The quinolines have been used in the treatment of malaria, arthritis, and lupus for many years, yet the precise mechanism of their action remains unclear. In this study, we used a functional proteomics approach that exploited the structural similarities between the quinoline compounds and the purine ring of ATP to identify quinoline-binding proteins. Several quinoline drugs were screened by displacement affinity chromatography against the purine binding proteome captured with ␥-phosphate-linked ATP-Sepharose. Screening of the human red blood cell purine binding proteome identified two human proteins, aldehyde dehydrogenase 1 (ALDH1) and quinone reductase 2 (QR2). In contrast, no proteins were detected upon screening of the Plasmodium falciparum purine binding proteome with the quinolines. In a complementary approach, we passed cell lysates from mice, red blood cells, or P. falciparum over hydroxychloroquine-or primaquine-Sepharose. Consistent with the displacement affinity chromatography screen, ALDH and QR2 were the only proteins recovered from mice and human red blood cell lysate and no proteins were recovered from P. falciparum. Furthermore, the activity of QR2 was potently inhibited by several of the quinolines in vitro. Our results show that ALDH1 and QR2 are selective targets of the quinolines and may provide new insights into the mechanism of action of these drugs.

Previous data indicate that dopamine neurotransmission is differently regulated in male and female rats. The purpose of the present study was to investigate the dopamine transporter and autoreceptor as potential loci responsible for this sex difference. Fast cyclic voltammetry at carbon-fiber microelectrodes was used to monitor changes in electrically evoked levels of extracellular dopamine in the striata of anesthetized male and female rats before and after administration of an uptake inhibitor, a dopamine D 2 antagonist, or a D 3 /D 2 agonist. Administration of 40 mg/kg cocaine ip increased electrically-evoked extracellular dopamine concentrations in both sexes, but to a significantly greater extent in female striatum at the higher stimulation frequencies. The typical antipsychotic, haloperidol, increased dopamine efflux in both sexes but the effect was twice as large in the female striatum. The D 3 /D 2 agonist quinpirole induced an unexpected, transient increase in dopamine efflux following high-frequency stimulation only in females, and evoked dopamine was higher in females across this entire time course. More detailed analysis of cocaine effects revealed no fundamental sex differences in the interaction of cocaine with DAT in vivo or in synaptosomes. These results indicate that nigrostriatal dopamine neurotransmission in the female rat is more tightly regulated by autoreceptor and transporter mechanisms, perhaps related by greater autoreceptor control of DAT activity. Thus, baseline sex differences in striatal dopamine regulation induce different pharmacologic responses. These results contribute to understanding sex differences in stimulant-induced locomotor activity in rats and may have broader implications for neurologic disorders and their pharmacotherapies in humans.