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The effects of somatostatin administration and its various antagonists on the uptake of the dopamine analogue [3H]-2 beta-carbomethoxy-3 beta-(4-iodophenyl)-tropane ([3H] beta CIT), a ligand of the dopamine transporter, have been investigated using primary cultures of rat neocortical neurons and Chinese hamster ovary cells expressing the DAT gene. Somatostatin was found to inhibit the uptake of [3H]beta CIT in cultured cells from both species. This effect was reversed by the antipsychotic neuroleptic haloperidol, a well-established somatostatin receptor antagonist. The specificity of this inhibition was demonstrated by the ability of an analog of somatostatin, BIM23127, to mimic the inhibitory effect of somatostatin. The effect of somatostatin on [3H]beta CIT uptake was blocked by the endogenous somatostatin analogue, somatostatin-14. The somatostatin receptor antagonist CGP 23996 did not block the inhibitory effects of somatostatin. These results support the hypothesis that somatostatin inhibits the dopamine transporter by an action at the somatostatin receptor(s) coupled to specific tyrosine kinases. These data also support the idea that, in contrast to the somatotopically organized somatostatin-containing tanycytes, the somat