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It is well established that midbrain dopamine neurons innervating the striatum, release their neurotransmitter through an exocytotic process triggered by the neural firing and involving a transient calcium entry in the terminals. Long ago, it had been proposed, however, that another mechanism of release could co-exist with classical exocytosis, involving the reverse-transport of the cytosolic amine by the carrier, ordinarily responsible for uptake function. This atypical mode of release could be evoked directly at the preterminal level by multiple environmental endogenous factors involving transient alterations of the sodium gradient. It cannot be excluded that this mode of release participates in the firing-induced release. In contrast with the classical exocytosis of a preformed DA pool, the reverse-transport of DA requires simultaneous alterations of intraterminal amine metabolism including synthesis and displacement from storage compartment. The concept of a reverse-transport of dopamine is coming from the observations that releasing substances, such as amphetamine-related molecules, actually induce this type of transport. A large set of arguments advocates that reverse-transport plays a role in the maintenance of basal extracellular DA concentration in striatum. It was also often evoked in physiopathological situations including ischemia, neurodegenerative processes, etc. The most recent studies suggest that this release could occur mainly outside the synapses, and thus could constitute a major feature in the paracrine transmission, sometimes evoked for DA.

To investigate the contribution of the dopamine (DA) synthesis to both the calcium-dependent and the carrier-mediated, mechanisms of DA release in the striatum, anaesthetized rats were locally superfused in the striatum with a push pull cannula supplied with an artificial CSF containing tritiated tyrosine. DA, dihydroxyphenylacetic acid (DOPAC) and their respective specific activity were measured in effluent and used to evaluate changes in the DA synthesizing rate. Excluding calcium ions from the CSF only partially reduced spontaneous DA release (70%) still leaving a possible carrier-mediated DA release. This effect was not additive with a local superfusion with 0.1 mM a-methyl-p-tyrosine, a blocker of DA synthesis, suggesting that synthesis could already be reduced by calcium-free superfusion. Local superfusion with 100 microM cadmium in the presence or not of calcium ions, increased the DA release (220 and 350%, respectively), simultaneously reducing DA synthesis. Local application of 1 microM calcium ionophore (A23187) was without effect on the basal release of DA but enhanced DA synthesis and increased the amphetamine-evoked and carrier-mediated amine release. We conclude that DA synthesis can be a modulatory process of the firing-independent and carrier-mediated amine release while it weakly affects the classical calcium-dependent release.

The release of newly synthesized [(3)H]adenosine has been studied in vivo in cat caudate nucleus and substantia nigra, using a push pull cannula. In the presence of [(3)H]adenosine as precursor, spontaneously released [(3)H]adenosine was easily detectable in superfusates of the push pull cannula. In the caudate nucleus, potassium and veratridine caused a marked and reversible increase in [(3)H]adenosine release. The effect of veratridine was completely blocked by tetrodotoxin (TTX) although TTX had no action by itself. Ouabain as well as glutamate, also markedly increased the release of [(3)H]adenosine. The specific 5? nucleotidase inhibitor ?,?-methylene ADP, did not alter the increase in the amount of [(3)H]adenosine obtained by veratridine, although it diminished the spontaneous release of [(3)H]adenosine by about 20%. Push pull cannulae were also implanted simultaneously into the caudate nucleus and substantia nigra. Potassium applied into the caudate nucleus increased the local release of adenosine but did not change that observed in the substantia nigra. When potassium was applied into the substantia nigra, it also increased the local release of adenosine but did not change that observed in the caudate nucleus. The results are discussed in term of the possible existence of "purinergic neurons" and of the relation between the adenosine release and central nervous activity.