Functional and pharmacological significance of brain dopamine and norepinephrine storage pools.

The concept that multiple pools of stored catecholamines exist in catechol~ine-containing neurons has been the subject of research interest for a number of years. The initial observations suggesting the existence of more than one pool came from studies utilizing various methods to determine catecholamine turnover. These methods included determination of decline rates of catecholamines after synthesis inhibition as well as administration of labeled catecholamine or precursor and comparison of the specific activity of released transmitter with that remaining in the tissue. The results of many of these experiments indicated that a non-uniform release of catechoiamines occurs and that the most recently stored amine is the first released. Although such experiments are valuable, they do not yield information on the functional roles of apparent multiple pools of catecholamines. The purpose of this commentary is to examine the evidence for the operational significance of transmitter pools in norepinephrine (NE)and dopamine (DA)-containing neurons of the CNS. The picture that emerges indicates that central DA-containing neurons operate with two distinct transmitter pools, whereas central NE-containing neurons appear to operate with a single functional pool. These considerations appear to dictate pharmacological responses to various dopaminergic and adrenergic drugs. Neff and Costa [l] showed that, after inhibition of catecholamine synthesis with the tyrosine hydroxylase inhibitor ct-methyl-p-tyrosine (a-MT), DA and NE exhibit a log-linear decline for several hours. As expected, receptor antagonists or agonists could enhance or inhibit, respectively, the rates of decline. If the catecholamine stores were labeled by administering either radio-labeled precursor or exogenous amines (thus allowing accurate measurements over a short time frame), radio-labeled DA and NE disappeared rapidly for the first 2CL30 min, after which disappearance curves similar to those of the endogenous transmitter substances were observed [Z-4]. The specific activity of catecholamines released shortly after labeling of the neurons was greater than that remaining in the tissue, but at later times the specific activity of NE or DA released into the medium was the same as that in the tissue [4-61. Glowinski and co-workers showed that endogenous striatal DA concentrations exhibited a two-phase decline after tyrosine hydroxylase inhibition and that the apparent rapidly disappearing * Author to whom all correspondence should be addressed. pool represented about 20 per cent of total DA (71. They obtained similar results with the noradrenergic system using radio-tracer methods [6]. By measuring radio-labeled DA and DA metabolites, Groppetti et al. [X] showed that newly synthesized DA was preferentially catabolized, as DA metabolites had a higher specific activity than DA in rat striatum. Recent studies with superfused striatal synaptosomes indicate that DA is taken up and released by two compartment kinetics [9, lo]. Thus, these data suggest that newly taken up or newly synthesized catecholamines are preferentially released over older amine. Other investigators [ll. 121 questioned the validity of some of these experiments. The question arose as to whether a sufficient blockade of tyrosine hydroxylase with rr-MT occurred in the earlier-mentioned studies and whether the initial rapid rate of [3H]DA decline might be due to possible metabolites of o-MT such as p-hydroxyamphetamine. It was claimed, based on kinetic consideration of the decline rates of newly labeled and endogenous DA. that if two pools of DA exist, then the rapidly turning over pool must be less than 5 per cent of the total striatal DA content (i.e. smaller than experimental error). These reports leave open the significance of the difference in specific activity of released amines that is observed after labeling DA or NE pools.