RESUMEN
The characterization of the first selective orally active and brain-penetrant beta3-adrenoceptor agonist, SR58611A (amibegron), has opened new possibilities for exploring the involvement of this receptor in stress-related disorders. By using a battery of tests measuring a wide range of anxiety-related behaviors in rodents, including the mouse defense test battery, the elevated plus-maze, social interaction, stress-induced hyperthermia, four-plate, and punished drinking tests, we demonstrated for the first time that the stimulation of the beta3 receptor by SR58611A resulted in robust anxiolytic-like effects, with minimal active doses ranging from 0.3 to 10 mg/kg p.o., depending on the procedure. These effects paralleled those obtained with the prototypical benzodiazepine anxiolytic diazepam or chlordiazepoxide. Moreover, when SR58611A was tested in acute or chronic models of depression in rodents, such as the forced-swimming and the chronic mild stress tests, it produced antidepressant-like effects, which were comparable in terms of the magnitude of the effects to those of the antidepressant fluoxetine or imipramine. Supporting these behavioral data, SR58611A modified spontaneous sleep parameters in a manner comparable to that observed with fluoxetine. Importantly, SR58611A was devoid of side effects related to cognition (as shown in the Morris water maze and object recognition tasks), motor activity (in the rotarod), alcohol interaction, or physical dependence. Antagonism studies using pharmacological tools targeting a variety of neurotransmitters involved in anxiety and depression and the use of mice lacking the beta3 adrenoceptor suggested that these effects of SR58611A are mediated by beta3 adrenoceptors. Taken as a whole, these findings indicate that the pharmacological stimulation of beta3 adrenoceptors may represent an innovative approach for the treatment of anxiety and depressive disorders.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 3 , Agonistas Adrenérgicos beta/uso terapéutico , Trastornos de Ansiedad/tratamiento farmacológico , Trastorno Depresivo/tratamiento farmacológico , Tetrahidronaftalenos/uso terapéutico , Agonistas Adrenérgicos beta/administración & dosificación , Agresión/efectos de los fármacos , Animales , Ansiolíticos/farmacología , Antidepresivos de Segunda Generación/farmacología , Antidepresivos Tricíclicos/farmacología , Trastornos de Ansiedad/psicología , Conducta Animal/efectos de los fármacos , Cognición/efectos de los fármacos , Trastorno Depresivo/psicología , Diazepam/farmacología , Etanol/farmacología , Conducta Exploratoria/efectos de los fármacos , Fluoxetina/farmacología , Gerbillinae , Imipramina/farmacología , Relaciones Interpersonales , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Ratas , Ratas Long-Evans , Ratas Sprague-Dawley , Ratas Wistar , Receptores Adrenérgicos beta 3/genética , Sueño/efectos de los fármacos , Trastornos Relacionados con Sustancias/psicología , Natación/psicología , Tetrahidronaftalenos/administración & dosificaciónRESUMEN
On native human, rat and mouse glycine transporter-1(GlyT1), SSR130800 behaves as a selective inhibitor with IC50 values of 1.9, 5.3 and 6.8 nM, respectively. It reversibly blocked glycine uptake in mouse brain cortical homogenates, increased extracellular levels of glycine in the rat prefrontal cortex, and potentiated NMDA-mediated excitatory postsynaptic currents in rat hippocampal slices. SSR103800 (30 mg/kg, p.o.) decreased MK-801- and PCP-induced locomotor hyperactivity in rodents. SSR103800 (1 and 10 mg/kg, p.o.) attenuated social recognition deficit in adult rats induced by neonatal injections of PCP (10 mg/kg, s.c., on post-natal day 7, 9 and 11). SSR103800 (3 mg/kg, p.o.) counteracted the deficit in short-term visual episodic-like memory induced by a low challenge dose of PCP (1 mg/kg, i.p.), in PCP-sensitized rats (10 mg/kg, i.p.). SSR103800 (30 mg/kg, i.p.) increased the prepulse inhibition of the startle reflex in DBA/1J mice. SSR103800 decreased defensive- and despair-related behaviors in the tonic immobility test in gerbils (10 and 30 mg/kg, p.o.) and in the forced-swimming procedure in rats (1 and 3 mg/kg, p.o.), respectively. These findings suggest that SSR103800 may have a therapeutic potential in the management of the core symptoms of schizophrenia and comorbid depression states.
Asunto(s)
Antipsicóticos/farmacología , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Esquizofrenia/tratamiento farmacológico , Animales , Antidepresivos/farmacología , Discriminación en Psicología/efectos de los fármacos , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Espacio Extracelular/efectos de los fármacos , Espacio Extracelular/metabolismo , Gerbillinae , Glicina/metabolismo , Masculino , Ratones , Actividad Motora/efectos de los fármacos , N-Metilaspartato/fisiología , Fenciclidina/farmacología , Reconocimiento en Psicología/efectos de los fármacos , Reflejo de Sobresalto/efectos de los fármacos , Estereoisomerismo , Natación/psicologíaRESUMEN
Noncompetitive N-methyl-D-aspartate (NMDA) blockers induce schizophrenic-like symptoms in humans, presumably by impairing glutamatergic transmission. Therefore, a compound potentiating this neurotransmission, by increasing extracellular levels of glycine (a requisite co-agonist of glutamate), could possess antipsychotic activity. Blocking the glycine transporter-1 (GlyT1) should, by increasing extracellular glycine levels, potentiate glutamatergic neurotransmission. SSR504734, a selective and reversible inhibitor of human, rat, and mouse GlyT1 (IC50=18, 15, and 38 nM, respectively), blocked reversibly the ex vivo uptake of glycine (mouse cortical homogenates: ID50: 5 mg/kg i.p.), rapidly and for a long duration. In vivo, it increased (minimal efficacious dose (MED): 3 mg/kg i.p.) extracellular levels of glycine in the rat prefrontal cortex (PFC). This resulted in an enhanced glutamatergic neurotransmission, as SSR504734 potentiated NMDA-mediated excitatory postsynaptic currents (EPSCs) in rat hippocampal slices (minimal efficacious concentration (MEC): 0.5 microM) and intrastriatal glycine-induced rotations in mice (MED: 1 mg/kg i.p.). It normalized activity in rat models of hippocampal and PFC hypofunctioning (through activation of presynaptic CB1 receptors): it reversed the decrease in electrically evoked [3H]acetylcholine release in hippocampal slices (MEC: 10 nM) and the reduction of PFC neurons firing (MED: 0.3 mg/kg i.v.). SSR504734 prevented ketamine-induced metabolic activation in mice limbic areas and reversed MK-801-induced hyperactivity and increase in EEG spectral energy in mice and rats, respectively (MED: 10-30 mg/kg i.p.). In schizophrenia models, it normalized a spontaneous prepulse inhibition deficit in DBA/2 mice (MED: 15 mg/kg i.p.), and reversed hypersensitivity to locomotor effects of d-amphetamine and selective attention deficits (MED: 1-3 mg/kg i.p.) in adult rats treated neonatally with phencyclidine. Finally, it increased extracellular dopamine in rat PFC (MED: 10 mg/kg i.p.). The compound showed additional activity in depression/anxiety models, such as the chronic mild stress in mice (10 mg/kg i.p.), ultrasonic distress calls in rat pups separated from their mother (MED: 1 mg/kg s.c.), and the increased latency of paradoxical sleep in rats (MED: 30 mg/kg i.p.). In conclusion, SSR504734 is a potent and selective GlyT1 inhibitor, exhibiting activity in schizophrenia, anxiety and depression models. By targeting one of the primary causes of schizophrenia (hypoglutamatergy), it is expected to be efficacious not only against positive but also negative symptoms, cognitive deficits, and comorbid depression/anxiety states.
Asunto(s)
Benzamidas/farmacología , Química Encefálica/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Neuronas/efectos de los fármacos , Piperidinas/farmacología , Acetilcolina/metabolismo , Potenciales de Acción/efectos de los fármacos , Anfetamina/farmacología , Análisis de Varianza , Animales , Animales Recién Nacidos , Conducta Animal/efectos de los fármacos , Isótopos de Carbono/metabolismo , Células Cultivadas , Corteza Cerebral/citología , Ritmo Circadiano/efectos de los fármacos , Inhibidores de Captación de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Inhibidores Enzimáticos/química , Antagonistas de Aminoácidos Excitadores/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Femenino , Glicina/metabolismo , Hipocampo/citología , Humanos , Técnicas In Vitro , Concentración 50 Inhibidora , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Inhibición Neural/efectos de los fármacos , Neuronas/fisiología , Técnicas de Placa-Clamp/métodos , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/efectos de los fármacosRESUMEN
It has been shown previously that the selective cannabinoid CB1 receptor antagonist, rimonabant (SR141716), reduced the intake of palatable food as well as the self-administration of several drugs of abuse, suggesting that endocannabinoid systems play a role in brain reward function. The present study investigated whether a cannabinoid step was involved in food-seeking behavior induced by explicit stimuli, using an operant reinstatement procedure in rats. Experimental sessions consisted of a 15-min food rewarded period, followed by a 45-min extinction period. Rimonabant did not affect the response reinstatement induced by noncontingent delivery of food pellets, but prevented (0.03-0.3 mg/kg) the potentiation by quinelorane, a dopamine D3 receptor-preferring agonist, of food-seeking behavior. A possible link between cannabinoid processes and D3- and/or D2-mediated dopaminergic transmission was further investigated by studying Fos protein expression in cortico-limbic structures in D3 (D3-/-) and D2 (D2-/-) knockout mice. Rimonabant (10 mg/kg) increased Fos immunoreactivity in the prefrontal cortex (pFCortex) and in the shell but not the core of the nucleus accumbens (NAcc). Fos induction by this dose of rimonabant was not seen in mice lacking CB1 receptors, providing clear evidence for the involvement of CB1 receptors. In the NAcc shell, the effect of rimonabant was suppressed in D3-/-, but remained unchanged in D2-/- mice. In contrast, Fos expression by rimonabant in the pFCortex was impervious to D2 or D3 receptor deletion. In conclusion, these data indicate first that rimonabant prevented the enhancement by quinelorane of the appetitive value of food pellets unexpectedly delivered during extinction and second that rimonabant effects might involve D3 receptor-mediated processes. Overall, these results are consistent with the notion that endocannabinoid functions control brain reward processes and in particular the capacity of explicit stimuli to precipitate food-seeking behavior.
Asunto(s)
Agonistas de Dopamina/farmacología , Conducta Alimentaria/efectos de los fármacos , Alimentos , Piperidinas/farmacología , Pirazoles/farmacología , Quinolinas/farmacología , Receptor Cannabinoide CB1/antagonistas & inhibidores , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Señales (Psicología) , Femenino , Inmunohistoquímica , Sistema Límbico/efectos de los fármacos , Sistema Límbico/metabolismo , Masculino , Ratones , Ratones Noqueados , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Proteínas Proto-Oncogénicas c-fos/biosíntesis , Ratas , Ratas Wistar , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/fisiología , Receptores de Dopamina D3 , RimonabantRESUMEN
SSR181507 ((3-exo)-8-benzoyl-N-[[(2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl]methyl]-8-azabicyclo[3.2.1]octane-3-methanamine monohydrochloride) is a novel tropanemethanamine benzodioxane derivative that possesses high and selective affinities for D2-like and 5-HT(1A) receptors (K(I)=0.8, 0.2, and 0.2 nM for human D(2), D(3), and 5-HT(1A), respectively). In vivo, SSR181507 inhibited [(3)H]raclopride binding to D(2) receptors in the rat (ID(50)=0.9 and 1 mg/kg, i.p. in limbic system and striatum, respectively). It displayed D(2) antagonist and 5-HT(1A) agonist properties in the same concentration range in vitro (IC(50)=5.3 nM and EC(50)=2.3 nM, respectively, in the GTPgammaS model) and in the same dose range in vivo (ED(50)=1.6 and 0.7 mg/kg, i.p. on striatal DA and 5-HT synthesis, respectively, and 0.03-0.3 mg/kg, i.v. on dorsal raphe nucleus firing rate). It selectively enhanced Fos immunoreactivity in mesocorticolimbic areas as compared to the striatum. This regional selectivity was confirmed in electrophysiological studies where SSR181507, given acutely (0.1-3 mg/kg, i.p.) or chronically (3 mg/kg, i.p., o.d., 22 days), increased or decreased, respectively, the number of spontaneous active DA cells in the ventral tegmental area, but not in the substantia nigra. Moreover, SSR181507 increased both basal and phasic DA efflux (as assessed by microdialysis and electrochemistry) in the medial prefrontal cortex and nucleus accumbens, but not in the striatum. This study shows that the combination of D(2) receptor antagonism and 5-HT(1A) agonism, in the same dose range, confers on SSR181507 a unique neurochemical and electrophysiological profile and suggests the potential of this compound for the treatment of the main dimensions of schizophrenia.
Asunto(s)
Encéfalo/efectos de los fármacos , Antagonistas de los Receptores de Dopamina D2 , Antagonistas del Receptor de Serotonina 5-HT1 , 5-Hidroxitriptófano/metabolismo , Potenciales de Acción/efectos de los fármacos , Animales , Antipsicóticos/farmacología , Conducta Animal/efectos de los fármacos , Sitios de Unión , Encéfalo/anatomía & histología , Encéfalo/fisiología , Recuento de Células , Dioxanos/farmacología , Dopamina/metabolismo , Antagonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Interacciones Farmacológicas , Estimulación Eléctrica , Electroquímica/métodos , Guanosina 5'-O-(3-Tiotrifosfato)/farmacocinética , Haloperidol/farmacología , Humanos , Inmunohistoquímica/métodos , Técnicas In Vitro , Levodopa/metabolismo , Masculino , Microdiálisis/métodos , Neuronas/efectos de los fármacos , Piperazinas/farmacología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Piridinas/farmacología , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT1A/química , Receptores de Dopamina D2/química , Antagonistas de la Serotonina/farmacología , Isótopos de Azufre/farmacocinética , Factores de Tiempo , Tropanos/farmacologíaRESUMEN
5-Hydroxytryptamine (5-HT)2A antagonists are promising therapeutic agents for the treatment of sleep maintenance insomnias, but unlike hypnotics, they have limited effects on sleep initiation. This study evaluated the effects of several 5-HT2A antagonists (eplivanserin, volinanserin and AVE8488) alone and/or in combination with the short-acting hypnotic, zolpidem, on the rat sleep profile. A repeated-measures design was used in which rats were treated with eplivanserin (3 and 10 mg/kg, i.p. or p.o.), volinanserin (0.3-3 mg/kg, i.p.), AVE8488 (0.1-3 mg/kg, i.p.) and zolpidem (3 and 10 mg/kg, p.o.). In addition, animals received a combination of eplivanserin (3 mg/kg, p.o.) and zolpidem (3 mg/kg, p.o.). Electroencephalogram was analyzed for 6 h after administration. Eplivanserin did not modify wakefulness and non-rapid eye movement sleep (NREMS), while zolpidem (10 mg/kg po) induced a marked increase in NREMS duration. Volinanserin (1 and 3 mg/kg) and AVE8488 (0.3 mg/kg) similarly increased NREMS, while reducing wakefulness. Moreover, the 5-HT2A antagonists and, to a lesser extent, zolpidem, increased duration of NREMS episodes, while decreasing their frequency. When eplivanserin was co-administered with zolpidem, a synergistic effect was observed as the combination produced an increase in NREMS time and bouts duration. These findings confirm further that 5-HT2A antagonists promote the maintenance of sleep, and suggest that combining a 5-HT2A antagonist with a short-acting hypnotic may be a useful strategy for the treatment of insomnia.
Asunto(s)
Piridinas/farmacología , Antagonistas de la Serotonina/farmacología , Fases del Sueño/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Fluorobencenos/farmacología , Hipnóticos y Sedantes/farmacología , Masculino , Fenoles/farmacología , Piperidinas/farmacología , Ratas , Vigilia/efectos de los fármacos , ZolpidemRESUMEN
The biochemical and pharmacological properties of a novel non-peptide antagonist of the bradykinin (BK) B(1) receptor, SSR240612 [(2R)-2-[((3R)-3-(1,3-benzodioxol-5-yl)-3-[[(6-methoxy-2-naphthyl)sulfonyl]amino]propanoyl)amino]-3-(4-[[2R,6S)-2,6-dimethylpiperidinyl]methyl]phenyl)-N-isopropyl-N-methylpropanamide hydrochloride] were evaluated. SSR240612 inhibited the binding of [(3)H]Lys(0)-des-Arg(9)-BK to the B(1) receptor in human fibroblast MRC5 and to recombinant human B(1) receptor expressed in human embryonic kidney cells with inhibition constants (K(i)) of 0.48 and 0.73 nM, respectively. The compound selectivity for B(1) versus B(2) receptors was in the range of 500- to 1000-fold. SSR240612 inhibited Lys(0)-desAr(9)-BK (10 nM)-induced inositol monophosphate formation in human fibroblast MRC5, with an IC(50) of 1.9 nM. It also antagonized des-Arg(9)-BK-induced contractions of isolated rabbit aorta and mesenteric plexus of rat ileum with a pA(2) of 8.9 and 9.4, respectively. Antagonistic properties of SSR240612 were also demonstrated in vivo. SSR240612 inhibited des-Arg(9)-BK-induced paw edema in mice (3 and 10 mg/kg p.o. and 0.3 and 1 mg/kg i.p.). Moreover, SSR240612 reduced capsaicin-induced ear edema in mice (0.3, 3 and 30 mg/kg p.o.) and tissue destruction and neutrophil accumulation in the rat intestine following splanchnic artery occlusion/reperfusion (0.3 mg/kg i.v.). The compound also inhibited thermal hyperalgesia induced by UV irradiation (1 and 3 mg/kg p.o.) and the late phase of nociceptive response to formalin in rats (10 and 30 mg/kg p.o.). Finally, SSR240612 (20 and 30 mg/kg p.o.) prevented neuropathic thermal pain induced by sciatic nerve constriction in the rat. In conclusion, SSR240612 is a new, potent, and orally active specific non-peptide bradykinin B(1) receptor antagonist.
Asunto(s)
Analgésicos/farmacología , Antagonistas del Receptor de Bradiquinina B1 , Dioxoles/farmacología , Íleon/efectos de los fármacos , Sulfonamidas/farmacología , Administración Oral , Analgésicos/uso terapéutico , Animales , Células CHO , Cricetinae , Modelos Animales de Enfermedad , Edema/inducido químicamente , Edema/tratamiento farmacológico , Formaldehído , Humanos , Íleon/metabolismo , Masculino , Ratones , Conejos , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión/tratamiento farmacológicoRESUMEN
SSR240600 [(R)-2-(1-[2-[4-[2-[3,5-bis(trifluoromethyl)phenyl]acetyl]-2-(3,4-dichlorophenyl)-2-morpholinyl]ethyl]-4-piperidinyl)-2-methylpropanamide], a new nonpeptide tachykinin neurokinin 1 (NK1) receptor antagonist, was evaluated against the neurochemical, electrophysiological, and behavioral effects provoked by direct activation of brain tachykinin NK1 receptors or by stress in guinea pigs. SSR240600 (0.1-10 mg/kg i.p. or p.o.) antagonized the excitatory effect of i.c.v. infusion of [Sar(9),Met(O2)(11)]substance P (SP) on the release of acetylcholine in the striatum of anesthetized and awake guinea pigs. This antagonistic action was still observed after repeated administration of SSR240600 (5 days, 10 mg/kg p.o., once a day). SSR240600 (10 mg/kg i.p.) inhibited the phosphorylation of the cAMP response element-binding protein in various brain regions induced by i.c.v. administration of [Sar9,Met(O2)(11)]SP. In slice preparations, neuronal firing of the locus coeruleus (LC) neurons elicited by the application of [Sar9,Met(O2)(11)]SP was suppressed by SSR240600 at 100 nM. Norepinephrine release in the prefrontal cortex, elicited either by an intra-LC application of [Sar9,Met(O2)(11)]SP or by an i.c.v administration of corticotropin-releasing factor, was reduced by SSR240600 (0.3-1 mg/kg and 1-10 mg/kg i.p., respectively). SSR240600 (1-10 mg/kg i.p.) inhibited vocalizations induced in adult guinea pigs by an i.c.v. administration of the NK1 receptor agonist, GR73632 [D-Ala-[L-Pro9,Me-Leu8]substance P(7-11)]. Furthermore, SSR240600 (1-10 mg/kg i.p.) inhibited distress vocalizations produced in guinea pig pups by maternal separation. SSR240600 also reduced maternal separation-induced increase in the number of neurons displaying NK1 receptor internalization in the amygdala. Finally, SSR240600 counteracted the increase in body temperature induced by isolation stress. In conclusion, SSR240600 is able to antagonize various NK1 receptor-mediated as well as stress-mediated effects in the guinea pig.