RESUMEN
Schizophrenia is a highly familial, neurodevelopmental disorder that is associated with several neuropsychiatric, psychological, and neuropathological features. Although pharmacological animal models of dopaminergic and glutamatergic dysfunction have helped advance our understanding of the disease biology, there is a clear need for translational models that capture the neuropathological and functional manifestations associated with the intermediate phenotype and the clinical illness. Neuroimaging of preclinical neurodevelopmental approaches such as methylazoxymethanol acetate (MAM) exposure may afford a powerful translational tool to establish endpoints with greater congruency across animals and humans. Using in vivo volumetric magnetic resonance imaging (MRI), manganese-enhanced MRI, and diffusion tensor imaging (DTI), we investigated morphological and cytoarchitectural changes of brain structures in MAM-exposed rats, a neurodevelopmental model of schizophrenia. Compared to saline-exposed controls, MAM-exposed rats showed significant enlargement of lateral and third ventricles as well as reduced hippocampal volumes, which is consistent with findings observed in schizophrenia. In addition, DTI revealed that diffusion fractional anisotropy retrieved from corpus callosum and cingulum were significantly decreased in MAM-exposed rats, suggesting that demyelination occurred in these white-matter fiber tracts. Imaging findings were confirmed by conducting histological analysis using hematoxylin and eosin and Luxol fast blue stainings. In summary, structural abnormalities resulting from a MAM environmental challenge parallel cerebral pathology observed in schizophrenia. The MAM model incorporating noninvasive imaging techniques may therefore serve as an improved translational research tool for assessing new treatments for schizophrenia.
Asunto(s)
Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/patología , Acetato de Metilazoximetanol/toxicidad , Neurotoxinas/toxicidad , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Factores de Edad , Animales , Animales Recién Nacidos , Mapeo Encefálico , Corteza Cerebral/crecimiento & desarrollo , Ventrículos Cerebrales/crecimiento & desarrollo , Ventrículos Cerebrales/patología , Cuerpo Calloso/crecimiento & desarrollo , Cuerpo Calloso/patología , Imagen de Difusión por Resonancia Magnética , Femenino , Hipocampo/crecimiento & desarrollo , Hipocampo/patología , Imagen por Resonancia Magnética/métodos , Masculino , Embarazo , Ratas , Ratas Sprague-DawleyRESUMEN
The alpha7 nicotinic acetylcholine receptor (nAChR) plays an important role in cognitive processes and may represent a drug target for treating cognitive deficits in neurodegenerative and psychiatric disorders. In the present study, we used a novel alpha7 nAChR-selective agonist, 2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole (A-582941) to interrogate cognitive efficacy, as well as examine potential cellular mechanisms of cognition. Exhibiting high affinity to native rat (Ki = 10.8 nM) and human (Ki = 16.7 nM) alpha7 nAChRs, A-582941 enhanced cognitive performance in behavioral assays including the monkey delayed matching-to-sample, rat social recognition, and mouse inhibitory avoidance models that capture domains of working memory, short-term recognition memory, and long-term memory consolidation, respectively. In addition, A-582941 normalized sensory gating deficits induced by the alpha7 nAChR antagonist methyllycaconitine in rats, and in DBA/2 mice that exhibit a natural sensory gating deficit. Examination of signaling pathways known to be involved in cognitive function revealed that alpha7 nAChR agonism increased extracellular-signal regulated kinase 1/2 (ERK1/2) phosphorylation in PC12 cells. Furthermore, increases in ERK1/2 and cAMP response element-binding protein (CREB) phosphorylation were observed in mouse cingulate cortex and/or hippocampus after acute A-582941 administration producing plasma concentrations in the range of alpha7 binding affinities and behavioral efficacious doses. The MEK inhibitor SL327 completely blocked alpha7 agonist-evoked ERK1/2 phosphorylation. Our results demonstrate that alpha7 nAChR agonism can lead to broad-spectrum efficacy in animal models at doses that enhance ERK1/2 and CREB phosphorylation/activation and may represent a mechanism that offers potential to improve cognitive deficits associated with neurodegenerative and psychiatric diseases, such as Alzheimer's disease and schizophrenia.
Asunto(s)
Fármacos del Sistema Nervioso Central/farmacología , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Procesos Mentales/efectos de los fármacos , Receptores Nicotínicos , Aminoacetonitrilo/análogos & derivados , Aminoacetonitrilo/farmacología , Animales , Cognición/efectos de los fármacos , Cognición/fisiología , Humanos , Aprendizaje/efectos de los fármacos , Aprendizaje/fisiología , Macaca mulatta , Masculino , Procesos Mentales/fisiología , Ratones , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Fosforilación , Piridazinas/farmacología , Pirroles/farmacología , Ratas , Transducción de Señal , Resultado del Tratamiento , Xenopus , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
A series of exceptionally potent agonists at neuronal nicotinic acetylcholine receptors (nAChRs) has been investigated. Several N-(3-pyridinyl) derivatives of bridged bicyclic diamines exhibit double-digit-picomolar binding affinities for the alpha 4 beta 2 subtype, placing them with epibatidine among the most potent nAChR ligands described to date. Structure-activity studies have revealed that substitutions, particularly hydrophilic groups in the pyridine 5-position, differentially modulate the agonist activity at ganglionic vs central nAChR subtypes, so that improved subtype selectivity can be demonstrated in vitro. Analgesic efficacy has been achieved across a broad range of pain states, including rodent models of acute thermal nociception, persistent pain, and neuropathic allodynia. Unfortunately, the hydrophilic pyridine substituents that were shown to enhance agonist selectivity for central nAChRs in vitro tend to limit CNS penetration in vivo, so that analgesic efficacy with an improved therapeutic window was not realized with those compounds.
Asunto(s)
Analgésicos/síntesis química , Diaminas/síntesis química , Compuestos Heterocíclicos de Anillo en Puente/síntesis química , Agonistas Nicotínicos/síntesis química , Piridinas/síntesis química , Analgésicos/química , Analgésicos/farmacología , Animales , Unión Competitiva , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Línea Celular , Diaminas/química , Diaminas/farmacología , Dopamina/metabolismo , Compuestos Heterocíclicos de Anillo en Puente/química , Compuestos Heterocíclicos de Anillo en Puente/farmacología , Técnicas In Vitro , Ligandos , Modelos Moleculares , Agonistas Nicotínicos/química , Agonistas Nicotínicos/farmacología , Dolor/tratamiento farmacológico , Dolor/etiología , Dimensión del Dolor , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Piridinas/química , Piridinas/farmacología , Ratas , Receptores Nicotínicos/metabolismo , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
5-[(1R,5S)-3,6-Diazabicyclo[3.2.0]heptan-6-yl]nicotinonitrile (A-366833) is a novel nicotinic acetylcholine receptor (nAChR) ligand that binds to the agonist-binding site ([3H]-cytisine) with Ki value of 3.1 nM and exhibits agonist selectivity at alpha4beta2 nAChR relative to the alpha3beta4 nAChR subtype. The analgesic effects of A-366833 were examined across a variety of animal models including the mouse model of writhing pain (abdominal constriction), the rat models of acute thermal (hot box), persistent chemical (formalin) and neuropathic (spinal nerve ligation, SNL) pain. In the abdominal constriction model, A-366833 was effective at doses ranging from 0.062 to 0.62 micromol/kg (i.p.). In addition, A-366833 demonstrated significant effects in acute thermal pain (6.2-19.0 micromol/kg, i.p.), formalin (1.9-19 micromol/kg i.p.) and SNL (1.9-19 micromol/kg i.p.) models. The systemic effects of A-366833 were attenuated by pretreatment with mecamylamine (5 micromol/kg i.p.) in both the formalin and SNL models, suggesting that the analgesic effects of A-366833 in models of persistent nociceptive and neuropathic pain are mediated by activation of nAChRs. Pharmacokinetic investigations of A-366833 in rat revealed moderate brain:plasma distribution, half-life of 1.5h and excellent oral bioavailability of 73%. Comparison of peak plasma levels at the minimal effective doses across rat models of acute thermal pain, formalin and SNL with the maximal exposure that does not evoke emesis in ferret revealed therapeutic margins ranging from 6- to 22-fold. These studies indicate that compounds like A-366833 with improved agonist selectivity at alpha4beta2 vs. alpha3beta4 nAChR can elicit a broad spectrum of analgesic efficacy without concurrent adverse effects.
Asunto(s)
Analgésicos/farmacología , Agonistas Nicotínicos/farmacología , Receptores Nicotínicos/efectos de los fármacos , Animales , Cistina/metabolismo , Hurones , Masculino , Ratones , Modelos Animales , Náusea/inducido químicamente , Agonistas Nicotínicos/síntesis química , Agonistas Nicotínicos/farmacocinética , Agonistas Nicotínicos/toxicidad , Ratas , Ratas Sprague-DawleyRESUMEN
A series of potent neuronal nicotinic acetylcholine receptor (nAChR) ligands based on a 3,8-diazabicyclo[4.2.0]octane core have been synthesized and evaluated for affinity and agonist efficacy at the human high affinity nicotine recognition site (halpha4beta2) and in a rat model of persistent nociceptive pain (formalin model). Numerous analogs in this series exhibit picomolar affinity in radioligand binding assays and nanomolar agonist potency in functional assays, placing them among the most potent nAChR ligands known for the halpha4beta2 receptor. Several of the compounds reported in this study (i.e., 24, 25, 28, 30, 32, and 47) exhibit equivalent or greater affinity for the halpha4beta2 receptor relative to epibatidine, and like epibatidine, many exhibit robust analgesic efficacy in the rat formalin model of persistent pain.
Asunto(s)
Analgésicos/metabolismo , Agonistas Nicotínicos/síntesis química , Octanos/síntesis química , Dolor/tratamiento farmacológico , Receptores Nicotínicos/metabolismo , Analgésicos/síntesis química , Analgésicos/química , Animales , Unión Competitiva , Compuestos Bicíclicos Heterocíclicos con Puentes/metabolismo , Calcio/metabolismo , Humanos , Ligandos , Conformación Molecular , Estructura Molecular , Agonistas Nicotínicos/química , Agonistas Nicotínicos/metabolismo , Octanos/química , Octanos/metabolismo , Piridinas/metabolismo , Ensayo de Unión Radioligante , Ratas , Receptores Nicotínicos/química , Relación Estructura-ActividadRESUMEN
Selective and brain penetrating pharmacological antagonists for use in clarifying a role of alpha7 nicotinic acetylcholine receptors (nAChR) in behavioral paradigms are presently unavailable. Studies in alpha7 knock-out mice (KO) have not revealed convincing changes in behavioral phenotype, in particular measures of cognition that include contextual fear conditioning and spatial memory, which may be due to compensatory developmental changes. Therefore, an antisense oligonucleotide (aON) targeted toward the 3'- and 5'-UTR coding regions of the rat alpha7 nicotinic acetylcholine receptor was used. Following central injection of aON into the lateral ventricle of Long Evans rats for 6 days, treated rats exhibited a significant 42% and 25% decrease in alpha7 nAChR densities in hippocampus and cortex, respectively, as measured by [(3)H]-methyllycaconitine (MLA) binding. There was no change in alpha4beta2 densities measured by [(3)H]-cytisine binding. Acquisition of Morris Water Maze (MWM) performance, a measure of spatial memory, was impaired in aON-treated rats. In addition, a reduction in target platform crossings during a subsequent probe-trial was observed. These data demonstrate the ability of this aON to reduce hippocampal and cortical alpha7 nicotinic receptor densities associated with impaired MWM performance and support the specific involvement of the alpha7 nAChR in spatial learning and memory, a phenotype not affected in alpha7 KO mice.
Asunto(s)
Trastornos de la Memoria/inducido químicamente , Oligodesoxirribonucleótidos Antisentido/efectos adversos , Receptores Nicotínicos/fisiología , Percepción Espacial/efectos de los fármacos , Aconitina/análogos & derivados , Aconitina/farmacocinética , Alcaloides/farmacología , Animales , Azocinas/farmacología , Conducta Animal/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Hipocampo/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Trastornos de la Memoria/fisiopatología , Antagonistas Nicotínicos/farmacocinética , Unión Proteica/efectos de los fármacos , Quinolizinas/farmacología , Ratas , Ratas Long-Evans , Receptores Nicotínicos/efectos de los fármacos , Receptores Nicotínicos/genética , Factores de Tiempo , Tritio/farmacocinética , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
The recent development of a highly selective dopamine D4 receptor agonist, A-412997 (2-(3',4',5',6'-tetrahydro-2'H-[2,4'] bipyridinyl-1'-yl)-N-m-tolyl-acetamide), has provided a pharmacological tool with which to conduct systematic investigations into the putative role for dopamine D4 receptors in the central nervous system. These present studies evaluated the potential cognitive enhancing properties of A-412997 in rat models of ADHD (5-trial repeated acquisition inhibitory avoidance in Spontaneous Hypertensive Rat pups) and short-term memory (Social Recognition), in comparison with the less selective dopamine D4 receptor agonists PD168077 and CP226269. A-412997 showed significant dose-dependent efficacy in both models. PD168077 repeatedly improved acquisition in the 5-trial inhibitory avoidance model but failed to reach significance at any dose tested, although significantly improved social recognition was observed (albeit less potent than A-412997). CP226269 showed a significant enhancement in the 5-trial inhibitory avoidance model. These results support a role for the dopamine D4 receptor subtype in cognition.
Asunto(s)
Acetamidas/farmacología , Cognición/efectos de los fármacos , Agonistas de Dopamina/farmacología , Piridinas/farmacología , Receptores de Dopamina D4/agonistas , Animales , Masculino , Memoria/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Ratas , Ratas Endogámicas SHR , Ratas Sprague-Dawley , Ratas WistarRESUMEN
Neuronal nicotinic receptor (NNR) agonists such as ABT 594 have been shown to be effective in a wide range of preclinical models of acute and neuropathic pain. The present study, using the NNR agonist A-85380, sought to determine if NNR agonists are acting via similar or differing mechanisms to induce anti-nociception and anti-allodynia. A systemic administration of the quaternary NNR antagonist chlorisondamine (0.4 micromol/kg, intraperitoneal (i.p.)) did not alter A-85380-induced (0.75 micromol/kg, i.p.) anti-nociception in the rat paw withdrawal model of acute thermal pain. In contrast, previous studies have demonstrated that blockade of central NNRs by prior administration of chlorisondamine (10 microg i.c.v.) prevents A-85380 induced anti-nociception indicating a predominantly central site of action of NNR agonists in relieving acute pain. In the rat spinal nerve ligation model of neuropathic pain, A-85380 induced a dose-dependent anti-allodynia (0.5-1.0 micromol/kg) that was blocked by pretreatment with mecamylamine (1 micromol/kg). Interestingly, unlike acute pain, both systemic and central administration of chlorisondamine blocked A-85380-induced anti-allodynia, an effect that was determined not to be due to a non-specific effect of chlorisondamine or to chlorisondamine crossing the blood-brain barrier. The peripheral site of action was shown not to be the primary receptive field, since A-85380 had equally potent anti-allodynic effects when it was injected into either the affected or unaffected paw. In contrast, infusion of A-85380 directly onto the L5 dorsal root ganglion on the affected side resulted in a dose-dependent and marked anti-allodynia (10-20 microg) at doses that had no effect when injected systemically. This effect was blocked by pretreatment with chlorisondamine. Together these data further support the idea that different mechanisms underlie different pain states and suggest that the effects of NNR agonists in neuropathic pain may be due in part to peripheral actions of the compounds.
Asunto(s)
Benzopiranos/uso terapéutico , Ganglios Espinales/efectos de los fármacos , Ligadura/métodos , Mononeuropatías/fisiopatología , Antagonistas Nicotínicos/uso terapéutico , Dolor/tratamiento farmacológico , Animales , Antihipertensivos/farmacología , Benzopiranos/administración & dosificación , Clorisondamina/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Vías de Administración de Medicamentos , Evaluación Preclínica de Medicamentos , Interacciones Farmacológicas , Hexametonio/farmacología , Masculino , Antagonistas Nicotínicos/administración & dosificación , Umbral del Dolor , Estimulación Física , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
In the mammalian central nervous system (CNS), a family of alpha and beta subunits (alpha2-7, beta2-4) assemble to form both hetero- and homopentameric neuronal nicotinic acetylcholine receptors (nAChRs). In contrast to alpha4beta2 and alpha7, the predominant brain subtypes, far less is known regarding the functional expression and significance of alpha3-containing nAChRs in the CNS. In trying to better understand the role alpha3 in the CNS, an antisense knockdown strategy was utilized in the present studies. Specifically, Isis 106567 was identified out of 80 antisense oligonucleotides (aONs) designed and screened for their ability to reduce alpha3 mRNA expression in PC-12 cells. In addition to reducing alpha3 mRNA by greater than 75%, Isis 106567 attenuated nicotine-induced calcium influx in alpha3-expressing F11 cells. In vivo studies revealed significant reduction of alpha3 mRNA levels in both thalamus and medial habenula, regions known to express alpha3, following continuous (7 days) intracerebroventricular (i.c.v.) infusion of Isis 106567 in rats. Consistent with functional alpha3 knockdown, epibatidine-induced c-Fos expression in the medial habenula was attenuated in aON-treated rats. Known physiological responses elicited by epibatidine, such as hypothermia and micturition, were not affected by alpha3 aON treatment. However, the incidence of epibatidine-induced seizures was reduced in alpha3-antisense aON-treated rats, suggesting that alpha3 may be involved in mediating seizures produced by the nAChR agonist. Results of our studies suggest that Isis 106567 may be a useful in vivo tool for characterizing the functional significance of alpha3 expression in the CNS.
Asunto(s)
Oligonucleótidos Antisentido/metabolismo , Subunidades de Proteína/metabolismo , Receptores Nicotínicos/metabolismo , Animales , Conducta Animal/efectos de los fármacos , Encéfalo/citología , Encéfalo/metabolismo , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Calcio/metabolismo , Hibridación in Situ , Masculino , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Agonistas Nicotínicos/farmacología , Oligonucleótidos Antisentido/administración & dosificación , Oligonucleótidos Antisentido/genética , Células PC12 , Subunidades de Proteína/genética , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Piridinas/farmacología , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores Nicotínicos/genéticaRESUMEN
RATIONALE: The rat neonatal ventral hippocampal (VH) ibotenic lesion model has been proposed as a developmental model of schizophrenia, based on evidence that it encompasses aspects of the disorder including psychomotor agitation (hyperactivity), deficits in prepulse inhibition (PPI), and deficits in social interaction (SI), measures presumed to reflect positive symptoms, sensory gating deficits and negative symptoms, respectively. However, validation of the model as a predictive pharmacological screening tool has been minimal. OBJECTIVE: Determine the effects of a chronic 3-week low dose treatment of clozapine or risperidone on locomotor hyperactivity, PPI and SI in lesioned and control rats. RESULTS: Both clozapine, 2.5 mg/kg per day IP and risperidone, 0.1 mg/kg per day IP, reversed lesion-induced locomotor hyperactivity; however, the compounds also decreased locomotor activity in the non-lesioned controls. Clozapine 2.5 mg/kg per day and risperidone 0.1 mg/kg per day significantly attenuated lesion-induced PPI deficits. Neither compound induced a significant attenuation of lesion-induced SI deficits. In order to see if SI deficits required a higher dose of an antipsychotic, the dose of clozapine was increased to 4 mg/kg per day; however this dose induced such marked decreases in the activity and startle responses in the control rats, i.e. up to 74% decrease, that the effects on the lesioned rats could not be adequately interpreted. CONCLUSIONS: These data add further support to the neonatal VH lesion model as a predictive pharmacological screening assay for identifying compounds effective in the treatment of positive symptoms of schizophrenia. However, the usefulness of the model in detecting compounds effective in treating negative symptoms of schizophrenia is still in question.
Asunto(s)
Animales Recién Nacidos/fisiología , Antipsicóticos/farmacología , Clozapina/farmacología , Hipocampo/lesiones , Hipocampo/fisiología , Risperidona/farmacología , Psicología del Esquizofrénico , Estimulación Acústica , Animales , Conducta Animal/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Actividad Motora/efectos de los fármacos , Embarazo , Ratas , Ratas Sprague-Dawley , Receptores de Dopamina D2/efectos de los fármacos , Receptores de Dopamina D2/metabolismo , Reflejo de Sobresalto/efectos de los fármacos , Conducta SocialRESUMEN
RATIONALE: Attention deficit hyperactivity disorder (ADHD) is currently treated with psychomotor stimulants, including methylphenidate and amphetamine. Several adverse effects are associated with these drugs, however, such as agitation and abuse. H(3) receptor antagonists are under clinical investigation for ADHD. OBJECTIVES: To investigate the potential of thioperamide, a prototypical H(3) receptor antagonist, to enhance learning and attention while inducing no effects on locomotor stimulation and sensitization, or alterations in ACTH levels. METHODS: Thioperamide (1, 3, 10, 30 mg/kg) was administered prior to testing in a multi-trial, inhibitory avoidance response in rat pups (five trials separated by 1 min) to evaluate attention/cognition. Locomotor sensitization and cross-sensitization was assessed following administration of methylphenidate (3 mg/kg), cocaine (10 mg/kg), or thioperamide (1, 3, 10 mg/kg). RESULTS: Thioperamide significantly enhanced performance of the five-trial inhibitory avoidance response with efficacy similar to that previously reported for methylphenidate. Administration of amphetamine, methylphenidate and cocaine produced significant locomotor sensitization, however. In contrast, thioperamide did not induce locomotor stimulation or sensitization, nor did it cross-sensitize to the stimulant effects of amphetamine or cocaine. The repeated administration of methylphenidate significantly elevated ACTH levels, while thioperamide did not affect this neuroendocrine endpoint. CONCLUSIONS: H(3) receptor blockade may offer a safer alternative to psychomotor stimulants for the treatment of ADHD.
Asunto(s)
Cognición/efectos de los fármacos , Antagonistas de los Receptores Histamínicos/farmacología , Actividad Motora/efectos de los fármacos , Piperidinas/farmacología , Receptores Histamínicos H3/metabolismo , Hormona Adrenocorticotrópica/sangre , Animales , Animales Recién Nacidos , Atención/efectos de los fármacos , Reacción de Prevención/efectos de los fármacos , Estimulantes del Sistema Nervioso Central/farmacología , Cocaína/farmacología , Dextroanfetamina/química , Dextroanfetamina/farmacología , Relación Dosis-Respuesta a Droga , Antagonistas de los Receptores Histamínicos/administración & dosificación , Masculino , Metilfenidato/farmacología , Piperidinas/administración & dosificación , Ratas , Ratas Endogámicas SHRRESUMEN
Histamine H3 receptor antagonists/inverse agonists have been proposed as potential therapeutic agents for the treatment of a number of neurological disorders ranging from attention deficit hyperactivity disorder and Alzheimer's disease to narcolepsy and schizophrenia. With respect to the latter, schizophrenic patients typically exhibit impaired prepulse inhibition (PPI) of startle, a reflex that can be modeled in many animal species. Certain strains of mice naturally display poor PPI and it was recently suggested that these mice might offer a new way to screen for novel antipsychotic compounds. To examine whether H3 receptor antagonists might enhance PPI in mice with naturally occurring deficits, DBA/2 and C57BL/6 were tested in a startle paradigm with three prepulse intensities: 5, 10 and 15 dB above background. Both thioperamide and ciproxifan enhanced PPI in the DBA/2 strain; thioperamide also showed a trend towards enhancing PPI in C57BL/6. Risperidone, an atypical antipsychotic, enhanced PPI in both the DBA/2 and the C57BL/6 strain. These data confirm previous reports describing a natural deficit in PPI in some mouse strains that is amenable to enhancement with known antipsychotics. Further, these data suggest that H3 receptor antagonists/inverse agonists have anti-psychotic potential for disorders such as schizophrenia.
Asunto(s)
Antagonistas de los Receptores Histamínicos/farmacología , Imidazoles/farmacología , Inhibición Psicológica , Piperidinas/farmacología , Receptores Histamínicos H3/fisiología , Reflejo de Sobresalto/efectos de los fármacos , Estimulación Acústica/métodos , Animales , Antagonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Relación Dosis-Respuesta en la Radiación , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Reflejo de Sobresalto/efectos de la radiación , Risperidona/farmacología , Especificidad de la EspecieRESUMEN
A role for neuronal nicotinic receptor (NNR) activation in animal models of depression has been established. In order to determine the mechanism by which NNR ligands exert their antidepressant effects, experiments using different NNR receptor antagonists in both the mouse and the rat forced swim test (RFST) were performed. In the mouse forced swim test (MFST), A-85380 (0.62 micromol/kg = 0.14 mg/kg, i.p.), an NNR agonist, increased swim distance when administered 15 min prior to test. This effect was blocked by pre-treatment with mecamylamine (1.5 micromol/kg = 0.3 mg/kg, i.p.), suggesting that an NNR mechanism is involved. Further, chlorisondamine at a non-central nervous system (CNS) penetrating dose (1.6 micromol/kg = 1 mg/kg, i.p.) did not antagonize A-85380 in this model, thus implicating central rather than peripheral nicotinic receptors. Dihydro-beta-erythroidine (DHbetaE, 0.3 micromol/kg = 0.1 mg/kg, i.p.) pre-treatment also blocked this effect, indicating that the alpha4beta2 receptor subtype may be involved in A-85380-induced antidepressant effects. Finally, methiothepin (0.33 micromol/kg = 0.14 mg/kg, i.p.) pre-treatment antagonized this effect, suggesting serotonergic involvement. In the rat modified forced swim test, sub-acute administration of A-85380 (0.62 micromol/kg, i.p.) increased swimming behavior and decreased immobility. Climbing behavior was unaffected. In contrast, desipramine treatment (33 micromol/kg = 10 mg/kg, i.p.) resulted in an increase in climbing behavior with no effect on swimming. This behavioral profile has been shown to be more typical of serotonergic rather than noradrenergic antidepressants, suggesting that A-85380 exerts its effects via NNR activation of serotonergic systems.
Asunto(s)
Antidepresivos , Azetidinas/farmacología , Trastorno Depresivo/tratamiento farmacológico , Agonistas Nicotínicos/farmacología , Amitriptilina/farmacología , Animales , Clorisondamina/farmacología , Dihidro-beta-Eritroidina/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Metiotepina/farmacología , Ratones , Actividad Motora/efectos de los fármacos , Neurotransmisores/metabolismo , Antagonistas Nicotínicos/farmacología , Ratas , Receptores Nicotínicos/efectos de los fármacos , Antagonistas de la Serotonina/farmacología , Natación/psicologíaRESUMEN
This study assessed the effects of the nicotinic agonist (+/-)-epibatidine (EPIB) on the C-fiber flexor reflex in the anesthetized rat. Electrical stimulation of the hindpaw produces a long latency (> 150 ms) C-fiber mediated electromyographic (EMG) burst in hindlimb flexor muscles. EPIB (0.01, 0.03 micromol/kg, i.p.) significantly reduced (p < 0.05) C-fiber -related EMG activity by 46 and 64%, respectively. This effect was similar to that produced by the opioid morphine (21.0 micromol/kg, i.p.) and the NMDA receptor antagonist MK-801 (3.0 micromol/kg, i.p.). Nicotinic receptor blockade with the antagonists mecamylamine (5.0 micromol/kg, i.p.) and chlorisondamine (23.0 nmol/rat, intracerebroventricular) attenuated the effects of systemic EPIB on the C-fiber reflex. EPIB injection (0.04 nmol/rat) into the nucleus raphe magnus significantly decreased C-fiber EMG activity by 67%, suggesting a supraspinal site of action. In contrast, EPIB (0.6 nmol/rat) administered into the lumbar spinal cord significantly increased the C-fiber reflex by 117%. In summary, systemic and supraspinal EPIB exerted an inhibitory effect on central pain transmitting pathways, while a stimulatory effect is elicited in the spinal cord. The inhibitory effects are consistent with the reported analgesic properties of EPIB. The excitatory effect may be related to the reported algogenic responses when EPIB is administered intrathecally.
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Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Músculo Esquelético/efectos de los fármacos , Fibras Nerviosas Amielínicas/efectos de los fármacos , Agonistas Nicotínicos/farmacología , Piridinas/farmacología , Reflejo/efectos de los fármacos , Análisis de Varianza , Animales , Clorisondamina/farmacología , Maleato de Dizocilpina/farmacología , Interacciones Farmacológicas , Estimulación Eléctrica/métodos , Electromiografía/métodos , Antagonistas de Aminoácidos Excitadores/farmacología , Inyecciones Intraarteriales/métodos , Inyecciones Intraventriculares/métodos , Inyecciones Espinales/métodos , Masculino , Morfina/farmacología , Músculo Esquelético/fisiología , Músculo Esquelético/efectos de la radiación , Narcóticos/farmacología , Fibras Nerviosas Amielínicas/efectos de la radiación , Antagonistas Nicotínicos/farmacología , Núcleos del Rafe/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/efectos de la radiación , Reflejo/fisiologíaRESUMEN
Mutant Tg2576 mice which possess the human "Swedish" APP mutation have been shown to demonstrate both Abeta plaque pathology and memory deficits in behavioral tasks. These mice are routinely maintained on a mixed C57BL/6xSJL genetic background which exhibits a high frequency of retinal degeneration allele and high variability in many behavioral assays. The same APP mutation is also available maintained on a 129 genetic background, providing more genetic homogeneity, but little data are published regarding the effects of the mutation on this background. We investigated whether transgenic mice expressing the Swedish mutation on the 129 background show similar behavioral deficits and Abeta pathology as those on the mixed background. Mice on the 129 background were tested at 6-7, 11-12, or 18-19 months of age in locomotor activity, Y-maze spontaneous alternation, and contextual fear conditioning. Differences were detected between WT and Tg mice in locomotor activity at 6-7 and 18-19 months, Y-maze at 6-7 and 11-12 months, and fear conditioning at 6-7, 11-12, and 18-19 months. In contrast, Tg mice on the mixed B6/SJL background tested at 6-7 months only demonstrated significant impairment in the contextual fear conditioning assay and in the Y-maze in one of 2 cohorts tested. Despite the behavioral differences observed, similar Abeta pathology was observed between Tg mice on the two genetic backgrounds. These results indicate that mice on the 129 genetic background may generate more consistent and robust behavioral differences, providing a useful model for testing therapeutic agents for Alzheimer's disease.
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Enfermedad de Alzheimer , Precursor de Proteína beta-Amiloide/genética , Conducta Animal , Modelos Animales de Enfermedad , Receptores de Superficie Celular/genética , Envejecimiento , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/sangre , Animales , Encéfalo/patología , Condicionamiento Clásico , Miedo , Humanos , Aprendizaje por Laberinto , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Ratones Transgénicos , Actividad Motora/genética , Mutación , Placa Amiloide/patología , Nexinas de Proteasas , Especificidad de la EspecieRESUMEN
BACKGROUND AND PURPOSE: Several agonists of the alpha7 nicotinic acetylcholine receptor (nAChR) have been developed for treatment of cognitive deficits. However, agonist efficacy in vivo is difficult to reconcile with rapid alpha7 nAChR desensitization in vitro; and furthermore, the correlation between in vitro receptor efficacy and in vivo behavioural efficacy is not well delineated. The possibility that agonists of this receptor actually function in vivo as inhibitors via desensitization has not been finally resolved. EXPERIMENTAL APPROACH: Two structurally related alpha7 nAChR agonists were characterized and used to assess the degree of efficacy required in a behavioural paradigm. KEY RESULTS: NS6784 activated human and rat alpha7 nAChR with EC(50)s of 0.72 and 0.88 microM, and apparent efficacies of 77 and 97% respectively. NS6740, in contrast, displayed little efficacy at alpha7 nAChR (<2% in oocytes, < or =8% in GH4C1 cells), although its agonist-like properties were revealed by adding a positive allosteric modulator of alpha7 nAChRs or using the slowly desensitizing alpha7V274T receptor. In mouse inhibitory avoidance (IA) memory retention, NS6784 enhanced performance as did the 60% partial agonist A-582941. In contrast, NS6740 did not enhance performance, but blocked effects of A-582941. CONCLUSIONS AND IMPLICATIONS: Collectively, these findings suggest that a degree of alpha7 nAChR agonist efficacy is required for behavioural effects in the IA paradigm, and that such behavioural efficacy is not due to alpha7 nAChR desensitization. Also, a partial agonist of very low efficacy for this receptor could be used as an inhibitor, in the absence of alpha7 nAChR antagonists with favourable CNS penetration.
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Compuestos de Azabiciclo/farmacología , Furanos/farmacología , Agonistas Nicotínicos/farmacología , Oxadiazoles/farmacología , Receptores Nicotínicos/efectos de los fármacos , Regulación Alostérica , Animales , Reacción de Prevención/efectos de los fármacos , Compuestos de Azabiciclo/administración & dosificación , Conducta Animal/efectos de los fármacos , Línea Celular , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/fisiopatología , Relación Dosis-Respuesta a Droga , Furanos/administración & dosificación , Humanos , Masculino , Ratones , Oocitos/efectos de los fármacos , Oocitos/metabolismo , Oxadiazoles/administración & dosificación , Piridazinas/farmacología , Pirroles/farmacología , Ratas , Receptores Nicotínicos/metabolismo , Xenopus laevis , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
Among the diverse sets of nicotinic acetylcholine receptors (nAChRs), the alpha7 subtype is highly expressed in the hippocampus and cortex and is thought to play important roles in a variety of cognitive processes. In this review, we describe the properties of a novel biaryl diamine alpha7 nAChR agonist, A-582941. A-582941 was found to exhibit high-affinity binding and partial agonism at alpha7 nAChRs, with acceptable pharmacokinetic properties and excellent distribution to the central nervous system (CNS). In vitro and in vivo studies indicated that A-582941 activates signaling pathways known to be involved in cognitive function such as ERK1/2 and CREB phosphorylation. A-582941 enhanced cognitive performance in behavioral models that capture domains of working memory, short-term recognition memory, memory consolidation, and sensory gating deficit. A-582941 exhibited a benign secondary pharmacodynamic and tolerability profile as assessed in a battery of assays of cardiovascular, gastrointestinal, and CNS function. The studies summarized in this review collectively provide preclinical validation that alpha7 nAChR agonism offers a mechanism with potential to improve cognitive deficits associated with various neurodegenerative and psychiatric disorders.
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Cognición/efectos de los fármacos , Agonistas Nicotínicos/farmacología , Piridazinas/farmacología , Pirroles/farmacología , Receptores Nicotínicos/fisiología , Animales , Humanos , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
A-85380 [3-(2(s)-azetidinylmethoxy) pyridine] is a neuronal nicotinic acetylcholine receptor (nAChR) agonist that has been a useful tool in the investigation of the function of nAChRs in both preclinical and clinical studies. Amongst nAChR subtypes, A-85380 shows selectivity for the alpha(4)beta(2) vs. the alpha(7) or alpha(1)beta(1)deltagamma nAChRs. In functional in vitro cation flux assays, A-85380 is a potent and full agonist. A-85380 has a broad-spectrum analgesic profile with efficacy in acute, persistent, and neuropathic pain models. As demonstrated using selective nAChR antagonists or alpha(4) antisense, the alpha(4)beta(2) nAChR mediates the analgesic effects of A-85380. Interestingly, the site of action depends upon the type of pain as antinociception is mediated by descending inhibition into the spinal cord whereas anti-allodynia in neuropathic pain is mediated at both central and peripheral sites. Radiolabelled forms of A-85380 have been developed and shown to be safe for use in vivo in humans. In clinical studies using positron and photon emission tomography, marked decreases in alpha(4)beta(2) nAChRs have been seen in patients with Parkinson's and Alzheimer's disease. Although not developed as a therapeutic agent, A-85380 has proven to be an important component in the development of novel nAChR ligands for the treatment of pain and other disorders.
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Azetidinas/farmacología , Agonistas Nicotínicos/farmacología , Farmacología Clínica , Receptores Nicotínicos/fisiología , Animales , Azetidinas/química , Azetidinas/uso terapéutico , Humanos , Técnicas In Vitro , Trastornos Mentales/tratamiento farmacológico , Agonistas Nicotínicos/química , Agonistas Nicotínicos/uso terapéutico , Dolor/tratamiento farmacológico , Ensayo de Unión Radioligante/métodosRESUMEN
PURPOSE: The objective of this study was to characterize the antiseizure and safety profiles of ABT-769 [(R)-N-(2 amino-2-oxoethyl)spiro[2,5]octane-1-carboxamide]. METHODS: ABT-769 was tested for protection against maximal electroshock and pentylenetetrazol-induced seizures in the mouse and for suppression of electrically kindled amygdala seizures and spontaneous absence-like seizures in the rat. The central nervous system safety profile was evaluated by using tests of motor coordination and inhibitory avoidance. The potential for liver toxicity was assessed in vitro by using a mitochondrial fatty acid beta-oxidation assay. Teratogenic potential was assessed in the mouse. RESULTS: ABT-769 blocked maximal electroshock, subcutaneous pentylenetetrazol and intravenous pentylenetetrazol-induced seizures with median effective dose (ED50) values of 0.25, 0.38, and 0.11 mmol/kg, p.o., respectively. No tolerance was evident in the intravenous pentylenetetrazol test after twice-daily dosing of ABT-769 (0.3 mmol/kg, p.o.) for 4 days. ABT-769 blocked absence-like spike-wave discharge (ED50, 0.15 mmol/kg, p.o.) and shortened the cortical and amygdala afterdischarge duration of kindled seizures (1 and 3 mmol/kg, p.o.). The protective indices (ED50 rotorod impairment/ED50 seizure protection) were 4.8, 3.2, and 10.9 in the maximal electroshock, subcutaneous pentylenetetrazol and intravenous pentylenetetrazol seizure tests, respectively. ABT-769 did not affect inhibitory avoidance performance (0.1-1 mmol/kg, p.o.). ABT-769 did not affect mitochondrial fatty acid beta-oxidation or induce neural tube defects. CONCLUSIONS: ABT-769 is an efficacious antiseizure agent in animal models of convulsive and nonconvulsive epilepsy and has a favorable safety profile. ABT-769 has a broad-spectrum profile like that of valproic acid. Its profile is clearly different from those of carbamazepine, phenytoin, lamotrigine, topiramate, vigabatrin, and tiagabine.