference for D3 versus D2 sites, blocked the PD128,907 DS, and the modestly-selective D3 antagonist, U99194A, was partially effective. Both nafadotride and U99194A blocked the 7-OH-DPAT DS. However, antagonist potency (n=4) versus PD128,907 correlated better with affinity at D2 (0.89) versus D3 (0.27) sites. Further, whereas the preferential D2 versus D3 antagonist, L741,626, antagonized the PD128,907 DS, the selective D3 antagonists, S11566, S14297 (its eutomer) and GR218,231 were ineffective against PD128907 and 7-OH-DPAT DS. S11566 and GR218,231 likewise did not generalize to PD128,907. In conclusion, under the present conditions, D2 receptors are principally implicated in the DS properties of PD128,907 and 7-OH-DPAT.
- Published
- 2000
- Full Text
- View/download PDF
22. Discriminative stimulus properties of the novel serotonin (5-HT)2C receptor agonist, RO 60-0175: a pharmacological analysis.
- Author
-
Dekeyne A, Girardon S, and Millan MJ
- Subjects
- 8-Hydroxy-2-(di-n-propylamino)tetralin pharmacology, Aminopyridines pharmacology, Animals, Conditioning, Operant physiology, Fluorobenzenes pharmacology, Male, Mianserin pharmacology, Piperazines pharmacology, Piperidines pharmacology, Pyrazines pharmacology, Rats, Rats, Wistar, Receptor, Serotonin, 5-HT2C, Reinforcement, Psychology, Thiophenes pharmacology, Conditioning, Operant drug effects, Ethylamines pharmacology, Indoles pharmacology, Receptors, Serotonin physiology, Serotonin Antagonists pharmacology, Serotonin Receptor Agonists pharmacology
- Abstract
Employing a Fixed-Ratio 10, food-reinforced protocol, rats were trained to recognize the discriminative stimulus (DS) properties of the novel, potent, 5-HT2C agonist, Ro 60-0175 (2.5 mg/kg, i.p.). This schedule generated appropriate drug versus vehicle responding after 50 + 5 training sessions and Ro 60-0175 elicited full (100%) drug selection with an effective dose50 (ED50) of 0.6 mg/kg, i.p.. The 5-HT2C receptor agonists, mCPP and MK 212, fully generalized to Ro 60-0175 with ED50s of 0.8 and 0.4 mg/kg, s.c., respectively, whereas the preferential 5-HT2B agonist, BW 723C86 ( > 10.0 mg/kg, s.c.) and the 5-HT2A agonist, DOI ( > 2.5 mg/kg, s.c.), were ineffective. The 5-HT2A/2B/2C receptor antagonist, mianserin, dose-dependently blocked the DS properties of Ro 60-0175 with an ED50 of 0.7 mg/kg, s.c. This action was mimicked by the novel, 5-HT2B/2C antagonist, SB 206,553 (ED50 = 0.3 mg/kg, s.c.), whereas the selective 5-HT2A antagonist, MDL 100,907 ( > 0.63 mg/kg, s.c.), was ineffective. Further, the selective 5-HT2C antagonist, SB 242,084, dose-dependently and fully blocked drug selection (ED50 = 0.2 mg/kg, i.p.), whereas the selective 5-HT2B antagonist, SB 204,741, was not active ( > 0.63 mg/kg, i.p.). In conclusion, these data demonstrate that Ro 60-0175 generates a robust DS and suggest that activation of 5-HT2C receptors is the principal mechanism underlying its DS properties.
- Published
- 1999
- Full Text
- View/download PDF
23. Citalopram elicits a discriminative stimulus in rats at a dose selectively increasing extracellular levels of serotonin vs. dopamine and noradrenaline.
- Author
-
Millan MJ, Gobert A, Girardon S, and Dekeyne A
- Subjects
- Animals, Cerebral Cortex drug effects, Cerebral Cortex metabolism, Clozapine pharmacology, Corpus Striatum drug effects, Corpus Striatum metabolism, Diazepam pharmacology, Dopamine metabolism, Dose-Response Relationship, Drug, Extracellular Space drug effects, Extracellular Space metabolism, GABA Agents pharmacology, Male, Norepinephrine metabolism, Nucleus Accumbens drug effects, Nucleus Accumbens metabolism, Paroxetine pharmacology, Rats, Rats, Wistar, Serotonin metabolism, Sertraline pharmacology, Biogenic Monoamines metabolism, Citalopram pharmacology, Selective Serotonin Reuptake Inhibitors pharmacology
- Abstract
Citalopram (2.5 mg/kg, i.p.) increased (+145-+180%) extracellular levels of serotonin (5-hydroxytryptamine, 5-HT) in the frontal cortex, nucleus accumbens and striatum of freely-moving rats, whereas dopamine and noradrenaline were unaffected. At this dose, employing a two-lever, food-reinforced, drug discrimination procedure, citalopram generated reliable recognition and fully (> 80%) generalized to itself with an Effective Dose50 (ED50) of 0.1 mg/kg, s.c. Two further selective 5-HT reuptake inhibitors, sertraline and paroxetine, fully generalized with ED50s of 0.01 and 0.04 mg/kg, s.c., respectively. In contrast, the anxiolytic, diazepam (0.63), and the antipsychotic, clozapine (2.5), did not (< or = 20%) generalize. In conclusion, the selective 5-HT reuptake inhibitor, citalopram, elicits a pharmacologically-specific discriminative stimulus in rats at a dose selectively elevating extracellular concentrations of 5-HT.
- Published
- 1999
- Full Text
- View/download PDF
24. 8-OH-DPAT-induced spontaneous tail-flicks in the rat are facilitated by the selective serotonin (5-HT)2C agonist, RO 60-0175: blockade of its actions by the novel 5-HT2C receptor antagonist SB 206,553.
- Author
-
Millan MJ, Girardon S, and Bervoets K
- Subjects
- 8-Hydroxy-2-(di-n-propylamino)tetralin antagonists & inhibitors, Animals, Behavior, Animal drug effects, Drug Interactions, Male, Rats, Rats, Wistar, 8-Hydroxy-2-(di-n-propylamino)tetralin pharmacology, Ethylamines pharmacology, Indoles pharmacology, Pain Measurement drug effects, Pyridines pharmacology, Serotonin Antagonists pharmacology, Serotonin Receptor Agonists pharmacology
- Abstract
The 5-HT1A receptor agonist, 8-OH-DPAT ((+/-)-8-dihydroxy-2-(di-n-propylamino) tetralin), (0.63 mg/kg, s.c.) elicited spontaneous tail-flicks (STFs) in rats. This response was potentiated by the selective 5-HT2C receptor agonist, RO 60-0175 ((S)-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine) fumarate) (0.16 mg/kg, s.c.), the action of which was abolished by the novel 5-HT2C antagonist, SB 206,553 (5 methyl-1-(3-pyridil-carbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3 -f]indole) (0.16 mg/kg, s.c.). These data show that 5-HT1A receptor-mediated STFs in rats are facilitated by activation of 5-HT2C receptors supporting the existence of functional interactions between these sites.
- Published
- 1997
- Full Text
- View/download PDF
25. Pro- and antinociceptive actions of serotonin (5-HT)1A agonists and antagonists in rodents: relationship to algesiometric paradigm.
- Author
-
Millan MJ, Seguin L, Honoré P, Girardon S, and Bervoets K
- Subjects
- Animals, Ataxia chemically induced, Behavior, Animal drug effects, Male, Mice, Pain psychology, Postural Balance drug effects, Tail, Vocalization, Animal drug effects, Analgesics pharmacology, Pain chemically induced, Pain drug therapy, Pain Measurement drug effects, Serotonin Antagonists pharmacology, Serotonin Receptor Agonists pharmacology
- Abstract
In mice injected with formalin into the hindpaw, the 5-HT1A receptor agonists, 8-OH-DPAT and flesinoxan, equipotently inhibited the early phase (EP) and late phase (LP) of licking. At higher doses, they provoked ataxia and inhibited the writhing elicited by intra-abdominal acetic acid. The antagonists, (-)-alprenolol, (-)-tertatolol, WAY-100,135 and S 15931 were more potent against the LP than the EP. They also inhibited writhing, and only at very high doses did they elicit ataxia. In rats, 8-OH-DPAT and flesinoxan increased the current required to elicit vocalisation upon electrical stimulation of the tail. The action of 8-OH-DPAT was blocked by WAY-100,135, which, like other antagonists, was inactive alone. Interestingly, a low dose of 8-OH-DPAT partially inhibited the antinociceptive action of the mu-opioid agonist, morphine, the action of which was dose-dependently facilitated by (-)-alprenolol and S 15931. Administered s.c., 8-OH-DPAT elicited spontaneous tail-flicks (STFs) in rats: these were abolished by WAY-100,135, (-)-tertatolol, (-)-alprenolol and S 15931. STFs were also eliminated by s.c. or i.t. administration of the alpha 2-adrenergic receptor agonist, clonidine, the GABAA agonist, muscimol or the GABAB agonist, baclofen. The mu-opioid, morphine, blocked STFs only at high doses and the kappa-opioid agonists, U 50,488 and U 69,593, even at supra-ataxic doses, were inactive. Antagonists at neurokinin (NK)1 (RP 67580), NK2 (SR 48,968) and bradykinin (BK)2 (Hoe 140) receptors, as well as aspirin, did not block STFs, though indomethacin was effective. Antagonists at the glycine B site coupled to the NMDA receptor, L 687,414, L 701,324 and (+)-HA966, blocked STFs. Furthermore, (+)-HA 966 and the competitive NMDA receptor antagonist, CPP, were active upon i.t. administration. STFs were also blocked by s.c. or i.t. administration of the AMPA antagonists, YM 900 and NBQX. In conclusion, the influence of 5-HT1A ligands upon nociception is dependent upon the algesiometric paradigm. Intriguingly, modulation of 5-HT1A receptor-mediated STFs reveals parallels to neuropathic pain.
- Published
- 1996
- Full Text
- View/download PDF
26. Functional correlates of dopamine D3 receptor activation in the rat in vivo and their modulation by the selective antagonist, (+)-S 14297: 1. Activation of postsynaptic D3 receptors mediates hypothermia, whereas blockade of D2 receptors elicits prolactin secretion and catalepsy.
- Author
-
Millan MJ, Peglion JL, Vian J, Rivet JM, Brocco M, Gobert A, Newman-Tancredi A, Dacquet C, Bervoets K, and Girardon S
- Subjects
- 2-Naphthylamine pharmacology, Animals, Body Temperature Regulation drug effects, CHO Cells, Cricetinae, Humans, Male, Rats, Rats, Wistar, Receptors, Dopamine classification, Receptors, Dopamine drug effects, Recombinant Proteins, Stereoisomerism, 2-Naphthylamine analogs & derivatives, Catalepsy etiology, Dopamine Antagonists pharmacology, Furans pharmacology, Prolactin metabolism, Receptors, Dopamine physiology, Receptors, Dopamine D2 physiology
- Abstract
Using [125I]-iodosulpride as a radioligand, the novel naphthofurane, (+/-)-S 11566 [(+/-)-[7-(N,N-dipropylamino)-5,6,7,8-tetra-hydro- naphtho(2,3b)dihydro,2,3-furane]) showed a marked preference for human, recombinant D3 as compared with D2 receptors stably transfected into Chinese hamster ovary cells (Kis = 24/529 nM). This activity resided in its (+)-eutomer, (+)-S 14297 (13/297 nM) as compared with its (-)-distomer, (-)-S 17777 (406/3544 nM). In contrast, (+)-AJ 76 manifested only a mild 2-fold preference for D3 sites (70/154 nM), whereas haloperidol and six additional antagonists showed a mild (2-7-fold) preference for D2 sites. As concerns agonists, (+)-7-OH-DPAT, (+/-)-CGS 15855A, quinelorane, (-)-quinpirole and N-0434 displayed a preference (6-40-fold) for D3 receptors, whereas piribedil showed a slight, 2-fold, preference for D2 sites (243/126 nM). (+)-S 14297 showed low (> 1.0 microM) affinity at rat D1 and D2 sites and at cloned, human D4 and D5 receptors and only low affinity (145 to > 10,000 nM) at all other sites examined. In vivo, administered s.c., (+)-7-OH-DPAT, CGS 15855A, quinelorane, (-)-quinpirole and N-0434 potently evoked hypothermia. Across all (8) agonists tested, potency correlated significantly with affinity at D3 sites (r = .84, P < .001) but not D2 sites (r = .50, P > .05). (+)-S 14297 (0.16-1.25 mg/kg, s.c.) blocked the induction of hypothermia by (+)-7-OH-DPAT, CGS 15855A and (-)-quinpirole, but not by the alpha 2-adrenergic agonist, clonidine, without influencing core temperature alone. In contrast, (-)-S 17777 (10.0 mg/kg, s.c.) was only partially active. Across all (9) antagonists, potency for inhibition of (+)-7-OH-DPAT-induced hypothermia correlated more strongly with affinity at D3 (r = .96, P < .001) than D2 (r = .75, P < .02) sites. Whereas haloperidol and the other antagonists provoked prolactin secretion and elicited catalepsy, (+)-S 14297 and (+/-)-S 11566 at doses of up to 10.0 and 40.0 mg/kg, s.c., respectively, were not significantly effective (P > .05). Across all antagonists, potency for eliciting prolactin secretion and catalepsy correlated better with affinity at D2 (r = .95 and .96) than D3 (r = .76 and .91) sites. In conclusion, these data demonstrate that the novel naphtofurane, (+)-S 14297, is a selective ligand (antagonist) at dopamine D3 receptors and suggest that their activation mediates hypothermia in the rat.(ABSTRACT TRUNCATED AT 400 WORDS)
- Published
- 1995
27. Characterization of potent and selective antagonists at postsynaptic 5-HT1A receptors in a series of N4-substituted arylpiperazines.
- Author
-
Peglion JL, Canton H, Bervoets K, Audinot V, Brocco M, Gobert A, Le Marouille-Girardon S, and Millan MJ
- Subjects
- 8-Hydroxy-2-(di-n-propylamino)tetralin pharmacology, Animals, Male, Rats, Rats, Wistar, Structure-Activity Relationship, Piperazines pharmacology, Serotonin Antagonists pharmacology
- Abstract
Benzocycloalkyl and benzocycloalkenyl moities linked, directly or via an alkyl chain, to oxygen-bearing heteroarylpiperazines were synthesized, in an attempt to obtain potent and selective antagonists at postsynaptic 5-HT1A receptors. From the numerous arylpiperazines described in the literature, 1-(2,3-dihydro-1,4-benzodioxin-5-yl)piperazine (3a) was chosen as a model of an arylpiperazine in view of its selectivity for 5-HT1A receptors versus alpha 1-, alpha 2-, and beta-adrenergic receptors, as well as dopamine D1 and D2 receptors. Two other closely-related arylpiperazines, 1-(1,5-benzodioxepin-6-yl)piperazine (3b) and 1-(benzofuran-7-yl)piperazine (3c), were also examined in this study. All compounds showed high affinity at 5-HT1A sites (8.10 < or = pKis < or = 9.35), and the majority behaved as antagonists in vivo in blocking the hypothermia induced by the 5-HT1A agonist 8-OH-DPAT in the absence of a marked effect alone at equivalent doses. An in vivo evaluation of dopamine D2 receptor antagonist properties revealed that the majority of compounds was devoid of activity at this site, in marked contrast to BMY 7378 which displayed virtually no selectivity for 5-HT1A versus dopamine D2 receptors. Moreover, six compounds of the present series, 8, 10, 11, 14, 25, and 37, showed > 10-fold selectivity in vitro for 5-HT1A versus alpha 1-adrenergic receptors. Compound 14 displayed an optimal compromise between potency (pKi = 8.75), marked antagonist activity, and selectivity toward alpha 1-adrenergic (81-fold) and dopamine D2 (195-fold) receptors. These characteristics clearly distinguish 14 from previously-reported ligands such as the postsynaptic 5-HT1A antagonist BMY 7378 and the weak partial agonist NAN 190 which, in contrast to the compounds of this series, belong to the well-exemplified class of imido derivatives of (o-methoxyphenyl)piperazines. The availability of 14 (S 15535) should facilitate the further elucidation of the functional role and potential therapeutic significance of 5-HT1A receptors.
- Published
- 1995
- Full Text
- View/download PDF
28. Multiple alpha-2 adrenergic receptor subtypes. II. Evidence for a role of rat R alpha-2A adrenergic receptors in the control of nociception, motor behavior and hippocampal synthesis of noradrenaline.
- Author
-
Millan MJ, Bervoets K, Rivet JM, Widdowson P, Renouard A, Le Marouille-Girardon S, and Gobert A
- Subjects
- Animals, Brimonidine Tartrate, Male, Quinoxalines pharmacology, Rats, Rats, Wistar, Receptors, Adrenergic, alpha-2 classification, Hippocampus metabolism, Motor Activity physiology, Norepinephrine biosynthesis, Pain, Receptors, Adrenergic, alpha-2 physiology
- Abstract
In this study, we attempted to identify of the subtype(s) of alpha-2 adrenergic receptor (AR) involved in the control of motor behavior, nociception and the hippocampal synthesis of noradrenaline (NA) in the rat. The high efficacy alpha-2 AR agonists, xylazine and UK 14,304 [5-bromo-6-[2-imidazolin-2-yl-amino]quinoxaline], inhibited striatal accumulation of L-dopa in rats pretreated with NSD 1015 (an inhibitor of aromatic amino acid-decarboxylase), elicited a loss of the righting reflex in rats, provoked ataxia in the rotarod test in mice and elicited antinociception in the writhing and hot-plate tests in mice. Guanfacine and guanabenz, agonists acting preferentially at rat alpha-2A (R alpha-2A)/human alpha-2A (H alpha-2A) AR, mimicked the antinociceptive and motor actions of xylazine and UK 14,304 and likewise inhibited NA synthesis. The preferential R alpha-2A/H alpha-2A AR antagonist, [2-(2H-(1-methyl-1, 3-dihydroisoindole)methyl)-4, 5-dihydro-imidazole (BRL 44408), enhanced hippocampal synthesis of NA and blocked the antinociceptive and motor effects of UK 14,304, xylazine, guanfacine and guanabenz. Similarly, fluparoxan and des-fluorofluparoxan, preferential antagonists at R alpha-2A AR as compared to H alpha-2A AR, were highly active. In contrast, the preferential alpha-2B/alpha-2C AR antagonists, ARC 239 [2-(2-(4-o-methoxyphenyl)piperazine-1-yl)-ethyl)-4,4-dimethyl-1,3- (2H,4H)-isoquinolinedione] prazosin, corynanthine, spiroxatrine and [1,2-dimethyl-2,3,9,13-betetrahydro-1H-dibenzo(c,f)- imidazo(1,5-a)azepine (BRL 41992)], as well as the preferential H alpha-2A AR antagonist, [2-(2,6-dimethoxyphenoxyethyl)- aminomethyl-1,4-benzodioxane] (WB 4101), were only weakly active. Based on the actions of a total of 16, structurally diverse alpha-2 AR antagonists, a correlation matrix was constructed. This revealed a strong correlation among the tests (median r = 0.82) and allowed for a comparison between drug potency in inhibiting these alpha-2 AR-mediated actions and affinity at various populations of alpha-2 AR subtypes (see companion paper). Correlations for potency in the two motor tests were pronounced with R alpha-2A sites (0.85), modest with H alpha-2A sites (0.60) and alpha-2B sites (0.58) and poor with alpha-2C sites (0.35). For the two antinociceptive tests, correlations were likewise pronounced with R alpha-2A sites (0.80) but less marked with H alpha-2A sites (0.73), alpha-2B sites (0.62) and alpha-2C sites (0.62).(ABSTRACT TRUNCATED AT 400 WORDS)
- Published
- 1994
29. Induction of hypothermia as a model of 5-hydroxytryptamine1A receptor-mediated activity in the rat: a pharmacological characterization of the actions of novel agonists and antagonists.
- Author
-
Millan MJ, Rivet JM, Canton H, Le Marouille-Girardon S, and Gobert A
- Subjects
- 5,7-Dihydroxytryptamine pharmacology, 5-Hydroxytryptophan metabolism, 8-Hydroxy-2-(di-n-propylamino)tetralin pharmacology, Animals, Corticosterone metabolism, Male, Piperazines pharmacology, Rats, Rats, Wistar, Receptors, Serotonin analysis, Receptors, Serotonin drug effects, Body Temperature Regulation drug effects, Hypothermia chemically induced, Receptors, Serotonin physiology, Serotonin Antagonists pharmacology, Serotonin Receptor Agonists pharmacology
- Abstract
In this study, we examined the localization of the 5-hydroxytryptamine (5-HT)1A receptors mediating hypothermia in the rat, evaluated the pharmacological specificity of this response and examined the influence of a series of novel 5-HT1A receptor ligands upon core temperature. Administered s.c., 8-hydroxy-(2-di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), an agonist at both pre- and postsynaptic 5-HT1A receptors, elicited pronounced hypothermia. In contrast, BMY 7378, which shows low efficacy at postsynaptic 5-HT1A receptors but high efficacy at presynaptic 5-HT1A receptors, elicited only mild hypothermia. Similarly, 8-OH-DPAT was more efficacious than BMY 7378 in eliciting corticosterone secretion, a response mediated by postsynaptic 5-HT1A receptors, whereas BMY 7378 was as efficacious as 8-OH-DPAT in inhibiting striatal accumulation of 5-hydroxytryptophan, a response mediated by presynaptic 5-HT1A receptors. These data suggest, by analogy, that postsynaptic 5-HT1A receptors mediate hypothermia, an interpretation supported by the observation that destruction of central 5-HT neurons with 5,7-dihydroxytryptamine failed to reduce 8-OH-DPAT-induced hypothermia (DIH). Agonists at 5-HT1B, 5-HT1C, 5-HT2 and/or 5-HT3 receptors did not elicit hypothermia, and drugs releasing 5-HT elicited hyperthermia. In contrast, DIH was fully mimicked by the novel 5-HT1A receptors agonists, eltoprazine, WY 48,723, MDL 72832, tandospirone, S 14671, S 14506 and WY 50,324, whereas the novel partial agonist, zalospirone, was less efficacious. DIH was blocked by (-)-alprenolol, (+/-)-pindolol and the novel beta-blocker, (-)-tertatolol, which also has high affinity for 5-HT1A receptors; in distinction, betaxolol and ICI 118,551, antagonists at beta-1 and beta-2 adrenoceptors, respectively, were inactive. Spiperone, NAN-190 and BMY 7378 also inhibited DIH whereas ritanserin, SCH 39166, raclopride and prazosin, antagonists at 5-HT2 receptors, D1 and D2 dopamine receptors and alpha-1 adrenoceptors, respectively, were inactive. The novel 5-HT1A antagonists, WAY 100,135, MDL 73005 EF and (very potently) SDZ 216-525 all blocked DIH. Potency for induction of hypothermia and inhibition of DIH correlated well with affinity for 5-HT1A binding sites. In conclusion, hypothermia is a highly specific and sensitive response to activation of postsynaptic 5-HT1A receptors. Furthermore, DIH is inhibited by their selective blockade. At postsynaptic 5-HT1A receptors mediating hypothermia, eltoprazine, WY 48,723, MDL 72832 and tandospirone are agonists, zalospirone is a partial agonist and (-)-tertatolol, WAY 100,135, MDL 73005 EF and SDZ 216-525 are antagonists.
- Published
- 1993
30. S 14671: a naphtylpiperazine 5-hydroxytryptamine1A agonist of exceptional potency and high efficacy possessing antagonist activity at 5-hydroxytryptamine1C/2 receptors.
- Author
-
Millan MJ, Rivet JM, Canton H, Lejeune F, Bervoets K, Brocco M, Gobert A, Lefebvre de Ladonchamps B, Le Marouille-Girardon S, and Verriele L
- Subjects
- 8-Hydroxy-2-(di-n-propylamino)tetralin, Analgesia, Animals, Body Temperature drug effects, Corticosterone metabolism, In Vitro Techniques, Male, Mice, Phosphatidylinositols metabolism, Piperazines metabolism, Posture, Raphe Nuclei drug effects, Rats, Rats, Inbred Strains, Receptors, Serotonin metabolism, Tetrahydronaphthalenes pharmacology, Thiophenes metabolism, Piperazines pharmacology, Receptors, Serotonin drug effects, Serotonin Antagonists pharmacology, Thiophenes pharmacology
- Abstract
The interaction at 5-hydroxytryptamine (5-HT) receptors of the novel naphtylpiperazine, S 14671 (1-[2-(2-thenoylamino)ethyl]-4[1-(7- methoxynaphtyl)]piperazine), was compared to that of the 5-HT1A ligands, 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT), WY 50,324 [N-(29(4-(2-pyrimidinyl)-1-piperazinyl)ethyl)tricyclo(3.3.1.1(3,7) )- decane-1-carboxamide], (+)-flesinoxan, buspirone and BMY 7378 [(8-[2-[4-(2-methoxyphenyl)- 1-piperazinyl]ethyl]-8-azaspirol[-4-]-decane-7,9-dione 2HCl]. S 14671 showed a very high affinity for 5-HT1A sites (pKi, 9.3) as compared to the reference ligands (pKi values, 9.2, 8.7, 8.7, 7.9 and 8.7, respectively). S 14671 bound in an apparently competitive manner and, in distinction to the reference compounds, possessed a Hill Coefficient (1.4) significantly superior to 1. Although showing low affinity at 5-HT1B and 5-HT3 sites, S 14671 displayed significant affinity at both 5-HT1C and 5-HT2 sites; pKi, 7.8 in each case. Furthermore, S 14671 acted as an antagonist of 5-HT-stimulated phosphoinositide turnover in rat choroid plexus (5-HT1C) and cortex (5-HT2). In vivo, upon s.c. administration, S 14671 acted as a high efficacy agonist in models of 5-HT1A receptor-mediated activity: induction of flat-body posture, spontaneous tail-flicks, hypothermia and corticosterone secretion and inhibition of morphine-induced antinociception. In every test, S 14671 was the most potent compound: it was active at doses as low as 5 micrograms/kg s.c. Relative potency across all tests was S 14671 greater than 8-OH-DPAT greater than WY 50,324 greater than (+)-flesinoxan greater than buspirone with BMY 7378 too weak for comparison to be meaningful. The action of S 14671 in 5-HT1A tests was blocked by BMY 7378 and the 5-HT1A antagonist, (-)-alprenolol, but unaffected by the 5-HT1C/2 antagonist, ritanserin, and the 5-HT3 antagonist, ondansetron. Activation of postsynaptic 5-HT1A receptors was confirmed in 5,7-dihydroxytryptamine-lesioned rats, in which the potency of S 14671 to elicit spontaneous tail-flicks was potentiated. Activation of presynaptic receptors was demonstrated by inhibition of the electrical activity of the dorsal raphe nucleus with the following order of relative potency: S 14671 greater than 8-OH-DPAT greater than WY 50,324 greater than BMY 7378 greater than buspirone. Spiperone, which acts as a pure 5-HT1A antagonist at raphe 5-HT1A receptors, blocked the action of S 14671. In conclusion, S 14671 is a structurally novel ligand manifesting high efficacy and exceptional potency at both pre- and postsynaptic 5-HT1A receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
- Published
- 1992
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.