Nigral dopamine release – preclinical studies of its implication in motor functions

Abstract

Since the discovery of nigral somatodendritic dopamine release thirty years ago, the physiological function and relevance of this phenomenon have been debated. Autoinhibitory functions, as well as modulation of GABA-ergic, glutamatergic and serotonergic transmission in substantia nigra (SN) pars reticulata have been described, but the physiological importance of these mechanism for motor functions has been difficult to determine. We have previously described a method for combining microdialysis dopamine measurements in SN and the striatum of awake rats with reverse dialysis of drugs during simultaneous motor performance assessments on an accelerating rod. To compare the importance of physiological nigral and striatal dopamine release, this method was used to induce a local pharmacological depletion of dopamine in SN or striatum by reverse dialysis of tetrabenazine (TBZ) in either or both of the regions. The extent of local depletion was evaluated by measuring dopamine in the dialysates ([DA]out)and by post mortem biochemistry of the dialysed regions. Local treatment with TBZ reduced [DA]out by over 90% in the treated region. Motor performance was, however, only significantly deteriorated by nigral or dual TBZ treatment. Furthermore, [DA]out was increased in SN during rotarod activity and striatal TBZ-treatment. Whereas striatal tissue content of dopamine was not affected by local TBZ treatment, nigral dopamine content was decreased by 50% by treatment in SN. For this reason it is not possible to justly compare the motor performance effects of nigral and striatal TBZ-treatment. Nevertheless, the results strengthen the idea that nigral dopamine release is physiologically important, and we suggest that it has a permissive role in basal ganglia output, which is important to consider when developing new treatments for movement disorders.