FUNCTIONAL IMPLICATIONS OF MULTIPLE DOPAMINE-RECEPTOR SUBTYPES - THE D-1 D-3 RECEPTOR COEXISTENCE/

The D-3 dopamine receptor, a D-2-like receptor, is selectively express ed in the ventral striatum, particularly in the shell of nucleus accum bens and islands of Calleja, where it is found in medium sized substan ce P neurons. The latter co-express the D-1 receptor whose interaction with the D-3 receptor was studied by treating rats with selective ago nists and antagonists. In agreement with the opposite cAMP response, t hey mediate in cultured neuroblastoma cells, the D-1 and D-3 receptors exerted opposite influences on c-fos expression in islands of Calleja . However, in agreement with the synergistic influence of cAMP on D-3 receptor-mediated mitogenesis on the same cultured cells, D-1 and D-3 receptor stimulation in vivo synergistically enhanced preprotachykinin mRNA in the shell of accumbens. This indicates that the two receptor subtypes may affect neurons in either synergy or opposition according to the cell or signal generated. Levodopa-induced behavioral sensitiza tion in hemiparkinsonian rats is another example of D-1/D-3 receptor i nteraction. Hence repeated levodopa administration induces the ectopic appearance of the D-3 receptor in substance P/dynorphin, striatonigra l neurons of the dorsal striatum. This induction is secondary to D-1 r eceptor stimulation in neurons of the denervated side and fully accoun ts for the sensitization, i.e. the increased behavioral responsiveness to levodopa. During brain development, a similar process could operat e to control the late appearance of the D-3 receptor in D-1-receptor b earing neurons of the ventral striatum at a time at which they start t o be innervated by dopamine neurons. Finally, taking into account a va riety of genetic, developmental, neuroimaging and pharmacological data , we postulate that imbalances between the levels of DI and Dg recepto rs in the same neurons could be responsible for schizophrenic disorder s. (C) 1998 Elsevier Science B.V. All rights reserved.