RESUMO
Recently the two vesicular-glutamate-transporters VGLUT1 and VGLUT2 have been cloned and characterized. VGLUT1 and VGLUT2 together label all glutamatergic neurons, but because of their distinct expression patterns in the brain they facilitate our ability to define between a VGLUT1-positive cortical and a VGLUT2-positive subcortical glutamatergic systems. We have previously demonstrated an increased cortical VGLUT1 expression as marker of antidepressant activity. Here, we assessed the effects of different psychotropic drugs on brain VGLUT2 mRNA and protein expression. The typical antipsychotic haloperidol, and the atypicals clozapine and risperidone increased VGLUT2 mRNA selectively in the central medial/medial parafascicular, paraventricular and intermediodorsal thalamic nuclei; VGLUT2 protein was accordingly amplified in paraventricular and ventral striatum and in prefrontal cortex. The antidepressants fluoxetine and desipramine and the sedative anxiolytic diazepam had no effect. These results highlight the implication of thalamo-limbic glutamatergic pathways in the action of antipsychotics. Increased VGLUT2 expression in these neurons might constitute a marker for antipsychotic activity and subcortical glutamate neurotransmission might be a possible novel target for future generation antipsychotics.
Assuntos
Antipsicóticos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Sistema Límbico/efeitos dos fármacos , Tálamo/efeitos dos fármacos , Proteína Vesicular 2 de Transporte de Glutamato/metabolismo , Análise de Variância , Animais , Sistema Límbico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vias Neurais/efeitos dos fármacos , Vias Neurais/metabolismo , RNA Mensageiro/metabolismo , Tálamo/metabolismo , Proteína Vesicular 2 de Transporte de Glutamato/genéticaRESUMO
BACKGROUND: Knockout (KO) mice invalidated for the dopamine transporter (DAT) constitute a powerful animal model of neurobiological alterations associated with hyperdopaminergia relevant to schizophrenia and attention-deficit/hyperactivity disorder (ADHD). METHODS: Because of continuously increasing evidence for a neuromodulatory role of endocannabinoids in dopamine-related pathophysiological responses, we assessed endocannabinoid signaling in DAT KO mice and evaluated the ability of endocannabinoid ligands to normalize behavioral deficits, namely spontaneous hyperlocomotion in these mice. RESULTS: In DAT KO mice, we found markedly reduced anandamide levels, specifically in striatum, the dopamine nerve terminal region. Furthermore, three distinct indirect endocannabinoid agonists, the selective anandamide reuptake inhibitors AM404 and VDM11 and the fatty acid amidohydrolase inhibitor AA5HT, attenuated spontaneous hyperlocomotion in DAT KO mice. The hypolocomotor effects of AM404, VDM11, and AA5HT were significantly attenuated by co-administration of the transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine but not the selective cannabinoid type 1 (CB1)receptor antagonist AM251. Interestingly, TRPV1 binding was increased in the striatum of DAT KO mice, while CB1 receptor binding was unaffected. CONCLUSIONS: These data indicate a dysregulated striatal endocannabinoid neurotransmission associated with hyperdopaminergic state. Restoring endocannabinoid homeostasis in active synapses might constitute an alternative therapeutic strategy for disorders associated with hyperdopaminergia. In this process, TRPV1 receptors seem to play a key role and represent a novel promising pharmacological target.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Moduladores de Receptores de Canabinoides/farmacologia , Moduladores de Receptores de Canabinoides/fisiologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/fisiologia , Dopamina/metabolismo , Endocanabinoides , Canais de Cátion TRPV/fisiologia , Amidoidrolases/antagonistas & inibidores , Animais , Ácidos Araquidônicos/metabolismo , Ácidos Araquidônicos/farmacologia , Capsaicina/análogos & derivados , Capsaicina/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/fisiopatologia , Modelos Animais de Doenças , Proteínas da Membrana Plasmática de Transporte de Dopamina/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Camundongos , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Alcamidas Poli-Insaturadas , Receptor CB1 de Canabinoide/efeitos dos fármacos , Receptor CB1 de Canabinoide/fisiologia , Serotonina/análogos & derivados , Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Canais de Cátion TRPV/efeitos dos fármacosRESUMO
The two recently characterized vesicular glutamate transporters (VGLUT) presynaptically mark and differentiate two distinct excitatory neuronal populations and thus define a cortical and a subcortical glutamatergic system (VGLUT1 and VGLUT2 positive, respectively). These two systems might be differentially implicated in brain neuropathology. Still, little is known on the modalities of VGLUT1 and VGLUT2 regulations in response to pharmacological or physiological stimuli. Given the importance of cortical neuronal activity in psychosis we investigated VGLUT1 mRNA and protein expression in response to chronic treatment with commonly prescribed psychotropic medications. We show that agents with antidepressant activity, namely the antidepressants fluoxetine and desipramine, the atypical antipsychotic clozapine, and the mood stabilizer lithium increased VGLUT1 mRNA expression in neurons of the cerebral cortex and the hippocampus and in concert enhanced VGLUT1 protein expression in their projection fields. In contrast the typical antipsychotic haloperidol, the cognitive enhancers memantine and tacrine, and the anxiolytic diazepam were without effect. We suggest that VGLUT1 could be a useful marker for antidepressant activity. Furthermore, adaptive changes in VGLUT1 positive neurons could constitute a common functional endpoint for structurally unrelated antidepressants, representing promising antidepressant targets in tracking specificity, mechanism, and onset at action.
Assuntos
Antidepressivos/farmacologia , Córtex Cerebral/citologia , Regulação da Expressão Gênica/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Proteína Vesicular 1 de Transporte de Glutamato/metabolismo , Animais , Antipsicóticos/farmacologia , Autorradiografia/métodos , Comportamento Animal , Cognição/efeitos dos fármacos , Diazepam/farmacologia , Hipocampo/citologia , Imuno-Histoquímica/métodos , Hibridização In Situ/métodos , Lítio/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Relaxantes Musculares Centrais/farmacologia , Neurônios/metabolismo , Psicotrópicos/administração & dosagem , Proteína Vesicular 1 de Transporte de Glutamato/genéticaRESUMO
Taurine is the most abundant amino acid in the retina. In the 1970s, it was thought to be involved in retinal diseases with photoreceptor degeneration, because cats on a taurine-free diet presented photoreceptor loss. However, with the exception of its introduction into baby milk and parenteral nutrition, taurine has not yet been incorporated into any commercial treatment with the aim of slowing photoreceptor degeneration. Our recent discovery that taurine depletion is involved in the retinal toxicity of the antiepileptic drug vigabatrin has returned taurine to the limelight in the field of neuroprotection. However, although the retinal toxicity of vigabatrin principally involves a deleterious effect on photoreceptors, retinal ganglion cells (RGCs) are also affected. These findings led us to investigate the possible role of taurine depletion in retinal diseases with RGC degeneration, such as glaucoma and diabetic retinopathy. The major antioxidant properties of taurine may influence disease processes. In addition, the efficacy of taurine is dependent on its uptake into retinal cells, microvascular endothelial cells and the retinal pigment epithelium. Disturbances of retinal vascular perfusion in these retinal diseases may therefore affect the retinal uptake of taurine, resulting in local depletion. The low plasma taurine concentrations observed in diabetic patients may further enhance such local decreases in taurine concentration. We here review the evidence for a role of taurine in retinal ganglion cell survival and studies suggesting that this compound may be involved in the pathophysiology of glaucoma or diabetic retinopathy. Along with other antioxidant molecules, taurine should therefore be seriously reconsidered as a potential treatment for such retinal diseases.
Assuntos
Degeneração Retiniana/prevenção & controle , Taurina/fisiologia , Animais , Humanos , Fármacos Neuroprotetores/uso terapêutico , Degeneração Retiniana/fisiopatologia , Taurina/química , Taurina/uso terapêuticoRESUMO
There is a prominent role of the cannabinoid system to control basal ganglia function, in respect to reward, psychomotor function and motor control. Cannabinoid dysregulations might have a pathogenetic role in dopamine- and basal ganglia related neuropsychiatric disorders, such as drug addiction, psychosis, Parkinson's disease and Huntington's disease. This review highlights interactions between cannabinoids, and dopamine, to modulate neurotransmitter release and synaptic plasticity in the context of drug addiction, psychosis and cognition. Modulating endocannabinoid function, as a plasticity based therapeutic strategy, in the above pathologies with particular focus on cannabinoid receptor type 1 (CB1 receptor) antagonists/inverse agonists, is discussed. On the basis of the existing literature and of new experimental evidence presented here, CB1 receptor antagonists might be beneficial in disease states associated with hedonic dysregulation, and with cognitive dysfunction in particular in the context of psychosis. It is suggested that this effects might be mediated via a hyperglutamatergic state through metabotropic glutamate activation. Indications for endocannabinoid catabolism inhibitors in psychiatric disorders, that might be CB1 receptor independent and might involve TRPV1 receptors, are also discussed.