On the role of storage granules in the functional utilization of newly synthesized dopamine

Previous studies have provided evidence for the prime importance of newly synthesized dopamine as compared with the large endogenous stores of amine in the functional mobilization of dopamine under conditions of a heavy demand on the neuron such as in the presence of a neuroleptic. The present study was designed to examine the role of storage granules in the utilization of newly synthesized dopamine and to examine the mechanism of the cataleptic action of reserpine-like drugs. It was found that the injection of a small dose of L-Dopa did not reverse the catalepsy produced by the short-acting dopamine depleter, Ro 4-1284, either when the depleter was given alone or was given after tyrosine hydroxylase blockade by alpha-methyltyrosine, provided that the L-Dopa was given at a time when Ro 4-1284 was present. However, the same dose of L-Dopa quickly reversed catalepsy when given at a time of dopamine depletion but in the absence of Ro 4-1284. Since alpha-methyltyrosine alone does not produce catalepsy until exhaustion of the large endogenous dopamine pool, but quickly potentiates neuroleptic-induced catalepsy, it is suggested that under normal conditions the slow transfer of stored dopamine to a releasable site is sufficiently rapid to maintain striatal function. However, the transfer rate appears to be too slow for adequate mobilization of the store under conditions of a heavy demand. It is further suggested that a prime role of storage granules is to channel newly synthesized dopamine into the synaptic cleft. Reserpine-like drugs appear to produce catalepsy, not by depletion per se of the main dopamine pool, but by interference with this granule channeling function.