RESUMO
Neuroleptics are thought to exert their anti-psychotic effects by counteracting a hyper-dopaminergic transmission. Here, we have examined the dopaminergic status of STOP (stable tubule only polypeptide) null mice, which lack a microtubule-stabilizing protein and which display neuroleptic-sensitive behavioural disorders. Dopamine transmission was investigated using both behavioural analysis and measurements of dopamine efflux in different conditions. Compared to wild-type mice in basal conditions or following mild stress, STOP null mice showed a hyper-locomotor activity, which was erased by neuroleptic treatment, and an increased locomotor reactivity to amphetamine. Such a behavioural profile is indicative of an increased dopaminergic transmission. In STOP null mice, the basal dopamine concentrations, measured by quantitative microdialysis, were normal in both the nucleus accumbens and the striatum. When measured by electrochemical techniques, the dopamine efflux evoked by electrical stimulations mimicking physiological stimuli was dramatically increased in the nucleus accumbens of STOP null mice, apparently due to an increased dopamine release, whereas dopaminergic uptake and auto-inhibition mechanisms were normal. In contrast, dopamine effluxes were slightly diminished in the striatum. Together with previous results, the present study indicates the association in STOP null mice of hippocampal hypo-glutamatergy and of limbic hyper-dopaminergy. Such neurotransmission defects are thought to be central to mental diseases such as schizophrenia.
Assuntos
Dopamina/fisiologia , Proteínas Associadas aos Microtúbulos/deficiência , Proteínas Associadas aos Microtúbulos/genética , Proteínas do Tecido Nervoso/deficiência , Proteínas do Tecido Nervoso/genética , Transmissão Sináptica/genética , Potenciais de Ação/genética , Potenciais de Ação/fisiologia , Animais , Antipsicóticos/farmacologia , Ritmo Circadiano/efeitos dos fármacos , Ritmo Circadiano/genética , Ritmo Circadiano/fisiologia , Escuridão , Estimulação Elétrica , Luz , Masculino , Camundongos , Camundongos Knockout , Proteínas Associadas aos Microtúbulos/fisiologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Atividade Motora/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Transmissão Sináptica/fisiologiaRESUMO
Abstract Neurotensin is a tridecapeptide neurotransmitter known to be involved in psychiatric disorders, various physiological processes and several different neurobiological mechanisms, including modulation of accumbal dopamine release. Two neurotensin extracellular binding sites, namely NT1- and NT2-receptor (NT1R and NT2R), have been cloned from the rat brain. These receptors are distinguishable by their different in vitro pharmacological properties but the available pharmacological tools have weak in vivo potency and specificity. The use of genetically engineered knock-out mice has provided a powerful alternative to the classical pharmacological approach to investigate their respective roles. In this study, using in vivo differential pulse amperometry, we show that, in wild-type mice, neurotensin application into the ventral tegmental area dose-dependently evokes dopamine efflux in the nucleus accumbens. This neurotensin-mediated efflux is dramatically decreased in mice lacking NT1R while it is unaffected in NT2R-deleted mice. This finding indicates that a large part of the dopamine efflux evoked by neurotensin in the nucleus accumbens of wild-type mice is mediated via NT1R present in the ventral tegmental area.
