Brain-derived neurotrophic factor (BDNF), like other neurotrophins, is a polypeptidic factor initially regarded to be responsible for neuron proliferation, differentiation and survival, through its uptake at nerve terminals and retrograde transport to the cell body. A more diverse role for BDNF has emerged progressively from observations showing that it is also transported anterogradely, is released on neuron depolarization, and triggers rapid intracellular signals and action potentials in central neurons. Here we report that BDNF elicits long-term neuronal adaptations by controlling the responsiveness of its target neurons to the important neurotransmitter, dopamine. Using lesions and gene-targeted mice lacking BDNF, we show that BDNF from dopamine neurons is responsible for inducing normal expression of the dopamine D3 receptor in nucleus accumbens both during development and in adulthood. BDNF from corticostriatal neurons also induces behavioural sensitization, by triggering overexpression of the D3 receptor in striatum of hemiparkinsonian rats. Our results suggest that BDNF may be an important determinant of pathophysiological conditions such as drug addiction, schizophrenia or Parkinson's disease, in which D3 receptor expression is abnormal.

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Traditionally, the interaction of G protein-coupled receptors has been described by models that assume that the receptor exists as a monomer coupled to G protein in a 1:1 stoichiometry. However, these classical models of receptor/G protein coupling may be oversimplified. It has now been shown that many G protein-coupled receptors can form dimers or higher order oligomers and that this phenomenon has relevance to receptor function (for a review, see Ref. 6). Dopamine receptors have also been shown to form dimers and higher order oligomers. Evidence has been provided for D 1 , D 2 , and D 3 homodimers in transfected cell lines (7-9), and D 2 receptors have been shown to exist as dimers in human and rat brain tissues (10). Moreover, Rocheville et al. (11) have recently shown that the dopamine D 2 receptors not only form homodimers but also form heterodimers with somatostatin SSTR 5 receptors. In addition, Gines et al. (12) have shown that the dopamine D 1 receptor forms hetero-oligomers with the adenosine A 1 receptor.As the issue of G protein-coupled receptor homo-and heterodimerization is becoming more and more important, it is crucial to define the mechanism(s) of receptor-receptor interactions in order to predict which receptors can interact with one another. The results obtained until now suggest that more than one mechanism exists and that one receptor can interact with another in more than one way.One of the mechanisms that have been proposed to explain receptor dimerization is the phenomenon of domain swapping