RESUMO
Preclinical and clinical data have identified ketamine, a non-selective NMDAR (N-methyl-D-aspartate receptor) antagonist, as a promising medication for patients who do not respond to treatment with monoamine-based antidepressants. Moreover, unlike the current monoamine-based antidepressants, ketamine has a long-lasting effect already after a single dose. The mechanisms of ketamine action remain to be fully understood. Using a recently developed microelectrode array (MEA), which allows sub-second measurements of fluctuating glutamate concentrations, we studied here the effects of in vivo local application of the ketamine and of the N2B subunit-specific antagonist Ro25-6981 upon evoked glutamate release. Both ligands inhibit glutamate release in subregions of the hippocampus and prefrontal cortex. Likewise, acute systemic ketamine treatment, at an antidepressant dose, caused a reduction in evoked glutamate release in the subiculum. We suggest that the effects of ketamine and Ro25-6981 in the subiculum could involve blockade of presynaptic NMDA receptors containing N2B subunits.
Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/provisão & distribuição , Hipocampo/metabolismo , Ketamina/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Animais , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Potenciais Pós-Sinápticos Excitadores/fisiologia , Ácido Glutâmico/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Ketamina/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microeletrodos , Fenóis/administração & dosagem , Fenóis/farmacologia , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Distribuição AleatóriaRESUMO
Cognitive impairments are common in depression and involve dysfunctional serotonin neurotransmission. The 5-HT1B receptor (5-HT(1B)R) regulates serotonin transmission, via presynaptic receptors, but can also affect transmitter release at heterosynaptic sites. This study aimed at investigating the roles of the 5-HT(1B)R, and its adapter protein p11, in emotional memory and object recognition memory processes by the use of p11 knockout (p11KO) mice, a genetic model for aspects of depression-related states. 5-HT(1B)R agonist treatment induced an impairing effect on emotional memory in wild type (WT) mice. In comparison, p11KO mice displayed reduced long-term emotional memory performance. Unexpectedly, 5-HT(1B)R agonist stimulation enhanced memory in p11KO mice, and this atypical switch was reversed after hippocampal adeno-associated virus mediated gene transfer of p11. Notably, 5-HT(1B)R stimulation increased glutamatergic neurotransmission in the hippocampus in p11KO mice, but not in WT mice, as measured by both pre- and postsynaptic criteria. Magnetic resonance spectroscopy demonstrated global hippocampal reductions of inhibitory GABA, which may contribute to the memory enhancement and potentiation of pre- and post-synaptic measures of glutamate transmission by a 5-HT(1B)R agonist in p11KO mice. It is concluded that the level of hippocampal p11 determines the directionality of 5-HT(1B)R action on emotional memory processing and modulates hippocampal functionality. These results emphasize the importance of using relevant disease models when evaluating the role of serotonin neurotransmission in cognitive deficits related to psychiatric disorders.