RESUMO
Cognitive deficits are long-lasting consequences of drug use, yet the convergent mechanism by which classes of drugs with different pharmacological properties cause similar deficits is unclear. We find that both phencyclidine and methamphetamine, despite differing in their targets in the brain, cause the same glutamatergic neurons in the medial prefrontal cortex of male mice to gain a GABAergic phenotype and decrease expression of their glutamatergic phenotype. Suppressing drug-induced gain of GABA with RNA-interference prevents appearance of memory deficits. Stimulation of dopaminergic neurons in the ventral tegmental area is necessary and sufficient to produce this gain of GABA. Drug-induced prefrontal hyperactivity drives this change in transmitter identity. Returning prefrontal activity to baseline, chemogenetically or with clozapine, reverses the change in transmitter phenotype and rescues the associated memory deficits. This work reveals a shared and reversible mechanism that regulates the appearance of cognitive deficits upon exposure to different drugs.
Assuntos
Metanfetamina , Fenciclidina , Córtex Pré-Frontal , Área Tegmentar Ventral , Ácido gama-Aminobutírico , Animais , Masculino , Metanfetamina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Camundongos , Fenciclidina/farmacologia , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismo , Ácido gama-Aminobutírico/metabolismo , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Camundongos Endogâmicos C57BL , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/efeitos dos fármacos , Ácido Glutâmico/metabolismo , Clozapina/farmacologia , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/metabolismoRESUMO
Cognitive deficits are a long-lasting consequence of drug use, yet the convergent mechanism by which classes of drugs with different pharmacological properties cause similar deficits is unclear. We find that both phencyclidine and methamphetamine, despite differing in their targets in the brain, cause the same glutamatergic neurons in the medial prefrontal cortex to gain a GABAergic phenotype and decrease their expression of the vesicular glutamate transporter. Suppressing the drug-induced gain of GABA with RNA-interference prevents the appearance of memory deficits. Stimulation of dopaminergic neurons in the ventral tegmental area is necessary and sufficient to produce this gain of GABA. Drug-induced prefrontal hyperactivity drives this change in transmitter identity. Returning prefrontal activity to baseline, chemogenetically or with clozapine, reverses the change in transmitter phenotype and rescues the associated memory deficits. The results reveal a shared and reversible mechanism that regulates the appearance of cognitive deficits upon exposure to different drugs.