RESUMO
Non-selective antagonists of metabotropic glutamate receptor subtypes 2 (mGlu2) and 3 (mGlu3) exert rapid antidepressant-like effects by enhancing prefrontal cortex (PFC) glutamate transmission; however, the receptor subtype contributions and underlying mechanisms remain unclear. Here, we leveraged newly developed negative allosteric modulators (NAMs), transgenic mice, and viral-assisted optogenetics to test the hypothesis that selective inhibition of mGlu2 or mGlu3 potentiates PFC excitatory transmission and confers antidepressant efficacy in preclinical models. We found that systemic treatment with an mGlu2 or mGlu3 NAM rapidly activated biophysically unique PFC pyramidal cell ensembles. Mechanistic studies revealed that mGlu2 and mGlu3 NAMs enhance thalamocortical transmission and inhibit long-term depression by mechanistically distinct presynaptic and postsynaptic actions. Consistent with these actions, systemic treatment with either NAM decreased passive coping and reversed anhedonia in two independent chronic stress models, suggesting that both mGlu2 and mGlu3 NAMs induce antidepressant-like effects through related but divergent mechanisms of action.
Assuntos
Regulação Alostérica/fisiologia , Córtex Cerebral/fisiologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Tálamo/fisiologia , Adaptação Psicológica/efeitos dos fármacos , Anedonia/efeitos dos fármacos , Animais , Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/metabolismo , Agonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/metabolismo , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Vias Neurais/fisiologia , Plasticidade Neuronal/fisiologia , Optogenética , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiologia , Proteínas Proto-Oncogênicas c-fos/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Células Piramidais/fisiologia , Tálamo/metabolismoRESUMO
Transient upregulation of GluN2B-containing NMDA receptors (R) in the nucleus accumbens (NAc) is proposed as an intermediate to long-term AMPAR plasticity associated with persistent cocaine-related behaviors. However, cell type- and input-specific contributions of GluN2B underlying lasting actions of cocaine remain to be elucidated. We utilized GluN2B cell type-specific knockouts and optogenetics to deconstruct the role of GluN2B in cocaine-induced NAc synaptic and behavioral plasticity. While reward learning was unaffected, loss of GluN2B in D1 dopamine receptor-expressing cells (D1) led to prolonged retention of reward memory. In control mice, prefrontal cortex (PFC)-D1(+) NAc AMPAR function was unaffected by cocaine exposure, while midline thalamus (mThal)-D1(+) NAc AMPAR function was potentiated but diminished after withdrawal. In D1-GluN2B-/- mice, the potentiation of mThal-D1(+) NAc AMPAR function persisted following withdrawal, corresponding with continued expression of cocaine reward behavior. These data suggest NAc GluN2B-containing NMDARs serve a feedback role and may weaken reward-related memories.