RESUMEN
The objective of the present study was to examine the idea that the decrease in 50-kHz ultrasonic vocalizations elicited by tickling in juvenile rats following the administration of the psychotomimetic drug phencyclidine (PCP) may represent a valid model of the negative symptoms of schizophrenia. Fifty-kilohertz calls in rodents have been suggested to represent an archaic model of human laughter. Our results showed that daily tickling sessions produced a gradual increase in 50-kHz vocalizations, an effect that reached statistical significance from day 3. Administration of PCP (1 mg/kg, intraperitoneally) attenuated the 50-kHz calls induced by 4 consecutive days of tickling. The ability of several clinically effective or potential antipsychotics to reverse the effects of PCP was investigated. The 5-HT1A receptor partial agonist, buspirone (0.3 and 1 mg/kg, intraperitoneally), the dual D2/5-HT1A receptor ligand, SSR181507 (0.5-0.75 mg/kg, intraperitoneally), but not the atypical antipsychotic, aripiprazole (0.1-1 mg/kg, intraperitoneally), the 5-HT2A receptor antagonist, eplivanserin (0.3-3 mg/kg, intraperitoneally), and the GlyT1 inhibitor, SSR103800 (0.3-3 mg/kg, intraperitoneally) significantly attenuated the effects of PCP on 50-kHz calls. Importantly, in animals not treated with PCP, none of the drugs affected 50-kHz calls elicited by a first handling-tickling session, indicating that the action of buspirone and SSR181507 cannot be explained by an intrinsic effect. To investigate further the specificity of these drug effects, we tested the anxiolytic and antidepressant agents, diazepam (0.1-1 mg/kg, intraperitoneally) and fluoxetine (1-10 mg/kg, intraperitoneally), respectively, in this procedure. Neither drug affected tickling-induced 50-kHz calls in naive or PCP-treated rats. In conclusion, the results of the present study confirm that 50-kHz calls elicited by several tickling sessions in rats can be reduced by acute administration of PCP, and that this effect can be reversed by previous administration of compounds with 5-HT1A receptor agonist properties. As evidence for clinical efficacy of both agents on the negative symptoms of schizophrenia is weak or lacking, the current findings do not allow a definite conclusion to be drawn on the validity of this procedure as a model of this aspect of schizophrenia.
Asunto(s)
Alucinógenos/farmacología , Fenciclidina/farmacología , Esquizofrenia/tratamiento farmacológico , Vocalización Animal/efectos de los fármacos , Animales , Ansiolíticos/administración & dosificación , Ansiolíticos/farmacología , Antipsicóticos/administración & dosificación , Antipsicóticos/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Masculino , Ratas , Ratas Sprague-Dawley , Esquizofrenia/fisiopatología , UltrasonidoRESUMEN
Previous studies have shown that compound 1 displayed high affinity towards histamine H3 receptor (H3R), (human (h-H3R), K(i)=8.6 nM, rhesus monkey (rh-H3R), K(i)=1.2 nM, and rat (r-H3R), K(i)=16.5 nM), but exhibited high affinity for hERG channel. Herein, we report the discovery of a novel, potent, and highly selective H3R antagonist/inverse agonist 5a(SS) (SAR110068) with acceptable hERG channel selectivity and desirable pharmacological and pharmacokinetic properties through lead optimization sequence. The significant awakening effects of 5a(SS) on sleep-wake cycles studied by using EEG recording in rats during their light phase support its potential therapeutic utility in human sleep-wake disorders.
Asunto(s)
Antagonistas de los Receptores Histamínicos H3/farmacología , Piranos/farmacología , Pirrolidinas/farmacología , Trastornos del Sueño del Ritmo Circadiano/tratamiento farmacológico , Administración Oral , Animales , Perros , Estabilidad de Medicamentos , Cobayas , Haplorrinos , Antagonistas de los Receptores Histamínicos H3/química , Antagonistas de los Receptores Histamínicos H3/farmacocinética , Humanos , Masculino , Ratones , Piranos/química , Piranos/farmacocinética , Pirrolidinas/química , Pirrolidinas/farmacocinética , Conejos , Ratas , Ratas Sprague-Dawley , Receptores Histamínicos H3/química , Receptores Histamínicos H3/metabolismo , Ovinos , Trastornos del Sueño del Ritmo Circadiano/metabolismo , Especificidad por SustratoRESUMEN
Glycogen synthase kinase 3 (GSK3) has been identified as a promising target for the treatment of Alzheimer's disease (AD), where abnormal activation of this enzyme has been associated with hyperphosphorylation of tau proteins. This study describes the effects of the selective GSK3 inhibitor, SAR502250, in models of neuroprotection and neuropsychiatric symptoms (NPS) associated with AD. In P301L human tau transgenic mice, SAR502250 attenuated tau hyperphosphorylation in the cortex and spinal cord. SAR502250 prevented the increase in neuronal cell death in rat embryonic hippocampal neurons following application of the neurotoxic peptide, Aß25-35. In behavioral studies, SAR502250 improved the cognitive deficit in aged transgenic APP(SW)/Tau(VLW) mice or in adult mice after infusion of Aß25-35. It attenuated aggression in the mouse defense test battery and improved depressive-like state of mice in the chronic mild stress procedure after 4 weeks of treatment. Moreover, SAR502250 decreased hyperactivity produced by psychostimulants. In contrast, the drug failed to modify anxiety-related behaviors or sensorimotor gating deficit. This profile confirms the neuroprotective effects of GSK3 inhibitors and suggests an additional potential in the treatment of some NPS associated with AD.
Asunto(s)
Agresión/efectos de los fármacos , Enfermedad de Alzheimer/tratamiento farmacológico , Disfunción Cognitiva/tratamiento farmacológico , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Fármacos Neuroprotectores/farmacología , Enfermedad de Alzheimer/complicaciones , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Animales , Apoptosis/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Células Cultivadas , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/patología , Disfunción Cognitiva/etiología , Disfunción Cognitiva/patología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos , Femenino , Humanos , Masculino , Ratones , Ratones Transgénicos , Neuronas/efectos de los fármacos , Neuronas/patología , Fármacos Neuroprotectores/uso terapéutico , Fosforilación/efectos de los fármacos , Cultivo Primario de Células , Ratas , Médula Espinal/efectos de los fármacos , Médula Espinal/patología , Proteínas tau/genética , Proteínas tau/metabolismoRESUMEN
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
The involvement of the noradrenergic system, particularly the beta1 and beta2 receptors, in depressive disorders has been frequently shown. Recently, however, it has been shown that the beta3 receptor may also contribute since amibegron (SR58611A), a selective beta3 receptor agonist, has antidepressant-like effects. The present experiment sought to confirm the antidepressant potential of amibegron by studying its effects in an animal model of depression, the Flinders Sensitive Line (FSL) rat. The FSL rat is innately highly immobile in the forced swim test and exhibits a decrease in immobility after chronic, not acute antidepressant treatment. FSL rats were treated for 14 consecutive days with amibegron (0.3, 1.0, or 3.0 mg/kg), fluoxetine (5 mg/kg) or desipramine (5 mg/kg) as positive controls, and vehicle, while the control strain, the Flinders Resistant Line (FRL) rats, was given either vehicle or 1.0 mg/kg amibegron. About 23-25 h after the last injection the rats were tested in the forced swim test. All doses of amibegron and the two active controls, fluoxetine and desipramine, significantly reduced immobility in the FSL rats. Thus, amibegron had a selective antidepressant-like effect in this study, confirming its antidepressant potential.
Asunto(s)
Agonistas Adrenérgicos beta/farmacología , Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Tetrahidronaftalenos/farmacología , Agonistas de Receptores Adrenérgicos beta 3 , Animales , Conducta Animal/efectos de los fármacos , Depresión/psicología , Modelos Animales de Enfermedad , Actividad Motora/efectos de los fármacos , Ratas , Conducta SocialRESUMEN
Central tachykinins have been shown to play a role in the modulation of stress-related behaviours. Saredutant, a tachykinin NK2 receptor antagonist, displayed mixed anxiolytic- and antidepressant-like activities in rodents. The present study aimed at further characterizing its psychotropic properties. Saredutant was tested in the rat social interaction test to further confirm its anxiolytic-like activity, and in a variety of behavioural models sensitive to antidepressant drugs. In the rat social interaction test, saredutant (20 mg/kg, i.p.) significantly increased the time spent in interaction, as did the prototypical anxiolytic agents, diazepam (1 mg/kg, i.p.) and buspirone (1 mg/kg, s.c.), but not the antidepressant, fluoxetine. In a differential reinforcement of low rate-72s task, saredutant (3 mg/kg, i.p.) displayed an antidepressant-like activity by increasing reinforced response rate and percentage of responses emitted in the inter-response time bin [49-96 s]. In bulbectomized rats, saredutant (20 mg/kg, i.p.) restored the deficit of acquisition of passive avoidance. In rat pups separated from their mother, saredutant (3-10 mg/kg, s.c.) reduced ultrasonic distress calls. Finally, in the chronic mild stress paradigm in mice, a 29-day treatment regimen with saredutant (10 mg/kg, i.p.) attenuated stress-induced physical degradation. Importantly, in the depression models, the effects of saredutant were comparable to those obtained under similar experimental conditions by reference antidepressants such as fluoxetine or imipramine. Together, these results suggest further that the NK2 receptor may represent an attractive target for the treatment of both depressive and anxiety disorders.
Asunto(s)
Ansiolíticos , Antidepresivos , Benzamidas/farmacología , Piperidinas/farmacología , Receptores de Neuroquinina-2/antagonistas & inhibidores , Animales , Antidepresivos Tricíclicos/farmacología , Ansiedad de Separación/psicología , Reacción de Prevención/efectos de los fármacos , Conducta Animal/efectos de los fármacos , Condicionamiento Operante/efectos de los fármacos , Interpretación Estadística de Datos , Femenino , Imipramina/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Bulbo Olfatorio/fisiología , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Esquema de Refuerzo , Aislamiento Social , Vocalización Animal/efectos de los fármacosRESUMEN
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
Enhancing endogenous cannabinoid (eCB) signaling has been considered as a potential strategy for the treatment of stress-related conditions. Fatty acid amide hydrolase (FAAH) represents the primary degradation enzyme of the eCB anandamide (AEA), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). This study describes a potent reversible FAAH inhibitor, SSR411298. The drug acts as a selective inhibitor of FAAH, which potently increases hippocampal levels of AEA, OEA and PEA in mice. Despite elevating eCB levels, SSR411298 did not mimic the interoceptive state or produce the behavioral side-effects (memory deficit and motor impairment) evoked by direct-acting cannabinoids. When SSR411298 was tested in models of anxiety, it only exerted clear anxiolytic-like effects under highly aversive conditions following exposure to a traumatic event, such as in the mouse defense test battery and social defeat procedure. Results from experiments in models of depression showed that SSR411298 produced robust antidepressant-like activity in the rat forced-swimming test and in the mouse chronic mild stress model, restoring notably the development of inadequate coping responses to chronic stress. This preclinical profile positions SSR411298 as a promising drug candidate to treat diseases such as post-traumatic stress disorder, which involves the development of maladaptive behaviors.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Ansiolíticos/farmacología , Trastornos de Ansiedad/tratamiento farmacológico , Agonistas de Receptores de Cannabinoides/metabolismo , Carbamatos/farmacología , Dioxanos/farmacología , Inhibidores Enzimáticos/farmacología , Receptores de Cannabinoides/genética , Estrés Psicológico/tratamiento farmacológico , Enfermedad Aguda , Amidas , Amidohidrolasas/genética , Amidohidrolasas/metabolismo , Animales , Ansiolíticos/síntesis química , Trastornos de Ansiedad/fisiopatología , Ácidos Araquidónicos/metabolismo , Carbamatos/síntesis química , Enfermedad Crónica , Dioxanos/síntesis química , Endocannabinoides/metabolismo , Inhibidores Enzimáticos/síntesis química , Etanolaminas/metabolismo , Femenino , Expresión Génica , Masculino , Ratones , Ácidos Oléicos/metabolismo , Ácidos Palmíticos/metabolismo , Alcamidas Poliinsaturadas/metabolismo , Ratas Sprague-Dawley , Receptores de Cannabinoides/metabolismo , Estrés Psicológico/fisiopatologíaRESUMEN
SSR180711 (4-bromophenyl 1,4diazabicyclo(3.2.2) nonane-4-carboxylate, monohydrochloride) is a selective alpha7 nicotinic receptor (n-AChR) partial agonist. Based on the purported implication of this receptor in cognitive deficits associated with schizophrenia, the present study assessed efficacy of SSR180711 (i.p. and p.o.) in different types of learning and memory involved in this pathology. SSR180711 enhanced episodic memory in the object recognition task in rats and mice (MED: 0.3 mg/kg), an effect mediated by the alpha7 n-AChR, as it was no longer seen in mice lacking this receptor. Efficacy was retained after repeated treatment (eight administrations over 5 days, 1 mg/kg), indicating lack of tachyphylaxia. SSR180711 also reversed (MED: 0.3 mg/kg) MK-801-induced deficits in retention of episodic memory in rats (object recognition). The drug reversed (MED: 0.3 mg/kg) selective attention impaired by neonatal phencyclidine (PCP) treatment and restored MK-801- or PCP-induced memory deficits in the Morris or linear maze (MED: 1-3 mg/kg). In neurochemical and electrophysiological correlates of antipsychotic drug action, SSR180711 increased extracellular levels of dopamine in the prefrontal cortex (MED: 1 mg/kg) and enhanced (3 mg/kg) spontaneous firing of retrosplenial cortex neurons in rats. Selectivity of SSR180711 was confirmed as these effects were abolished by methyllycaconitine (3 mg/kg, i.p. and 1 mg/kg, i.v., respectively), a selective alpha7 n-AChR antagonist. Additional antidepressant-like properties of SSR180711 were demonstrated in the forced-swimming test in rats (MED: 1 mg/kg), the maternal separation-induced ultrasonic vocalization paradigm in rat pups (MED: 3 mg/kg) and the chronic mild stress procedure in mice (10 mg/kg o.d. for 3 weeks). Taken together, these findings characterize SSR180711 as a promising new agent for the treatment of cognitive symptoms of schizophrenia. The antidepressant-like properties of SSR180711 are of added interest, considering the high prevalence of depressive symptoms in schizophrenic patients.
Asunto(s)
Trastornos del Conocimiento/tratamiento farmacológico , Agonistas Nicotínicos/uso terapéutico , Receptores Nicotínicos/fisiología , Análisis de Varianza , Animales , Animales Recién Nacidos , Conducta Animal/efectos de los fármacos , Trastornos del Conocimiento/etiología , Modelos Animales de Enfermedad , Maleato de Dizocilpina/farmacología , Dopamina/metabolismo , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Interacciones Farmacológicas , Antagonistas de Aminoácidos Excitadores/farmacología , Conducta Exploratoria/efectos de los fármacos , Femenino , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fenciclidina/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Nicotínicos/deficiencia , Reconocimiento en Psicología/efectos de los fármacos , Esquizofrenia/complicaciones , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
In this paper, we report on the pharmacological and functional profile of SSR180711 (1,4-Diazabicyclo[3.2.2]nonane-4-carboxylic acid, 4-bromophenyl ester), a new selective alpha7 acetylcholine nicotinic receptor (n-AChRs) partial agonist. SSR180711 displays high affinity for rat and human alpha7 n-AChRs (K(i) of 22+/-4 and 14+/-1 nM, respectively). Ex vivo (3)[H]alpha-bungarotoxin binding experiments demonstrate that SSR180711 rapidly penetrates into the brain (ID(50)=8 mg/kg p.o.). In functional studies performed with human alpha7 n-AChRs expressed in Xenopus oocytes or GH4C1 cells, the compound shows partial agonist effects (intrinsic activity=51 and 36%, EC(50)=4.4 and 0.9 microM, respectively). In rat cultured hippocampal neurons, SSR180711 induced large GABA-mediated inhibitory postsynaptic currents and small alpha-bungarotoxin sensitive currents through the activation of presynaptic and somato-dendritic alpha7 n-AChRs, respectively. In mouse hippocampal slices, the compound increased the amplitude of both glutamatergic (EPSCs) and GABAergic (IPSCs) postsynaptic currents evoked in CA1 pyramidal cells. In rat and mouse hippocampal slices, a concentration of 0.3 muM of SSR180711 increased long-term potentiation (LTP) in the CA1 field. Null mutation of the alpha7 n-AChR gene totally abolished SSR180711-induced modulation of EPSCs, IPSCs and LTP in mice. Intravenous administration of SSR180711 strongly increased the firing rate of single ventral pallidum neurons, extracellularly recorded in anesthetized rats. In microdialysis experiments, administration of the compound (3-10 mg/kg i.p.) dose-dependently increased extracellular acetylcholine (ACh) levels in the hippocampus and prefrontal cortex of freely moving rats. Together, these results demonstrate that SSR180711 is a selective and partial agonist at human, rat and mouse alpha7 n-AChRs, increasing glutamatergic neurotransmission, ACh release and LTP in the hippocampus.
Asunto(s)
Agonistas Nicotínicos/farmacología , Agonistas Nicotínicos/farmacocinética , Receptores Nicotínicos/fisiología , Animales , Animales Recién Nacidos , Sitios de Unión/efectos de los fármacos , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Células Cultivadas , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Expresión Génica/efectos de los fármacos , Expresión Génica/fisiología , Hipocampo/citología , Humanos , Técnicas In Vitro , Potenciales de la Membrana/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuronas/efectos de los fármacos , Neuronas/fisiología , Agonistas Nicotínicos/química , Antagonistas Nicotínicos/farmacología , Oocitos/fisiología , Técnicas de Placa-Clamp/métodos , Subunidades de Proteína/efectos de los fármacos , Subunidades de Proteína/fisiología , Ratas , Ratas Sprague-Dawley , Receptores Nicotínicos/deficiencia , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiología , Receptor Nicotínico de Acetilcolina alfa 7 , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
The vasopressin 1b receptor antagonist, SSR149415, and the corticotropin-releasing factor 1 receptor antagonist, SSR125543, are orally active non-peptidic compounds with anxiolytic- and antidepressant-like activities in animal models. Presently, SSR149415 and SSR125543 were evaluated in a differential reinforcement of low-rate 72 s (DRL-72 s) schedule, a procedure known to respond differentially to antidepressants and anxiolytics. Male Wistar rats were trained to lever-press for food reinforcement, but only lever-presses occurring after a 72 s delay were reinforced; otherwise, presses were not rewarded, and the timer was reset to 0 s. The selective serotonin reuptake inhibitor, fluoxetine, and the benzodiazepine anxiolytic, diazepam, were tested in parallel. SSR149415 (10-30 mg/kg, i.p.) and SSR125543 (30 mg/kg, i.p.) increased the percentage of responses emitted in the inter-response time (IRT) bin (49-96 s), which resulted in a greater number of reinforced presses. Both compounds shifted the frequency distribution of responses toward longer IRT durations, with a preservation of the bell shape of the IRT distribution curve. Fluoxetine (10 mg/kg, i.p.) had an effect on DRL-72 s similar to that of SSR149415 and SSR125543. By contrast, diazepam increased the number of responses in IRT bin (0-12 s), and the IRT distribution curve was shifted toward shorter IRT durations and flattened. In summary, these results show that SSR149415 and SSR125543 displayed antidepressant-like activity in a DRL-72 s schedule in rat, confirming their therapeutic potential for the treatment of pathological states induced by chronic frustration such as depression.
Asunto(s)
Antagonistas de los Receptores de Hormonas Antidiuréticas , Condicionamiento Operante/efectos de los fármacos , Hidrocarburos Halogenados/farmacología , Indoles/farmacología , Pirrolidinas/farmacología , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Refuerzo en Psicología , Tiazinas/farmacología , Animales , Ansiolíticos/farmacología , Conducta Animal/efectos de los fármacos , Diazepam/farmacología , Fluoxetina/farmacología , Masculino , Ratas , Ratas Wistar , Esquema de Refuerzo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
Brief exposure of mice to unavoidable predatory stimuli is associated with behavioral and neurochemical changes consistent with increased anxiety and produces short-term impaired learning restored by acute fluoxetine treatment, but not by diazepam. The present study investigated long-lasting changes induced by a unique unavoidable cat exposure in BALB/c mice on learning abilities using learning tests (radial maze, spatial configuration of objects recognition test). Results from the group comparison showed that predatory exposure induced significant learning disabilities in the radial maze (16 to 22 days poststressor) and in the spatial configuration of objects recognition test (26 to 28 days poststressor). These findings indicate that memory impairments may persist for extended periods beyond a predatory stress. This animal model of unique exposure of mice to unavoidable predatory stimuli has proven to be a useful model for the study of reactions to traumatic stress.
Asunto(s)
Aprendizaje por Laberinto/fisiología , Trastornos de la Memoria/psicología , Memoria/fisiología , Estrés Psicológico/fisiopatología , Animales , Masculino , Trastornos de la Memoria/etiología , Ratones , Ratones Endogámicos BALB C , Conducta Predatoria/fisiología , Distribución Aleatoria , Conducta Espacial/fisiología , Estadísticas no Paramétricas , Estrés Psicológico/complicaciones , Estrés Psicológico/psicología , Factores de TiempoRESUMEN
Normalization of altered glutamate neurotransmission through activation of the mGluR2 has emerged as a new approach to treat schizophrenia. These studies describe a potent brain penetrant mGluR2 positive allosteric modulator (PAM), SAR218645. The compound behaves as a selective PAM of mGluR2 in recombinant and native receptor expression systems, increasing the affinity of glutamate at mGluR2 as inferred by competition and GTPγ35S binding assays. SAR218645 augmented the mGluR2-mediated response to glutamate in a rat recombinant mGluR2 forced-coupled Ca2+ mobilization assay. SAR218645 potentiated mGluR2 agonist-induced contralateral turning. When SAR218645 was tested in models of the positive symptoms of schizophrenia, it reduced head twitch behavior induced by DOI, but it failed to inhibit conditioned avoidance and hyperactivity using pharmacological and transgenic models. Results from experiments in models of the cognitive symptoms associated with schizophrenia showed that SAR218645 improved MK-801-induced episodic memory deficits in rats and attenuated working memory impairment in NMDA Nr1neo-/- mice. The drug reversed disrupted latent inhibition and auditory-evoked potential in mice and rats, respectively, two endophenotypes of schizophrenia. This profile positions SAR218645 as a promising candidate for the treatment of cognitive symptoms of patients with schizophrenia, in particular those with abnormal attention and sensory gating abilities.
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Atención/efectos de los fármacos , Trastornos del Conocimiento/tratamiento farmacológico , Cognición/efectos de los fármacos , Indanos/farmacología , Memoria/efectos de los fármacos , Oxazoles/farmacología , Pirimidinas/farmacología , Receptores AMPA/química , Esquizofrenia/tratamiento farmacológico , Sitio Alostérico , Anfetaminas/farmacología , Animales , Calcio/metabolismo , Corteza Cerebral/metabolismo , AMP Cíclico/metabolismo , Maleato de Dizocilpina/química , Maleato de Dizocilpina/farmacología , Terapia Electroconvulsiva , Células HEK293 , Humanos , Indanos/uso terapéutico , Masculino , Aprendizaje por Laberinto , Memoria a Corto Plazo/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Oxazoles/uso terapéutico , Fenotipo , Pirimidinas/uso terapéutico , Ratas , Ratas Sprague-DawleyRESUMEN
The health burden of stress-related diseases, including depression and anxiety disorders, is rapidly increasing, whereas the range of available pharmacotherapies to treat these disorders is limited and suboptimal with regard to efficacy and tolerability. Recent findings support a major role for neuropeptides in mediating the response to stress and thereby identify neuropeptide systems as potential novel therapeutic targets for the treatment of depression and anxiety disorders. In preclinical models, pharmacological and/or genetic manipulation of substance P, corticotropin-releasing factor (CRF), vasopressin, neuropeptide Y and galanin function alters anxiety- and depression-related responses. Recently, specific and highly potent small-molecule neuropeptide receptor agonists and antagonists have been developed that can readily cross the blood-brain barrier. Clinical assessment of several compounds is currently underway, with antidepressant efficacy confirmed in double-blind, placebo-controlled trials of tachykinin NK(1) (substance P) receptor antagonists, and preliminary evidence of antidepressant activity in an open-label trial of a CRF(1) receptor antagonist.
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Trastornos de Ansiedad/tratamiento farmacológico , Trastorno Depresivo/tratamiento farmacológico , Receptores de Neuropéptido/agonistas , Receptores de Neuropéptido/antagonistas & inhibidores , Animales , Antagonistas de los Receptores de Hormonas Antidiuréticas , Trastornos de Ansiedad/metabolismo , Ensayos Clínicos como Asunto , Trastorno Depresivo/metabolismo , Humanos , Antagonistas del Receptor de Neuroquinina-1 , Receptores de Hormona Liberadora de Corticotropina/agonistas , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Receptores de Galanina/agonistas , Receptores de Galanina/antagonistas & inhibidores , Receptores de Galanina/metabolismo , Receptores de Neuroquinina-1/agonistas , Receptores de Neuroquinina-1/metabolismo , Receptores de Neuropéptido/metabolismo , Receptores de Neuropéptido Y/agonistas , Receptores de Neuropéptido Y/antagonistas & inhibidores , Receptores de Neuropéptido Y/metabolismo , Receptores de Vasopresinas/agonistas , Receptores de Vasopresinas/metabolismoRESUMEN
BACKGROUND: The endocannabinoid system has been implicated in the modulation of emotional processes. METHODS: These experiments aimed to investigate the effects of the cannabinoid CB1 receptor antagonist rimonabant (SR141716) in animal models measuring aspects of emotional reactivity and depression. RESULTS: Rimonabant had weak anxiolytic-like activity in the elevated plus-maze and failed to affect flight and risk assessment activities in the mouse defense test battery (MDTB). It produced clear anxiolytic-like effects in the Vogel conflict test (.3-3 mg/kg intraperitoneal [i.p.]) and on defensive aggression in the MDTB (1 and 10 mg/kg, i.p.). The effects of rimonabant in the MDTB paralleled those observed with CB1 receptor knockout mice in this procedure. In the forced-swimming test in rats and the tonic immobility paradigm in gerbils, rimonabant (3 and 10 mg/kg per os [p.o.]) produced antidepressant-like effects that were comparable to those observed with the reference antidepressant, fluoxetine. In the chronic mild stress model in mice, repeated administration of rimonabant (10 mg/kg, p.o.) for 5 weeks improved the deleterious effects produced by stress. CONCLUSIONS: These findings point further to a role for the endocannabinoid system in the modulation of emotional processes and suggest that it may be primarily involved in the adaptive responses to unavoidable stressful stimuli.
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Conducta Animal/efectos de los fármacos , Emociones/efectos de los fármacos , Modelos Animales , Piperidinas/farmacología , Pirazoles/farmacología , Receptor Cannabinoide CB1/antagonistas & inhibidores , Agresión/efectos de los fármacos , Análisis de Varianza , Animales , Ansiolíticos/farmacología , Antidepresivos de Segunda Generación/uso terapéutico , Depresión/tratamiento farmacológico , Diazepam/farmacología , Relación Dosis-Respuesta a Droga , Electrochoque/efectos adversos , Fluoxetina/uso terapéutico , Gerbillinae , Pérdida de Tono Postural/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Pruebas Neuropsicológicas , Piperidinas/uso terapéutico , Pirazoles/uso terapéutico , Ratas , Ratas Wistar , RimonabantRESUMEN
Since vasopressin has been shown to be critical for adaptation of the hypothalamo-pituitary-adrenal axis during stress through its ability to potentiate the stimulatory effect of CRF, it has been hypothesized that this peptide may provide a good opportunity for pharmacological treatment of stress-related disorders. The availability of the first orally active non-peptide V(1b) receptor antagonist, SSR149415, opened a new era for examining the role of vasopressin in animal models of anxiety and depression. In rats, SSR149415 blocked several endocrine (i.e. ACTH release), neurochemical (i.e. noradrenaline release) and autonomic (i.e. hyperthermia) responses following various stress exposures. Moreover, the drug was able to attenuate some but not all stress-related behaviors in rodents. While the antidepressant-like activity of the compound was comparable to that of reference antidepressants, the overall profile displayed in anxiety tests was different from that of classical anxiolytics, such as benzodiazepines. These latter were highly effective and reliably produced robust effects in most anxiety tests, while SSR149415 showed clear-cut effects only in particularly stressful situations. Experiments with mice or hamsters indicated that V(1b) receptor blockade is associated with reduced aggressiveness, suggesting that SSR149415 could prove useful for treating aggressive behavior. It is important to note that SSR149415 is devoid of adverse effects on motor functions or cognitive processes, and it did not produce tolerance to its anxiolytic- or antidepressant-like activity. Altogether, these findings suggest that V(1b) receptor antagonists represent a promising alternative to agents currently used for the treatment of depression and some forms of anxiety disorders.
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Antidepresivos/farmacología , Antagonistas de los Receptores de Hormonas Antidiuréticas , Ansiedad/tratamiento farmacológico , Depresión/tratamiento farmacológico , Indoles/uso terapéutico , Pirrolidinas/uso terapéutico , Agresión/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Humanos , Indoles/farmacología , Pirrolidinas/farmacología , Ratas , Receptores de Vasopresinas/análisisRESUMEN
Previous experiments with the first selective nonpeptide vasopressin V1b receptor antagonist SSR149415 ((2S, 4R)-1-[5-chloro-1-[(2,4-dimethoxyphenyl)sulfonyl]-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-4-hydroxy-N,N-dimethyl-2-pyrrolidinecarboxamide) have shown that the drug elicits anxiolytic- and antidepressant-like effects following systemic administration. Extrahypothalamic V1b receptors have been suggested to be involved in these effects as evidenced by the findings that hypophysectomized rats were still sensitive to the antistress action of SSR149415. The first objective of the present work aimed at locating V1b receptors in the rat limbic brain using anti-V1b receptor immunohistochemistry. The immunolabeling revealed high densities of V1b receptors in the lateral septum, the amygdala, the bed nucleus of the stria terminalis, the hippocampal formation, and in several cortical areas. Since the lateral septum is well known to participate in the modulation of emotional processes, the second objective of this study went on to evaluate the behavioral effects of an infusion of SSR149415 into the lateral septum and to determine whether its behavioral effects are mediated by this structure. Animals were tested in models classically used for the screening of anxiolytics (ie the punished drinking and elevated plus-maze tests) and antidepressants (ie the forced-swimming test). Bilateral intraseptal infusion of SSR149415 (10 and 100 ng) produced a decrease in immobility time in the forced-swimming test, indicating antidepressant-like effects. In contrast, the behavior of rats in the punished drinking procedure or in the elevated plus-maze test was not modified by intraseptal infusion of SSR149415. These findings suggest that V1b receptors located in the lateral septum participate in the antidepressant- but not the anxiolytic-like action of SSR149415 in rats.
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Antidepresivos/farmacología , Antagonistas de los Receptores de Hormonas Antidiuréticas , Lateralidad Funcional/fisiología , Indoles/farmacología , Pirrolidinas/farmacología , Tabique del Cerebro/fisiología , Animales , Ansiedad/psicología , Encéfalo/anatomía & histología , Química Encefálica , Ingestión de Líquidos/efectos de los fármacos , Inmunohistoquímica , Indoles/administración & dosificación , Masculino , Microinyecciones , Neostriado , Pirrolidinas/administración & dosificación , Ratas , Ratas Sprague-Dawley , Natación/psicologíaRESUMEN
Conditioned stimuli are important for nicotine dependence and may trigger craving and relapse after prolonged nicotine abstinence. However, little is known about the pharmacology of this process. Among the systems that have been shown to play a role in drug-seeking behavior is the endocannabinoid transmission. Therefore, the present study examined the resistance to extinction of drug-seeking behavior elicited by nicotine-associated environmental stimuli and the effects of the selective CB1 cannabinoid antagonist rimonabant (SR141716) on the reinforcing effects of nicotine-related stimuli. Rats were trained to self-administer nicotine (0.03 mg/kg/injection, i.v.) under conditions in which responding was reinforced jointly by response-contingent nicotine injections and stimuli (light and tone). After self-administration acquisition, nicotine was withdrawn and lever pressing was only reinforced by contingent presentation of the audiovisual stimuli. Under such a condition, responding persisted for 3 months, following which nonpresentation of the cues produced a progressive extinction of responding. As expected, rats trained to lever-press for saline injections paired with the audiovisual stimuli did not acquire the self-administration. These findings indicate that the cues required learned association with nicotine to acquire reinforcing properties and to function as conditioned reinforcers. When administered 1 month following nicotine withdrawal, rimonabant (1 mg/kg, i.p.) decreased conditioned behavior. These results showing the persistence of a nicotine-conditioned behavior are congruent with the role of nicotine-related environmental stimuli in nicotine craving in abstinent smokers. Rimonabant, which has been shown previously to reduce nicotine self-administration, may be effective not only as an aid for smoking cessation but also in the maintenance of abstinence.
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Señales (Psicología) , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Piperidinas/farmacología , Pirazoles/farmacología , Receptor Cannabinoide CB1/antagonistas & inhibidores , Síndrome de Abstinencia a Sustancias/psicología , Tabaquismo/psicología , Estimulación Acústica , Animales , Dopamina/fisiología , Ambiente , Extinción Psicológica/efectos de los fármacos , Luz , Masculino , Motivación , Actividad Motora/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Rimonabant , Autoadministración , Transmisión Sináptica/efectos de los fármacosRESUMEN
In the present study, we investigated whether mice lacking the arginine vasopressin (AVP) V1b receptor (V1bR) exhibit deficits of prepulse inhibition (PPI) of the startle reflex, reminiscent of the sensorimotor gating deficits observed in a large majority of schizophrenic patients. V1bR knockout (KO) mice displayed significantly reduced levels of PPI of the startle reflex. In addition to PPI deficits, V1bR KO mice showed increased acoustic startle response. However, acoustic startle response was not significantly correlated to the PPI of the startle reflex in V1bR KO mice. V1bR KO mice also showed a decrease in basal levels of extracellular dopamine (DA) in the medial prefrontal cortex, which is thought to be an important brain region for PPI. Moreover, PPI deficits observed in the V1bR KO mice are significantly reversed by atypical antipsychotics such as risperidone and clozapine but not by a typical neuroleptic haloperidol, like in schizophrenic patients. By contrast, we did not observe any significant differences between V1bR KO mice and wild-type mice in the open-field, light/dark, elevated plus maze, and forced swimming tests. The results of the present study indicate that V1bR may be involved in the regulation of PPI of the startle reflex. The V1bR has been considered an important molecular target for the development of antipsychotic drugs.