Functional implications of multiple dopamine receptor subtypes: the D1/D3 receptor coexistence1

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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 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 influence 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.

Introduction

The existence of multiple receptor subtypes represents both a challenge and an opportunity for neuropharmacologists. The challenge is to understand the functional significance of such an apparent redundancy which is, in most cases, maintained all over the evolution. The opportunity is obviously the possibility of developing novel classes of investigational tools or even novel classes of innovative drugs.

These ideas are well illustrated in the case of the six dopamine receptor subtypes which belong to two subfamilies, the D1- and D2-like subfamilies 29, 31, 34. Indeed, the various members among each subfamily display a high degree of resemblance regarding sequence homology, pharmacology and transduction pathways, with the D1- and D2-like receptors being all positively an negatively linked to adenylate cyclase, respectively.

Since the discovery of the D3 receptor [33] we have been trying to delineate its functional role. Our main strategy has consisted in using first the recombinant receptor permanently expressed in a neuroblastoma cell line to define the signaling events and the pharmacology, design selective agents and, then, assess their activity in vivo.

Section snippets

Two intracellular signaling pathways for the D3 receptor: opposite and synergistic interactions with cyclic AMP

Stimulation of NG 108-15 cells transfected with human D3 receptor cDNA [26] led to strong inhibition of cAMP formation (Fig. 1A). Quinpirole inhibited cAMP accumulation triggered by 10 μM forskolin in a concentration-dependent fashion, with an ED50 of 0.3 nM and a maximal inhibition of about 50%. The effect of quinpirole was antagonized by haloperidol, and reproduced by dopamine and several agonists.

Thus, in agreement with their structural homologies, the D3 receptor seems to use similar

Coexisting D1 and D3 receptors in ventral striatum mediate both synergistic and opposite responses

The D3 receptor is selectively distributed in the ventral striatum, a projection area of mesolimbic dopamine neurons, namely in the islands of Calleja and the ventral part of the shell subdivision of nucleus accumbens, regions in which the D2 receptor is not or scarcely expressed 2, 8, 9, 33, but in which D1 receptor mRNA and protein are found 12, 17.

We examined to which degree the D1 and D3 receptor mRNAs are co-expressed in these two areas by using in situ hybridization histochemistry on thin

D1/D3 receptor interplay in the induction and expression of behavioral sensitization

The expression of the D3 receptor in medium sized neurons of the nucleus accumbens is highly dependent upon the dopaminergic innervation: ablation of the afferent neurons by unilateral 6-hydroxydopamine results in a dramatic decrease in the D3 receptor density in ipsilateral nucleus accumbens [22]. This paradoxical change (the D2 receptor is upregulated under these circumstances) depends on the deprivation of an anterogradly-transported factor from dopaminergic neurons, distinct from dopamine

D1/D3 receptor interplay in schizophrenia: a hypothesis

The so-called dopaminergic hypothesis of schizophrenia is based upon essentially pharmacological arguments: all antipsychotics used so far block dopamine D2 receptors, whereas direct or indirect dopamine agonists elicit some of the symptoms of the disease 4, 32. This has led to the suggestion that excessive dopaminergic transmission underlies schizophrenic symptomatology. Nevertheless, it has not been possible to show convincingly any change in either dopaminergic neuron activity or dopamine D2

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