Is drug inhibition of dopamine uptake a misinterpretation of in vitro experiments?

Abstract

COYLE and Snyder1 reported that various antiparkinson drugs inhibit the uptake of labelled dopamine (DA) into striatal synaptosomes. They suggested that these drugs may act in part by a potentiation of dopaminergic neurotransmission caused by inhibition of DA uptake. Measurement of drug effects on the uptake of labelled DA into slices or synaptosomes from the corpus striatum has become a widely used test for the evaluation of drugs affecting central dopaminergic functions. Some observations made in our laboratory, however, suggest that the apparent reduction of 3H-DA uptake caused by a variety of drugs in in vitro experiments may, in fact, be the result of a DA-depleting action. Benztropine and nomifensine are said to be potent DA-uptake inhibitors2; however, in our experience, benztropine (30 mg kg−1 subcutaneously) does not inhibit, and nomifensine (100 mg kg−1 orally) only slightly inhibits, the uptake of 3H-DA into striatal synaptosomes prepared from rats pretreated 1 h before killing. In contrast, pretreatment with tricyclic antidepressants does inhibit NA and 5-hydroxytryptamine (5-HT) uptake into midbrain synaptosomes3. Using the method of Farnebo4, we studied the effects of benztropine, haloperidol, chlorpromazine, d-amphetamine, piroheptine5 and cocaine on the release of tritium from field-stimulated, 3H-DA-prelabelled striatal slices. We observed that, at concentrations between 10−6M and 10−5M, these drugs increase the spontaneous release of tritium soon after their addition to the superfusion medium.