Effects of severe dopamine depletion on dopamine neuronal impulse flow and on tyrosine hydroxylase regulation

Reserpine depletes dopamine (DA) levels and increases tyrosine hydroxylase (TH) activity in the rat corpus striatum. TH is activated not only by enhancement of DA neuronal impulse flow, but also by cessation of impulse flow. To assist in the understanding of the relative contribution of impulse flow to the regulation of TH activity in the DA depleted neuron, we examined the consequences of severe DA depletion on substantia nigra DA neuronal impulse flow and on in vivo TH activity in the rat corpus striatum. One day after reserpine or 30 min after the reversible reserpine-like compound, Ro4-1284, striatal DA levels were severely depleted and in vivo TH activity was enhanced about three-fold. DA depletion was found to significantly increase DA neuronal impulse flow. Although the DA neuron is firing faster than normal in the DA depleted rat, because there is no DA being released it is still not clear whether the elevation in TH activity is due to the enhancement of impulse flow or to the lack of DA at presynaptic receptor sites, or both. γ-Butyrolactone (GBL), causes a cessation of DA neuronal impulse flow and activates TH by a presynaptic autoreceptor mechanism. GBL inhibited by over 50 percent the elevation in TH activity produced by severe DA depletion. This finding suggests that the enhanced TH activation after DA depletion is in large part due to increased DA impulse flow. Furthermore, the TH activity seen with GBL in DA depleted rats was significantly less than that seen after GBL administration in normal rats. This finding is consistent with the hypothesis that the DA storage granule also plays a role in TH regulation.