RESUMEN
Our knowledge regarding the molecular pathophysiology underlying anxiety disorders remains incomplete. Increasing evidence points to a role of glutamate in anxiety. The group III metabotropic glutamate receptors (mGlu4, mGlu6, mGlu7 and mGlu8 receptors) remain the least investigated glutamate receptor subtypes partially due to a delay in the development of specific pharmacological tools. Early work using knockout animals and pharmacological tools aimed at investigating the role of mGlu7 receptor in the pathophysiology of anxiety disorders has yielded exciting yet not always consistent results. To further investigate the role this receptor plays in anxiety-like behaviour, we knocked down mGlu7 receptor mRNA levels in the adult mouse brain using siRNA delivered via an osmotic minipump. This reduced anxiety-like behaviour in the light-dark box coupled with an attenuation of stress-induced hyperthermia (SIH) and a reduction of the acoustic startle response (ASRs) in the fear-potentiated startle paradigm (FPS). These effects on anxiety-like behaviour were independent of any impairment of locomotor activity and surprisingly, no behavioural changes were observed in the forced swim test (FST), which is in contrast to mGlu7 receptor knockout animals. Furthermore, the previously reported epilepsy-prone phenotype seen in mGlu7 receptor knockout animals was not observed following siRNA-induced knockdown of the receptor. These data suggest targeting mGlu7 receptors with selective antagonist drugs may be an effective and safe strategy for the treatment of anxiety disorders.
Asunto(s)
Ansiedad/tratamiento farmacológico , Ansiedad/metabolismo , ARN Interferente Pequeño/uso terapéutico , Receptores de Glutamato Metabotrópico/metabolismo , Adaptación Ocular/efectos de los fármacos , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Miedo/efectos de los fármacos , Hipertermia Inducida/psicología , Masculino , Ratones , Ratones Endogámicos BALB C , Actividad Motora/efectos de los fármacos , Pentilenotetrazol/toxicidad , Receptores de Glutamato Metabotrópico/genética , Reflejo de Sobresalto/efectos de los fármacos , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Estrés Fisiológico/fisiología , Natación/psicologíaRESUMEN
The metabotropic glutamate receptor subtype 7 (mGluR7) is presynaptically located and modulates transmitter release. An earlier study from our group demonstrated that systemic administration of N,N'-dibenzyhydryl-ethane-1,2-diamine dihydrochloride (AMN082), a selective allosteric mGluR7 agonist, attenuates the acquisition of conditioned fear measured by fear-potentiated startle. Aim of this study was to explore whether this effect is mediated by the basolateral amygdala, a crucial brain structure for acquisition of conditioned fear. Therefore, AMN082 was locally injected into the basolateral amygdala of rats and the effects of these injections on the acquisition of conditioned fear was measured. Our data clearly show that intra-amygdala injection of AMN082 impairs fear acquisition. This finding demonstrates that amygdaloid mGluR7 controls the learning of conditioned fear.
Asunto(s)
Amígdala del Cerebelo/efectos de los fármacos , Compuestos de Bencidrilo/farmacología , Condicionamiento Clásico/efectos de los fármacos , Receptores de Glutamato Metabotrópico/fisiología , Estimulación Acústica/métodos , Amígdala del Cerebelo/anatomía & histología , Amígdala del Cerebelo/fisiología , Animales , Compuestos de Bencidrilo/administración & dosificación , Condicionamiento Clásico/fisiología , Electrochoque/métodos , Extinción Psicológica/efectos de los fármacos , Extinción Psicológica/fisiología , Miedo/efectos de los fármacos , Miedo/fisiología , Miedo/psicología , Inyecciones/métodos , Aprendizaje/efectos de los fármacos , Aprendizaje/fisiología , Masculino , Memoria/efectos de los fármacos , Memoria/fisiología , Ratas , Ratas Sprague-Dawley , Receptores de Glutamato Metabotrópico/agonistas , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/fisiologíaRESUMEN
Four stereoisomers of (2S)-2-(2'-phosphono-3'-phenylcyclopropyl)glycine were synthesized by a stereocontrolled synthetic procedure and evaluated as mGluRs ligands. The (2S,1'R,2'S,3'R)-isomer (PPCG-2) showed to be a group III mGluRs selective ligand endowed with a moderate potency as mGluR4/mGluR6 agonist.