RESUMO
One approach to treating drug abuse uses antidrug antibodies to immunize subjects against the illicit substance rather than administering therapeutics that target the specific CNS site of action. At present, passive vaccination has recognized efficacy in treating certain gross symptoms of drug misuse, namely, motor activation, self-administration, and overdose. However, the potential for antibodies to prevent drug-induced changes involving finer cognitive processes, such as benzodiazepine-associated amnesia, remains unexplored. To address this concept, a flunitrazepam hapten was synthesized and employed in the generation of a panel of high affinity monoclonal antibodies. Anti-flunitrazepam mAb RCA3A3 ( K d,app = 200 nM) was tested in a mouse model of passive immunization and subsequent mole-equivalent challenge with flunitrazepam. Not only was flunitrazepam-induced sedation prevented but immunization also conferred protection to memory consolidation as assessed through contextual and cued fear conditioning paradigms. These results provide evidence that immunopharmacotherapeutic blockade of drug intoxication also preserves complex cognitive function.
Assuntos
Imunoterapia , Transtornos da Memória/imunologia , Transtornos da Memória/prevenção & controle , Animais , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Feminino , Flunitrazepam/imunologia , Locomoção/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Camundongos , Estrutura MolecularRESUMO
Cortistatin-14 (CST) is a neuropeptide expressed in cortical and hippocampal interneurons that shares 11 of 14 residues with somatostatin. In contrast to somatostatin, infusion of CST decreases locomotor activity and selectively enhances slow wave sleep. Here, we show that transgenic mice that overexpress cortistatin under the control of neuron-specific enolase promoter do not express long-term potentiation in the dentate gyrus. This blockade of dentate LTP correlates with profound impairment of hippocampal-dependent spatial learning. Exogenously applied CST to slices of wild-type mice also blocked induction of LTP in the dentate gyrus. Our findings implicate cortistatin in the modulation of synaptic plasticity and cognitive function. Thus, increases in hippocampal cortistatin expression during aging could have an impact on age-related cognitive deficits.
Assuntos
Hipocampo/metabolismo , Deficiências da Aprendizagem/genética , Aprendizagem/fisiologia , Potenciação de Longa Duração/genética , Peptídeos/metabolismo , Transmissão Sináptica/genética , Envelhecimento/genética , Envelhecimento/metabolismo , Animais , Giro Denteado/metabolismo , Giro Denteado/fisiopatologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/genética , Peptídeos e Proteínas de Sinalização Intercelular , Deficiências da Aprendizagem/metabolismo , Deficiências da Aprendizagem/fisiopatologia , Masculino , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Transtornos da Memória/fisiopatologia , Camundongos , Camundongos Transgênicos , Peptídeos/genética , Regiões Promotoras Genéticas/genéticaRESUMO
Using 5-HT(7) receptor knockout mice it has been shown that the 5-HT(7) receptor is the main mediator of serotonin-induced hypothermia but very little is known about the relevance of 5-HT(7) receptors in behaviour. We here report that lack of 5-HT(7) receptors leads to a specific learning deficit that is not due to general sensory or behavioural deficits. The knockout mice show impaired contextual fear conditioning but no significant deficits in motor and spatial learning or cued and operant conditioning. In addition, we demonstrate that 5-HT(7) receptor knockout mice display decreased long-term synaptic plasticity within the CA1 region of the hippocampus. The results indicate an important role for the 5-HT(7) receptor in contextual hippocampal-dependent learning and suggest a possible neuronal correlate for such a role is present within the CA1 region of the hippocampus.