Towards an Understanding of Integrative Brain Functions

Functional implications of multiple dopamine receptor subtypes: the D₁/D₃ receptor coexistence

Jean-Charles Schwartz ^a,*, Jorge Diaz ^b, Régis Bordet^b, Nathalie Griffon^a, Sylvie Perachon ^a, Catherine Pilon^a, Sophie Ridray^b, Pierre Sokoloff<sup>a

a</sup>Unité de Neurobiologe et Pharmacologie (U.109) de l'INSERM, Centre Paul Broca, 2ter rue d'Alésia, 75014 Paris, France, ^bLaboratoire de Physiologie, Faculté de Pharmacie, 4 Avenue de l'Observatoire, 75006 Paris, France

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Abstract
The D₃ dopamine receptor, a D₂-like receptor, is selectively expressed in the ventral striatum, particularly in the shell of the nucleus accumbens and islands of Calleja, where it is found in medium sized substance P neurons. The latter co-express the D₁ receptor whose interaction with the D₃ receptor was studied by treating rats with selective agonists and antagonists. In agreement with the opposite cAMP response, they mediate in cultured neuroblastoma cells, the D₁ and D₃ receptors exerted opposite influences on c-fos expression in islands of Calleja. However, in agreement with the synergistic infuence of cAMP on D₃ receptor-mediated mitogenesis on the same cultured cells, D₁ and D₃ 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 sensitization in hemiparkinsonian rats is another example of D₁/D₃ receptor interaction. Hence repeated levodopa administration induces the ectopic appearance of the D₃ receptor in substance P/dynorphin, striatonigral neurons of the dorsal striatum. This induction is secondary to D₁ receptor stimulation in neurons of the denervated side and fully accounts for the sensitization, i.e. the increased behavioral responsiveness to levodopa. During brain development, a similar process could operate to control the late appearance of the D₃ receptor in D₁-receptor bearing neurons of the ventral striatum at a time at which they start to be innervated by dopamine neurons. Finally, taking into account a variety of genetic, developmental, neuroimaging and pharmacological data, we postulate that imbalances between the levels of D₁ and D₃ receptors in the same neurons could be responsible for schizophrenic disorders.

*Corresponding author: schwartz@broca.inserm.fr

Brain Research Reviews 26 (1998) 236-242
Copyright © 1998 Elsevier Science B. V. All rights reserved.