Functional roles for dopamine-receptor subtypes
Membranes from CHO cell lines expressing D1, D2, D3, and D4 receptors were used to demonstrate preferential affinities of the dopamine (DA) agonists U-91356A and pramipexole to D2 and D3 receptors, respectively; quinpirole bound with approximately equal affinities to D2, D3, and D4 receptors, and apomorphine bound with good affinity to all subtypes. Both pramipexole and U-91356A depressed DA neuronal cell firing in the substantia nigra pars compacta and the ventral tegmental area. Combinations of the two agonists resulted in greater than additive effects, indicating D2-D3 synergism at the somatodendritic autoreceptor level. The D3-selective antagonist U-99194A selectively bound to D3 receptors and more effectively blocked apomorphine and the pramipexole-U-91356A combination than it blocked either compound alone. Type 11 caudate neurons of anesthetized rats were excited by amphetamine, apomorphine, quinpirole, and pramipexole, the preferential D3 agonist, but not by U-91356A, the preferential D2 agonist. In anesthetized rats, recording electrodes were also placed in the substantia nigra pars reticulata (SNPR), a major output target of the caudate. In the SNPR, amphetamine, apomorphine, and quinpirole excited some neurons and inhibited others. Pramipexole inhibited a subpopulation of SNPR neurons, whereas U-91356A stimulated a subpopulation of SNPR neurons. Similarly, pramipexole stimulated some nucleus accumbens (NA) neurons and inhibited others. In 2-deoxyglucose imaging studies, quinpirole almost totally stimulated responsive areas; however, some inhibitory effects were observed. The effects of pramipexole on energy metabolism were limited to stimulation, whereas the effects of U-91356A were almost totally inhibitory. U-99194A blocked stimulation by amphetamine in cortical areas but not in others. It is concluded that these preferential D2- and D3-receptor agonists synergistically interact at somatodendritic DA autoreceptors and that, at higher doses, they have opposite effects, albeit on separate postsynaptic pathways. The relevance to new approaches for treating schizophrenia and Parkinson's disease is discussed.
Piercey, MF; Camacho-Ochoa, M; Smith, MW; Caron, MG; Bedard, PJ; Willner, P
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