Functional interactions between somatodendritic dopamine release, glutamate receptors and brain-derived neurotrophic...

Dopaminergic nigrostriatal neurons may be considered as bipolar functional entities since they are endowed with the ability to synthesize, store and release the transmitter dopamine (DA) at the somatodendritic level in the substantia nigra (SN). Such dendritic DA release seems to be distinct from the transmitter release occurring at the axon terminal and seems to rely preferentially on volume transmission to exert its physiological effects. An increased glutamatergic (Gluergic) transmission into the SN facilitates such dendritic DA release via activation of NMDA-receptors (NMDA-Rs) and to a lesser extent through group II metabotropic glutamate receptors (mGluRs). In addition, nigral mGluRs functionally interact with NMDA-Rs in the SN, further modulating the NMDA-R-mediated increase of DA release from dendrites in the SN. In turn, dendritically released DA may exert, via D1 receptors, a tonic inhibitory control upon nigral glutamate (Glu). Furthermore, released DA, via D2/D3 autoreceptors, produces an autoinhibitory effect upon DA cell firing and its own release process. An increased Gluergic transmission into the SN may also induce, via activation of NMDA-Rs, an augmented expression of different brain-derived neurotrophic factor (BDNF) gene transcripts in this brain area. Pharmacological evidence suggests that non-NMDA-Rs could also participate in the regulation of BDNF gene expression in the SN. Glu-mediated changes of nigral BDNF expression could regulate, in turn, the expression of important transmitter-related proteins in the SN, such as different NMDA-R subunits, mGluRs and DA-D3 receptors. In conclusion, Glu-DA-BDNF interactions in the SN may play an important role in modulating the flow of neuronal information in this brain structure under normal conditions, as well as during adaptive and plastic responses associated with various neurological and psychiatric disorders.