In order to investigate the physiological importance of the membrane pump in 
eliminating released dopamine (DA) we have studied the effects of the putative 
selective dopamine re-uptake inhibitor, GBR 12909, on synthesis and metabolism 
of monoamines in the rat striatum, limbic forebrain, cortical hemispheres and 
substantia nigra (SN). The effects of the drug on the firing rate of 
catecholamine containing neurons in the SN and locus coeruleus (LC) were also 
investigated. For comparison we have investigated the effects of desipramine and 
maprotiline. As a measure of the synthesis of noradrenaline (NA), DA and 
5-hydroxytryptamine (5-HT) we determined the 3,4-dihydroxyphenylalanine (DOPA) 
and 5-hydroxytryptophan (5-HTP) accumulation after inhibition of aromatic 
L-amino acid decarboxylase by 3-hydroxy-benzylhydrazine (NSD 1015). As indirect 
measurements of DA and NA release in vivo, we have assessed pargyline-induced 
3-methoxytyramine (3-MT) and normetanephrine (NM) accumulation and disappearance 
rates of DA and NA after inhibition of their synthesis by 
alpha-methyl-p-tyrosine (alpha-MT). Administration of GBR 12909 (2.5, 5, 10, 20 
or 40 mg/kg) decreased the NSD 1015-induced DOPA accumulation in the striatum 
and in the limbic forebrain. In contrast, only minor effects of the drug were 
seen on the DOPA accumulation in the cortical hemisphere and on the cerebral 
5-HTP accumulation. GBR 12909 increased the 3-MT accumulation in the striatum, 
limbic forebrain and the cortical hemispheres, an effect that was even more 
pronounced in haloperidol-pretreated animals. However, GBR 12909 did not alter 
the 3-MT accumulation in the SN either when given alone or when given to 
haloperidol-pretreated rats. In haloperidol-pretreated rats GBR 12909 markedly 
enhanced the DA disappearance in the striatum and in the limbic forebrain, but 
not in the SN. Furthermore, GBR 12909 did not significantly affect the firing 
rate of dopaminergic neurons in the SN or that of noradrenergic neurons in the 
LC. Taken together, our results support the notion that GBR 12909 is a specific 
DA uptake inhibitor without a transmitter releasing action. In addition, our 
findings indicate that DA re-uptake is of physiological importance in the 
elimination of DA from the synaptic cleft in the striatum, limbic forebrain and 
cortical hemispheres, but not in the SN. Furthermore, a large part of the DA 
taken up by the dopaminergic terminals in the striatum and in the limbic 
forebrain seems to be re-incorporated into the storage vesicles.