RESUMEN
Treatments for cognitive deficits associated with central nervous system (CNS) disorders such as Alzheimer disease and schizophrenia remain significant unmet medical needs that incur substantial pressure on the health care system. The α7 nicotinic acetylcholine receptor (nAChR) has garnered substantial attention as a target for cognitive deficits based on receptor localization, robust preclinical effects, genetics implicating its involvement in cognitive disorders, and encouraging, albeit mixed, clinical data with α7 nAChR orthosteric agonists. Importantly, previous orthosteric agonists at this receptor suffered from off-target activity, receptor desensitization, and an inverted U-shaped dose-effect curve in preclinical assays that limit their clinical utility. To overcome the challenges with orthosteric agonists, we have identified a novel selective α7 positive allosteric modulator (PAM), BNC375. This compound is selective over related receptors and potentiates acetylcholine-evoked α7 currents with only marginal effect on the receptor desensitization kinetics. In addition, BNC375 enhances long-term potentiation of electrically evoked synaptic responses in rat hippocampal slices and in vivo. Systemic administration of BNC375 reverses scopolamine-induced cognitive deficits in rat novel object recognition and rhesus monkey object retrieval detour (ORD) task over a wide range of exposures, showing no evidence of an inverted U-shaped dose-effect curve. The compound also improves performance in the ORD task in aged African green monkeys. Moreover, ex vivo 13C-NMR analysis indicates that BNC375 treatment can enhance neurotransmitter release in rat medial prefrontal cortex. These findings suggest that α7 nAChR PAMs have multiple advantages over orthosteric α7 nAChR agonists for the treatment of cognitive dysfunction associated with CNS diseases. SIGNIFICANCE STATEMENT: BNC375 is a novel and selective α7 nicotinic acetylcholine receptor (nAChR) positive allosteric modulator (PAM) that potentiates acetylcholine-evoked α7 currents in in vitro assays with little to no effect on the desensitization kinetics. In vivo, BNC375 demonstrated robust procognitive effects in multiple preclinical models across a wide exposure range. These results suggest that α7 nAChR PAMs have therapeutic potential in central nervous system diseases with cognitive impairments.
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Bencetonio/farmacología , Clorobencenos/farmacología , Receptor Nicotínico de Acetilcolina alfa 7/agonistas , Regulación Alostérica , Animales , Encéfalo/efectos de los fármacos , Encéfalo/fisiología , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Cognición/efectos de los fármacos , Potenciación a Largo Plazo/efectos de los fármacos , Macaca mulatta , Masculino , Neurotransmisores/metabolismo , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Escopolamina/farmacologíaRESUMEN
Herein we describe the discovery of a 2-aminopyridine scaffold as a potent and isoform selective inhibitor of the Nav1.8 sodium channel. Parallel library synthesis, guided by in silico predictions, rapidly transformed initial hits into a novel 2-aminopyridine lead class possessing good ADME and pharmacokinetic profiles that were able to display activity in a clinically translatable nonhuman primate capsaicin-sensitized thermode pharmacodynamic assay. Progress toward the lead identification, optimization, and in vivo efficacy of these compounds will be discussed.
RESUMEN
Parkinson's disease is the second most prevalent progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra. Loss-of-function mutations in GBA, the gene that encodes for the lysosomal enzyme glucosylcerebrosidase, are a major genetic risk factor for the development of Parkinson's disease potentially through the accumulation of glucosylceramide and glucosylsphingosine in the CNS. A therapeutic strategy to reduce glycosphingolipid accumulation in the CNS would entail inhibition of the enzyme responsible for their synthesis, glucosylceramide synthase (GCS). Herein, we report the optimization of a bicyclic pyrazole amide GCS inhibitor discovered through HTS to low dose, oral, CNS penetrant, bicyclic pyrazole urea GCSi's with in vivo activity in mouse models and ex vivo activity in iPSC neuronal models of synucleinopathy and lysosomal dysfunction. This was accomplished through the judicious use of parallel medicinal chemistry, direct-to-biology screening, physics-based rationalization of transporter profiles, pharmacophore modeling, and use a novel metric: volume ligand efficiency.
RESUMEN
Glutamate plays a key role in cognition and mood, and it has been shown that inhibiting ionotropic glutamate receptors disrupts cognition, while enhancing ionotropic receptor activity is pro-cognitive. One approach to elevating glutamatergic tone has been to antagonize presynaptic metabotropic glutamate receptor 2 (mGluR2). A desire for selectivity over the largely homologous mGluR3 motivated a strategy to achieve selectivity through the identification of mGluR2 negative allosteric modulators (NAMs). Extensive screening and optimization efforts led to the identification of a novel series of 4-arylquinoline-2-carboxamides. This series was optimized for mGluR2 NAM potency, clean off-target activity, and desirable physical properties, which resulted in the identification of improved C4 and C7 substituents. The initial lead compound from this series was Ames-positive in a single strain with metabolic activation, indicating that a reactive metabolite was likely responsible for the genetic toxicity. Metabolic profiling and Ames assessment across multiple analogs identified key structure-activity relationships associated with Ames positivity. Further optimization led to the Ames-negative mGluR2 negative allosteric modulator MK-8768.
RESUMEN
Numerous changes occur during aging and Alzheimer's disease (AD) progression, including a decline in cholinergic functioning and cognition, as well as alterations in gene expression and activity in the nitric oxide/cyclic guanosine monophosphate (NO/cGMP) pathway. Donepezil, the current standard of care for Alzheimer's disease, improves cholinergic functioning and has demonstrated effects on multiple domains of cognition, including memory and attention in both preclinical species and patients. We previously found that increasing activation of the NO/cGMP pathway via phosphodiesterase 9 (PDE9) inhibition also improves memory in rodents and suggested that PDE9 might be a promising target for novel treatments for AD. Here we investigated whether PDE9 inhibition also enhances attention using a novel attention task in rats. We validated this task using several pharmacological manipulations and showed that the selective PDE9 inhibitor PF-04447943 produced effects similar to those of donepezil. These data confirm and extend the hypothesis that PDE9 inhibition might serve as a novel treatment for AD and age-related cognitive decline.
Asunto(s)
3',5'-AMP Cíclico Fosfodiesterasas/antagonistas & inhibidores , Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/enzimología , Nootrópicos/farmacología , Inhibidores de Fosfodiesterasa/farmacología , Pirazoles/farmacología , Pirimidinonas/farmacología , 3',5'-AMP Cíclico Fosfodiesterasas/fisiología , Animales , Trastornos del Conocimiento/inducido químicamente , Modelos Animales de Enfermedad , Masculino , Nootrópicos/uso terapéutico , Inhibidores de Fosfodiesterasa/uso terapéutico , Pirazoles/uso terapéutico , Pirimidinonas/uso terapéutico , Ratas , Ratas Wistar , Escopolamina/efectos adversosRESUMEN
Alzheimer's disease (AD) is a profoundly debilitating neurodegenerative disorder characterized most notably by progressive cognitive decline, but also agitation and behavioral disturbances that are extremely disruptive to patient and caregiver. Current pharmacological treatments for these symptoms have limited efficacy and significant side effects. We have recently reported the discovery of Compound 24, an M4 positive allosteric modulator (PAM) that is potent, highly selective, and devoid of cholinergic-like side effects in rats. In order to further evaluate the translatability of the effects of compound 24 in primates, here we describe the effect of Compound 24 on three behavioral and cognition assays in rhesus monkeys, the stimulant induced motor activity (SIMA) assay, the object retrieval detour task (ORD), and the visuo-spatial paired-associates learning (vsPAL) task. As far as we know, this is the first such characterization of an M4 PAM in non-human primate. Compound 24 and the clinical standard olanzapine attenuated amphetamine induced hyperactivity to a similar degree. In addition, Compound 24 demonstrated procognitive effects in scopolamine-impaired ORD and vsPAL, and these effects were of similar magnitude to donepezil. These findings suggest that M4 PAMs may be beneficial to diseases such as Alzheimer's disease and schizophrenia, which are marked by behavioral disturbances as well as deficits in cognitive function.
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Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/psicología , Conducta Animal/efectos de los fármacos , Colinérgicos/farmacología , Trastornos del Conocimiento/tratamiento farmacológico , Receptor Muscarínico M4/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Psicología del Esquizofrénico , Anfetamina/antagonistas & inhibidores , Anfetamina/farmacología , Animales , Aprendizaje por Asociación/efectos de los fármacos , Estimulantes del Sistema Nervioso Central , Colinérgicos/farmacocinética , Trastornos del Conocimiento/psicología , Hipercinesia/inducido químicamente , Hipercinesia/prevención & control , Macaca mulatta , Masculino , Actividad Motora/efectos de los fármacos , Olanzapina/farmacología , Orientación/efectos de los fármacosRESUMEN
Humans with loss-of-function mutations in the Nav1.7 channel gene (SCN9A) show profound insensitivity to pain, whereas those with gain-of-function mutations can have inherited pain syndromes. Therefore, inhibition of the Nav1.7 channel with a small molecule has been considered a promising approach for the treatment of various human pain conditions. To date, clinical studies conducted using selective Nav1.7 inhibitors have not provided analgesic efficacy sufficient to warrant further investment. Clinical studies to date used multiples of in vitro IC50 values derived from electrophysiological studies to calculate anticipated human doses. To increase the chance of clinical success, we developed rhesus macaque models of action potential propagation, nociception, and olfaction, to measure Nav1.7 target modulation in vivo. The potent and selective Nav1.7 inhibitors SSCI-1 and SSCI-2 dose-dependently blocked C-fiber nociceptor conduction in microneurography studies and inhibited withdrawal responses to noxious heat in rhesus monkeys. Pharmacological Nav1.7 inhibition also reduced odor-induced activation of the olfactory bulb (OB), measured by functional magnetic resonance imaging (fMRI) studies consistent with the anosmia reported in Nav1.7 loss-of-function patients. These data demonstrate that it is possible to measure Nav1.7 target modulation in rhesus macaques and determine the plasma concentration required to produce a predetermined level of inhibition. The calculated plasma concentration for preclinical efficacy could be used to guide human efficacious exposure estimates. Given the translatable nature of the assays used, it is anticipated that they can be also used in phase 1 clinical studies to measure target modulation and aid in the interpretation of phase 1 clinical data.
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Canal de Sodio Activado por Voltaje NAV1.7 , Dolor , Animales , Humanos , Macaca mulatta , Nocicepción , NociceptoresRESUMEN
INTRODUCTION: The development of novel analgesics to treat acute or chronic pain has been a challenge due to a lack of translatable measurements. Preclinical end points with improved translatability are necessary to more accurately inform clinical testing paradigms, which may help guide selection of viable drug candidates. METHODS: In this study, a nonhuman primate biomarker which is sensitive to standard analgesics at clinically relevant plasma concentrations, can differentiate analgesia from sedation and utilizes a protocol very similar to that which can be employed in human clinical studies is described. Specifically, acute heat stimuli were delivered to the volar forearm using a contact heat thermode in the same manner as the clinical setting. RESULTS: Clinically efficacious exposures of morphine, fentanyl, and tramadol produced robust analgesic effects, whereas doses of diazepam that produce sedation had no effect. CONCLUSION: We propose that this assay has predictive utility that can help improve the probability of success for developing novel analgesics.
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RATIONALE: Much preclinical data, almost exclusively using rodent, supports the notion that phosphodiesterase 10A (PDE10A) inhibition may offer an alternative to the current standard of care in schizophrenia. However, concerns persist regarding the clinical translatability of these models for newer drug classes like PDE10A inhibitors. OBJECTIVES: We therefore sought to characterize the clinical standard risperidone and the PDE10A inhibitor THPP-1 in nonhuman primate, both alone and when used as a combination therapy. METHODS: THPP-1 and risperidone were tested in a novel rhesus model of stimulant-induced motor activity (SIMA) and in rhesus electroencephalography (EEG). RESULTS: Consistent with rodent data, both THPP-1 and risperidone significantly attenuated the stimulant effects in SIMA when administered alone, though some differences were noted. Combination therapy with a low dose of risperidone produced significantly more robust effects. THPP-1 and risperidone also produced a marked reduction of wake cycle time and gamma frequency power in EEG. However, THPP-1 differed from risperidone by reducing spectral power of lower frequencies (delta). CONCLUSIONS: SIMA results suggest that PDE10A inhibition produces antipsychotic-like effects in higher species, and that combination therapy with PDE10A inhibitors may produce more robust efficacy compared to monotherapies. EEG and qEEG results confirm that PDE10A inhibition does share some central signaling effects with clinically effective antipsychotics. The present combination therapy results may carry implications for the manner in which clinical testing of PDE10A inhibitors is conducted.
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Antipsicóticos/farmacología , Conducta Animal/efectos de los fármacos , Electroencefalografía/efectos de los fármacos , Inhibidores de Fosfodiesterasa/farmacología , Hidrolasas Diéster Fosfóricas/farmacología , Risperidona/farmacología , Esquizofrenia/tratamiento farmacológico , Análisis de Varianza , Animales , Estimulantes del Sistema Nervioso Central/farmacología , Modelos Animales de Enfermedad , Quimioterapia Combinada , Macaca mulatta , Masculino , Actividad Motora/efectos de los fármacosRESUMEN
We have recently shown that the M1 muscarinic receptor positive allosteric modulator, PQCA, improves cognitive performance in rodents and non-human primates administered the muscarinic receptor antagonist scopolamine. The purpose of the present experiments was to characterize the effects of PQCA in a model more relevant to the disease pathology of Alzheimer's disease. Tg2576 transgenic mice that have elevated Aß were tested in the novel object recognition task to characterize recognition memory as a function of age and treatment with the PQCA. The effects of PQCA were compared to the acetylcholinesterase inhibitor donepezil, the standard of care for Alzheimer's disease. In addition, the effect of co-administering PQCA and donepezil was evaluated. Aged Tg2576 mice demonstrated a deficit in recognition memory that was significantly attenuated by PQCA. The positive control donepezil also reversed the deficit. Furthermore, doses of PQCA and donepezil that were inactive on their own were found to improve recognition memory when given together. These studies suggest that M1 muscarinic receptor positive allosteric modulation can ameliorate memory deficits in disease relevant models of Alzheimer's disease. These data, combined with our previous findings demonstrating PQCA improves scopolamine-induced cognitive deficits in both rodents and non-human primates, suggest that M1 positive allosteric modulators have therapeutic potential for the treatment of Alzheimer's disease.
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Enfermedad de Alzheimer/tratamiento farmacológico , Colinérgicos/farmacología , Trastornos de la Memoria/tratamiento farmacológico , Nootrópicos/farmacología , Piperidinas/farmacología , Quinolizinas/farmacología , Envejecimiento/efectos de los fármacos , Envejecimiento/psicología , Enfermedad de Alzheimer/fisiopatología , Animales , Inhibidores de la Colinesterasa/farmacología , Modelos Animales de Enfermedad , Donepezilo , Relación Dosis-Respuesta a Droga , Sinergismo Farmacológico , Quimioterapia Combinada , Femenino , Indanos/farmacología , Trastornos de la Memoria/fisiopatología , Ratones Transgénicos , Receptor Muscarínico M1/metabolismo , Reconocimiento en Psicología/efectos de los fármacos , Reconocimiento en Psicología/fisiologíaRESUMEN
RATIONALE: The standards of care for Alzheimer's disease, acetylcholinesterase inhibitors such as donepezil (Aricept®), are dose-limited due to adverse side-effects. These adverse events lead to significant patient non-compliance, constraining the dose and magnitude of efficacy that can be achieved. Non-selective muscarinic receptor orthosteric agonists such as Xanomeline have been shown to be effective in treating symptoms as well, but were also poorly tolerated. Therefore, there is an unmet medical need for a symptomatic treatment that improves symptoms and is better tolerated. METHODS: We compared donepezil, xanomeline, and the novel selective muscarinic 1 receptor positive allosteric modulator PQCA in combination with donepezil in the object retrieval detour (ORD) cognition test in rhesus macaque. Gastrointestinal (GI) side effects (salivation and feces output) were then assessed with all compounds to determine therapeutic window. RESULTS: All three compounds significantly reduced a scopolamine-induced deficit in ORD. Consistent with what is observed clinically in patients, both donepezil and xanomeline produced significant GI effects in rhesus at doses equal to or less than a fivefold margin from the minimum effective dose that improves cognition. In stark contrast, PQCA produced no GI side effects when tested at the same dose range. CONCLUSIONS: These data suggest M1 positive allosteric modulators have the potential to improve cognition in Alzheimer's disease with a greater therapeutic margin than the current standard of care, addressing an important unmet medical need.
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Cognición/efectos de los fármacos , Indanos/farmacología , Agonistas Muscarínicos/farmacología , Piperidinas/farmacología , Piridinas/farmacología , Quinolizinas/farmacología , Receptor Muscarínico M1/efectos de los fármacos , Tiadiazoles/farmacología , Anciano , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Conducta Apetitiva/efectos de los fármacos , Atención/efectos de los fármacos , Defecación/efectos de los fármacos , Donepezilo , Femenino , Humanos , Indanos/toxicidad , Macaca mulatta , Masculino , Pruebas Neuropsicológicas , Orientación/efectos de los fármacos , Piperidinas/toxicidad , Solución de Problemas/efectos de los fármacos , Piridinas/toxicidad , Quinolizinas/toxicidad , Salivación/efectos de los fármacos , Tiadiazoles/toxicidadRESUMEN
Phosphodiesterase 10A (PDE10A) is a novel target for the treatment of schizophrenia that may address multiple symptomatic domains associated with this disorder. PDE10A is highly expressed in the brain and functions to metabolically inactivate the important second messengers cAMP and cGMP. Here we describe effects of a potent and orally bioavailable PDE10A inhibitor [2-(6-chloropyridin-3-yl)-4-(2-methoxyethoxy)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl](imidazo[1,5-a]pyridin-1-yl)methanone] (THPP-1) on striatal signaling pathways, in behavioral tests that predict antipsychotic potential, and assays that measure episodic-like memory in rat and executive function in rhesus monkey. THPP-1 exhibits nanomolar potency on the PDE10A enzyme, demonstrates excellent pharmacokinetic properties in multiple preclinical animal species, and is selective for PDE10A over other PDE families of enzymes. THPP-1 significantly increased phosphorylation of proteins in the striatum involved in synaptic plasticity, including the a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor (AMPA) GluR1 subunit, extracellular receptor kinase (ERK), and cAMP-response element binding protein (CREB). THPP-1 produced dose-dependent effects in preclinical assays predictive of antipsychotic activity including attenuation of MK-801-induced psychomotor activation and condition avoidance responding in rats. At similar plasma exposures, THPP-1 significantly increased object recognition memory in rat and attenuated a ketamine-induced deficit in the object retrieval detour task in rhesus monkey. These findings suggest that PDE10A inhibitors have the potential to impact multiple symptomatic domains of schizophrenia including positive symptoms and cognitive impairment. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
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Antipsicóticos/uso terapéutico , Trastornos del Conocimiento/prevención & control , Terapia Molecular Dirigida , Nootrópicos/uso terapéutico , Inhibidores de Fosfodiesterasa/uso terapéutico , Hidrolasas Diéster Fosfóricas/metabolismo , Esquizofrenia/tratamiento farmacológico , Animales , Antipsicóticos/administración & dosificación , Antipsicóticos/sangre , Antipsicóticos/farmacocinética , Conducta Animal/efectos de los fármacos , Trastornos del Conocimiento/etiología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/enzimología , Cuerpo Estriado/metabolismo , Relación Dosis-Respuesta a Droga , Función Ejecutiva/efectos de los fármacos , Macaca mulatta , Masculino , Memoria Episódica , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de los fármacos , Neuronas/enzimología , Neuronas/metabolismo , Nootrópicos/administración & dosificación , Nootrópicos/sangre , Nootrópicos/farmacocinética , Inhibidores de Fosfodiesterasa/administración & dosificación , Inhibidores de Fosfodiesterasa/sangre , Inhibidores de Fosfodiesterasa/farmacocinética , Hidrolasas Diéster Fosfóricas/química , Fosforilación/efectos de los fármacos , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Piridinas/administración & dosificación , Piridinas/sangre , Piridinas/farmacocinética , Piridinas/uso terapéutico , Pirimidinas/administración & dosificación , Pirimidinas/sangre , Pirimidinas/farmacocinética , Pirimidinas/uso terapéutico , Distribución Aleatoria , Ratas , Ratas Wistar , Esquizofrenia/sangre , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologíaRESUMEN
T-type calcium channels are important in burst firing and expressed in brain regions implicated in schizophrenia. Therefore, we examined the effects of novel selective T-type calcium channel antagonists in preclinical assays predictive of antipsychotic-like activity. TTA-A2 blocked the psychostimulant effects of amphetamine and MK-801 and decreased conditioned avoidance responding. These effects appeared mechanism based, rather than compound specific, as two structurally dissimilar T-type antagonists also reduced amphetamine-induced psychomotor activity. Importantly, the ability to reduce amphetamine's effects was maintained following 20 days pre-treatment with TTA-A2. To explore the neural substrates mediating the observed behavioral effects, we examined the influence of TTA-A2 on amphetamine-induced c-fos expression as well as basal and stimulant-evoked dopamine and glutamate release in the nucleus accumbens. TTA-A2 decreased amphetamine-induced c-fos expression as well as MK-801-induced, but not basal, glutamate levels in the nucleus accumbens. Basal, amphetamine- and MK-801-induced dopamine efflux was altered. These findings suggest that T-type calcium channel antagonism could represent a novel mechanism for treating schizophrenia.
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Antipsicóticos/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio Tipo T/metabolismo , Ácido Glutámico/metabolismo , Actividad Motora/efectos de los fármacos , Núcleo Accumbens/efectos de los fármacos , Anfetamina/farmacología , Animales , Bencenoacetamidas/farmacología , Maleato de Dizocilpina/farmacología , Relación Dosis-Respuesta a Droga , Masculino , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Ratas WistarRESUMEN
Currently prescribed antipsychotics attenuate the positive symptoms of schizophrenia but fail or only mildly improve negative symptoms. The present study aimed to establish an animal model of negative symptoms by examining the effects of the NMDA receptor antagonist MK-801 on sucrose preference. We sought to validate the model by examining the effects of clozapine and D-serine, for which there are positive clinical data regarding their effects on negative symptoms, and haloperidol which is clinically ineffective. We extended our analysis by examining CDPPB, an mGlu5 receptor positive allosteric modulator. Acute MK-801 produced effects indicative of a shift in the hedonic experience of sucrose not confounded by disruptions in motor abilities or taste as revealed by: 1) a decrease in sucrose intake at low concentrations (0.8% or 1.2%), but no effect on water, 2) an increase in consumption for higher (7%) sucrose concentrations, reflecting a shift to the right in the concentration-consumption curve, and 3) no effect on quinine intake. Sub-chronic clozapine and acute d-serine attenuated the MK-801-induced deficit in 1.2% sucrose consumption, whereas sub-chronic haloperidol (0.02 mg/kg) did not. Finally, acute treatment with CDPPB also attenuated this deficit. These data suggest that this model may be useful for identifying novel agents that improve negative symptoms, and that compounds which enhance NMDA receptor function, such as mGlu5 receptor PAMs, may have clinical utility in this regard.
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Benzamidas/farmacología , Clozapina/farmacología , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Pirazoles/farmacología , Receptores de Glutamato Metabotrópico/efectos de los fármacos , Esquizofrenia/fisiopatología , Serina/farmacología , Sacarosa/administración & dosificación , Regulación Alostérica , Animales , Masculino , Quinina/administración & dosificación , Ratas , Ratas Wistar , Receptor del Glutamato Metabotropico 5RESUMEN
BACKGROUND: Recent evidence suggests an involvement of T-type calcium channels in the effects of drugs of abuse. METHODS: We examined the influence of the novel, potent, and selective T-type calcium channel antagonist [2-(4-cyclopropylphenyl)-N-((1R)-1-{5-[2,2,2-trifluoroethyl]oxo}pyridine-2-yl)ethyl]acetamide] (TTA-A2) (.3, 1, or 3 mg/kg) on motivation for nicotine, as measured by nicotine self-administration on a progressive ratio (PR) schedule, and nicotine- and cue-induced reinstatement for a response previously reinforced with nicotine delivery (n = 11 or 12 Long Evans rats/group). Furthermore, we examined the specificity of the TTA-A2 effects by characterizing its influence on PR responding for food (in the absence or presence of nicotine-potentiated responding), food- versus nicotine-induced cue-potentiated reinstatement for a response previously reinforced by food administration (n = 11 or 12 Wistar Hannover rats/group), and its ability to induce a conditioned place aversion. RESULTS: TTA-A2 dose-dependently decreased self-administration of nicotine on a PR schedule and the ability of both nicotine and a cue paired with nicotine to reinstate responding. The effects were specific for nicotine's incentive motivational properties, as TTA-A2 did not influence responding for food on a PR schedule but did attenuate the ability of nicotine to potentiate responding for food. Likewise, TTA-A2 did not alter food-induced cue-potentiated reinstatement for a response previously reinforced by food but did decrease nicotine-induced cue-potentiated reinstatement. Finally, TTA-A2 did not produce an aversive state, as indicated by a lack of ability to induce conditioned place aversion. CONCLUSIONS: These data suggest that T-type calcium channel antagonists have potential for alleviating nicotine addiction by selectively decreasing the incentive motivational properties of nicotine.
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Bencenoacetamidas/farmacología , Canales de Calcio Tipo T/efectos de los fármacos , Extinción Psicológica/efectos de los fármacos , Motivación/efectos de los fármacos , Nicotina/farmacología , Piridinas/farmacología , Refuerzo en Psicología , Animales , Bloqueadores de los Canales de Calcio/farmacología , Condicionamiento Operante/efectos de los fármacos , Señales (Psicología) , Relación Dosis-Respuesta a Droga , Alimentos , Masculino , Nicotina/administración & dosificación , Nicotina/antagonistas & inhibidores , Ratas , Ratas Long-Evans , Ratas Wistar , Esquema de Refuerzo , AutoadministraciónRESUMEN
RATIONALE: It was recently reported that administration of the metabotropic glutamate 2 and 3 (mGlu2/3) receptor agonist prodrug LY2140023 to schizophrenic patients decreased positive symptoms. However, at the single, potentially suboptimal, dose that was tested, LY2140023 trended towards being inferior to olanzapine on several indices of efficacy within the Positive and Negative Syndrome Scale. OBJECTIVES: In this study, we examined whether the antipsychotic potential of mGlu2/3 receptor agonism can be enhanced with 5-HT(2A) receptor antagonism. MATERIALS AND METHODS: Specifically, we characterized the effects of co-administering submaximally effective doses of the 5-HT(2A) receptor antagonist M100907 (0.2 mg/kg) and the mGlu2/3 receptor agonist LY379268 (1 mg/kg) on amphetamine-induced and MK-801-induced psychomotor activity in rats, an assay sensitive to antipsychotics. We also determined the effects of co-administering these two compounds on MK-801-induced dopamine and norepinephrine efflux in the nucleus accumbens (NAc). RESULTS: At the submaximally effective doses tested, the effects of M100907 and LY379268 on amphetamine-induced and MK-801-induced psychomotor activity were significantly greater when given together than when given separately. Furthermore, coadministration of these doses of M100907 and LY379268 reduced MK-801-induced dopamine efflux in the NAc. This effect on dopamine release was not observed with the administration of either compound alone, even at higher doses that attenuated MK-801-induced psychomotor activity. CONCLUSIONS: Our results suggest that a single compound having both mGlu2/3 receptor agonist and 5-HT(2A) receptor antagonist activity, or coadministration of two compounds selective for these receptors, could be superior in terms of efficacy and/or reduced side-effect liability relative to an mGlu2/3 receptor agonist alone.