ABSTRACT
Cholinergic signaling plays a key role in regulating striatal function. The principal source of acetylcholine in the striatum is the cholinergic interneurons which, although low in number, densely arborize to modulate striatal neurotransmission. This modulation occurs via strategically positioned nicotinic and muscarinic acetylcholine receptors that influence striatal dopamine, GABA and other neurotransmitter release. Cholinergic interneurons integrate multiple striatal synaptic inputs and outputs to regulate motor activity under normal physiological conditions. Consequently, an imbalance between these systems is associated with basal ganglia disorders. Here, we provide an overview of how striatal cholinergic interneurons modulate striatal activity under normal and pathological conditions. Numerous studies show that nigrostriatal damage such as that occurs with Parkinson's disease affects cholinergic receptor-mediated striatal activity. This altered cholinergic signaling is an important contributor to Parkinson's disease as well as to the dyskinesias that develop with L-dopa therapy, the gold standard for treatment. Indeed, multiple preclinical studies show that cholinergic receptor drugs may be beneficial for the treatment of L-dopa-induced dyskinesias. In this review, we discuss the evidence indicating that therapeutic modulation of the cholinergic system, particularly targeting of nicotinic cholinergic receptors, may offer a novel approach to manage this debilitating side effect of dopamine replacement therapy for Parkinson's disease.
Subject(s)
Corpus Striatum/physiopathology , Dyskinesia, Drug-Induced/physiopathology , Interneurons/metabolism , Parkinson Disease/physiopathology , Animals , Corpus Striatum/metabolism , Dyskinesia, Drug-Induced/metabolism , Humans , Levodopa/adverse effects , Parkinson Disease/metabolismABSTRACT
Clinical symptoms of Parkinson's disease only become evident after 70-80% reductions in striatal dopamine. To investigate the importance of pre-synaptic dopaminergic mechanisms in this compensation, we determined the effect of nigrostriatal damage on dopaminergic markers and function in primates. MPTP treatment resulted in a graded dopamine loss with moderate to severe declines in ventromedial striatum (approximately 60-95%) and the greatest reductions (approximately 95-99%) in dorsolateral striatum. A somewhat less severe pattern of loss was observed for striatal nicotinic receptor, tyrosine hydroxylase and vesicular monoamine transporter expression. Declines in striatal dopamine uptake and transporter sites were also less severe than the reduction in dopamine levels, with enhanced dopamine turnover in the dorsolateral striatum after lesioning. The greatest degree of adaptation occurred for nicotine-evoked [(3)H]dopamine release from striatal synaptosomes, which was relatively intact in ventromedial striatum after lesioning, despite > 50% declines in dopamine. This maintenance of evoked release was not due to compensatory alterations in nicotinic receptor characteristics. Rather, there appeared to be a generalized preservation of release processes in ventromedial striatum, with K(+)-evoked release also near control levels after lesioning. These combined compensatory mechanisms help explain the finding that Parkinson's disease symptomatology develops only with major losses of striatal dopamine.
Subject(s)
Corpus Striatum/pathology , Dopamine/metabolism , Presynaptic Terminals/physiology , Substantia Nigra/pathology , 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Animals , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Female , Male , Neurotoxins , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/pathology , Potassium/pharmacology , Presynaptic Terminals/drug effects , Saimiri , Substantia Nigra/drug effects , Substantia Nigra/metabolismABSTRACT
Se realizo determinacion serica de magnesio (Mg++) en 79 ninos; 17 casos eran desnutridos con kwashiorkor y 22 eran marasmaticos. Cuarenta ninos eutroficos que sirvieron de control. El valor promedio de Mg++ serico en ninos desnutridos con kwashiorkor fue de 1.08 +/- 0.05 mEq/l mientras que en los marasmaticos fue de 1.83 +/- 0.08 mEq/l. En los eutroficos el valor promedio de Mg++ fue de 1.7 +/- 0.06 mEq/l El valor promedio de Mg++ en los ninos con kwashiorkor fue significativamente menor que en los desnutridos marasmaticos y los ninos eurotroficos, p < 0.01. No se encontro diferencia entre los desnutridos mararasmaticos y el grupo control. Se analizan las posibles hipotesis que explicarian estas diferencias
