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agents which have been used empirically for many years in the treatment of Parkinson disease and dystonia depends on their capacity to antagonize ACh at sites within the basal ganglia and in projections from the pedunculopontine nuclei Acetylcholine appears also to act on the presynaptic membrane of striatal cells and to in uence their release of neurotransmitters, as discussed below In addition, the basal ganglia contain other biologically active substances substance P, enkephalin, cholecystokinin, somatostatin, and neuropeptide Y which may enhance or diminish the effects of other neurotransmitters, ie, they act as neuromodulators The neurons utilizing these substances and the manner in which they operate are just now being identi ed Of the catecholamines, dopamine has the most pervasive role in the function of the basal ganglia It can be said that it is among the most important in brain disease, since disturbances of dopamine signaling are essential abnormalities of several CNS disorders including Parkinsonism, schizophrenia, attention de cit disorder, and drug abuse Within the basal ganglia, the areas richest in dopamine are the substantia nigra, where it is synthesized in the nerve cell bodies of the pars compacta, and the termination of these bers in the striatum In the most simpli ed models, stimulation of the dopaminergic neurons of the substantia nigra induces a speci c response in the striatum namely, an inhibitory effect on the already low ring rate of neostriatal neurons However, the effects of dopamine have proved more dif cult to resolve, in large part because there are now ve known types of postsynaptic dopamine receptors (D1 to D5), each with its particular anatomic distribution and pharmacologic action This heterogeneity is re ected in the excitatory effect of dopamine on the small spiny neurons of the putamen and an inhibitory effect on others The ve types of dopamine receptors are found in differing concentration throughout various parts of the brain, each displaying differing af nities for dopamine itself and for various drugs and other agents (Table 4-2; see Jenner) The D1 and D2 receptors are highly represented in the striatum, D3 in the nucleus accumbens, D4 in the frontal cortex and certain limbic structures, and D5 in the hippocampus In the striatum, the effects of dopamine act as a class of D1-like (D1 and D5 subtypes) and D2-like (D2, D3, and D4 subtypes) receptors Stimulation of the D1 class stimulates adenyl cyclase, while D2 receptor binding inhibits this enzyme Whether dopamine functions in an excitatory or inhibitory manner at a particular synapse is determined by the local receptor As mentioned earlier, excitatory D1 receptors predominate on the small spiny putamenal neurons that are the origin of the direct striatopallidal output pathway, while D2 receptors mediate the inhibitory in uence of dopamine on the indirect striatopallidal output, as indicated in Fig 4-4 Some of the clinical and pharmacologic effects of dopamine are made clear by considering both the anatomic sites of various receptors and their physiologic effects For example, it appears that drug-induced parkinsonian syndromes and tardive dyskinesias (described further on) are prone to occur when drugs are administered that competitively bind to the D2 receptor, but that the newer antipsychotic drugs, which produce fewer of these effects, have a stronger af nity for the D4 receptor However, the situation is actually far more complex, in part due to the synergistic activities of D1 and D2 receptors, each potentiating the other at some sites of convergence, and the presence on the presynaptic terminals of nigrostriatal neurons of D2 receptors, which inhibit dopamine synthesis and release Even these intricacies do not capture the complexity of neural. birt pdf 417 Eclipse BIRT PDF417 Barcode Maker add-in makes PDF417 ...
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