PHARMACOLOGY, BIOCHEMISTRY AND PHYSIOLOGY OF CENTRAL NEUROTRANSMITTERS

点击翻译按钮获取中文摘要

Our goal is to develop improved pharmacotherapies for central nervous sytem disorders based on the relation between transmitter mechanisms and clinical function. Investigations continue to focus on Parkinson's disease and Alzheimer's disease. In Parkinson's disease, alterations in central pharmacokinetic or pharmacodynamic factors appear responsible for the marked reductions in efficacy half-life of levodopa in patients with wearing-off and especially those with on-off phenomena. The stabilization of circulating levodopa levels, with continuous levodopa or levodopa methylester infusions or sustained release formulations, rapidly eliminates wearing-off responses; on-off phenomenon diminish more slowly and less completely. D-1 and D-2 dopamine receptor mechanisms, evaluated preclinically in relation to their potential contribution to the pathogenesis of these motor fluctuation, appear complexly interactive: D-1 receptor stimulation may provide a tonic background allowing the phasic component of D-2 stimulation to become effective. In parkinsonian patients, however, administration of a selective D-1 agonist failed to influence motor function. In Alzheimer's disease, efforts to identify transmitter system abnormalities which might provide a basis for symptomatic therapies have recently emphasized cortical peptidergic neurons, especially the somatostatin system. Spinal fluid levels of this neuropeptide are substantially below control levels; the magnitude of these reductions correlate closely with dementia severity as well as with PET determined rates of cortical glucose utilization, especially in the posterior parietal area. Nevertheless, treatment with a potent somatostatin depleting agent, designed in part to elucidate the role of this peptidergic system in dementia, significantly increased plasma growth hormone levels but had no effect on cognitive or motor function.