RESUMO
Acute treatment with positive allosteric modulators (PAMs) of mGlu1 and mGlu5 metabotropic glutamate receptors (RO0711401 and VU0360172, respectively) reduces the incidence of spike-and wave discharges in the WAG/Rij rat model of absence epilepsy. However, from the therapeutic standpoint, it was important to establish whether tolerance developed to the action of these drugs. We administered either VU0360172 (3 mg/kg, s.c.) or RO0711401 (10 mg/kg, s.c.) to WAG/Rij rats twice daily for ten days. VU0360172 maintained its activity during the treatment, whereas rats developed tolerance to RO0711401 since the 3rd day of treatment and were still refractory to the drug two days after treatment withdrawal. In response to VU0360172, expression of mGlu5 receptors increased in the thalamus of WAG/Rij rats after 1 day of treatment, and remained elevated afterwards. VU0360172 also enhanced mGlu5 receptor expression in the cortex after 8 days of treatment without changing the expression of mGlu1a receptors. Treatment with RO0711401 enhanced the expression of both mGlu1a and mGlu5 receptors in the thalamus and cortex of WAG/Rij rats after 3-8 days of treatment. These data were different from those obtained in non-epileptic rats, in which repeated injections of RO0711401 and VU0360172 down-regulated the expression of mGlu1a and mGlu5 receptors. Levels of VU0360172 in the thalamus and cortex remained unaltered during the treatment, whereas levels of RO0711401 were reduced in the cortex at day 8 of treatment. These findings suggest that mGlu5 receptor PAMs are potential candidates for the treatment of absence epilepsy in humans.
Assuntos
Anticonvulsivantes/farmacologia , Epilepsia Tipo Ausência/tratamento farmacológico , Epilepsia Tipo Ausência/fisiopatologia , Fármacos Atuantes sobre Aminoácidos Excitatórios/farmacologia , Receptor de Glutamato Metabotrópico 5/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Western Blotting , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Modelos Animais de Doenças , Tolerância a Medicamentos , Eletrodos Implantados , Eletroencefalografia , Masculino , Camundongos Transgênicos , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Ratos , Ratos Endogâmicos ACI , Ratos Wistar , Receptor de Glutamato Metabotrópico 5/genética , Receptores de Glutamato Metabotrópico/genética , Tálamo/efeitos dos fármacos , Tálamo/fisiopatologia , Fatores de TempoRESUMO
Impaired transmission through glutamatergic circuits has been postulated to play a role in the underlying pathophysiology of schizophrenia. Furthermore, inhibition of the N-methyl-d-aspartate (NMDA) subtype of ionotropic glutamate receptors (NMDAR) induces a syndrome that recapitulates many of the symptoms observed in patients with schizophrenia. Selective activation of metabotropic glutamate receptor subtype 5 (mGlu5) may provide a novel therapeutic approach for treatment of symptoms associated with schizophrenia through facilitation of transmission through central glutamatergic circuits. Here, we describe the characterization of two novel N-aryl piperazine mGlu5 positive allosteric modulators (PAMs): 2-(4-(2-(benzyloxy)acetyl)piperazin-1-yl)benzonitrile (VU0364289) and 1-(4-(2,4-difluorophenyl)piperazin-1-yl)-2-((4-fluorobenzyl)oxy)ethanone (DPFE). VU0364289 and DPFE induced robust leftward shifts in the glutamate concentration-response curves for Ca(2+) mobilization and extracellular signal-regulated kinases 1 and 2 phosphorylation. Both PAMs displayed micromolar affinity for the common mGlu5 allosteric binding site and high selectivity for mGlu5. VU0364289 and DPFE possessed suitable pharmacokinetic properties for dosing in vivo and produced robust dose-related effects in reversing amphetamine-induced hyperlocomotion, a preclinical model predictive of antipsychotic-like activity. In addition, DPFE enhanced acquisition of contextual fear conditioning in rats and reversed behavioral deficits in a mouse model of NMDAR hypofunction. In contrast, DPFE had no effect on reversing apomorphine-induced disruptions of prepulse inhibition of the acoustic startle reflex. These mGlu5 PAMs also increased monoamine levels in the prefrontal cortex, enhanced performance in a hippocampal-mediated memory task, and elicited changes in electroencephalogram dynamics commensurate with procognitive effects. Collectively, these data support and extend the role for the development of novel mGlu5 PAMs for the treatment of psychosis and cognitive deficits observed in individuals with schizophrenia.
Assuntos
Antipsicóticos/farmacologia , Hipercinese/tratamento farmacológico , Memória de Curto Prazo/efeitos dos fármacos , Nootrópicos/farmacologia , Piperazinas/farmacologia , Receptor de Glutamato Metabotrópico 5/agonistas , Receptores de N-Metil-D-Aspartato/metabolismo , Regulação Alostérica , Animais , Antipsicóticos/química , Antipsicóticos/farmacocinética , Antipsicóticos/uso terapêutico , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Células HEK293 , Humanos , Hipercinese/metabolismo , Hipercinese/psicologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Nootrópicos/química , Nootrópicos/farmacocinética , Nootrópicos/uso terapêutico , Piperazinas/química , Piperazinas/farmacocinética , Piperazinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Receptor de Glutamato Metabotrópico 5/genética , Receptores de N-Metil-D-Aspartato/genética , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , TransfecçãoRESUMO
Previous preclinical and clinical studies have demonstrated the efficacy of group II metabotropic glutamate receptor (mGluR) agonists as potential antipsychotics. Recent studies utilizing mGluR2-, mGluR3-, and double knockout mice support that the antipsychotic effects of those compounds are mediated by mGluR2. Indeed, biphenyl indanone-A (BINA), an allosteric potentiator of mGluR2, is effective in experimental models of psychosis, blocking phencyclidine (PCP)-induced hyperlocomotion and prepulse inhibition deficits in mice. In this study, we administered the NMDA receptor antagonist PCP (5.6 mg/kg i.p.) to rats, an established animal model predictive of schizophrenia. Here, we show that BINA (32 mg/kg i.p.) attenuated PCP-induced locomotor activity in rats. Using behaviorally relevant doses of BINA and PCP, we performed pharmacological magnetic resonance imaging (phMRI) to assess the specific brain regions that underlie the psychotomimetic effects of PCP, and examined how BINA modulated the PCP-induced functional changes in vivo. In anesthetized rats, acute administration of PCP produced robust, sustained blood oxygenation level-dependent (BOLD) activation in specific cortical, limbic, thalamic, and striatal regions. Pretreatment with BINA suppressed the amplitude of the BOLD response to PCP in the prefrontal cortex, caudaute-putamen, nucleus accumbens, and mediodorsal thalamus. Our results show key brain structures underlying PCP-induced behaviors in a preclinical model of schizophrenia, and, importantly, its reversal by potentiation of mGluR2 by BINA, revealing specific brain regions functionally involved in its pharmacological action. Finally, our findings bolster the growing body of evidence that mGluR2 is a viable target for the treatment of schizophrenia.
Assuntos
Compostos de Bifenilo/farmacologia , Encéfalo/efeitos dos fármacos , Indanos/farmacologia , Atividade Motora/efeitos dos fármacos , Fenciclidina , Receptores de Glutamato Metabotrópico/agonistas , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Regulação Alostérica , Animais , Encéfalo/irrigação sanguínea , Encéfalo/fisiologia , Avaliação Pré-Clínica de Medicamentos , Imageamento por Ressonância Magnética , Masculino , Oxigênio/sangue , Ratos , Ratos Sprague-DawleyRESUMO
The basal ganglia (BG) are a set of interconnected subcortical structures that play a critical role in motor control. The BG are thought to control movements by a delicate balance of transmission through two BG circuits that connect the input and output nuclei: the direct and the indirect pathways. The BG are also involved in a number of movement disorders. Most notably, the primary pathophysiological change that gives rise to the motor symptoms of Parkinson's Disease (PD) is the loss of dopaminergic neurons of the substantia nigra pars compacta (SNc) that are involved in modulating function of the striatum and other BG structures. This ultimately results in an increase in activity of the indirect pathway relative to the direct pathway and the hallmark PD symptoms of rigidity, bradykinesia, and akinesia. A great deal of effort has been dedicated to finding treatments for this disease. The current pharmacotherapies are aimed at replacing the missing dopamine, while the current surgical treatments are aimed at reducing transmission through the indirect pathway. Dopamine replacement therapy has proven to be helpful, but is associated with severe side effects that limit treatment and a loss of efficacy with progression of the disease. Recently developed surgical therapies have been highly effective, but are highly invasive, expensive, and assessable to a small minority of patients. For these reasons, new effort has been dedicated to finding pharmacological treatment options that will be effective in reducing transmission through the indirect pathway. Members of the metabotropic glutamate receptor (mGluR) family have emerged as interesting and promising targets for such a treatment. This review will explore the most recent advances in the understanding of mGluR localization and function in the BG motor circuit and the implications of those findings for the potential therapeutic role of mGluR-targeted compounds for PD.