Harmine is a β-carboline compound that targets glutamatergic, monoaminergic, and GABAergic pathways underlying drug addiction. We compared the efficacy of harmine against different psychoactive drugs using an invertebrate (planarian) assay designed to quantify ‘C-shape’ responses. Harmine itself (0.01 – 10 µM) did not produce C-shapes. However, when applied over the same concentration range, harmine significantly inhibited C-shapes elicited by cocaine, with a concentration of 0.1 µM producing almost 90% inhibition. Consistent with its putative actions, harmine produced a similar, though less efficacious, inhibition of C-shapes elicited by the substituted amphetamines methamphetamine and mephedrone (4-methylmethcathinone) but was much less effective against nicotine. When tested in the presence of the glutamate transporter inhibitor dihydrokainate (DHK) (0.1, 1 µM), harmine (0.1 µM) efficacy against cocaine-induced C-shapes was significantly reduced. Harmine also attenuated C-shapes elicited by N-methyl-D-aspartate (NMDA) and by glutamate itself. The present data suggest that harmine displays preferential efficacy against different addictive substances (cocaine > amphetamines > nicotine) and, at least for cocaine, is dependent on the glutamate system.
Abstract. The main objective of the current work is to demonstrate the process of passive lateral diffusion in the human nail plate and its effect on the passive transungual permeation of antifungal drug ciclopirox olamine (CPO). A water soluble dye, methyl red sodium salt (MR) was used to visualize the process of lateral diffusion using a novel suspended nail experiment. The decline in concentration of CPO correlates with that of concentration of MR from the proximal to the distal end of the nail in suspended nail study. Three toenails each were trimmed to 5 mm×5 mm (25 mm 2 ), 7 mm×7 mm (49 mm 2 ), and 9 mm×9 mm (81 mm 2 ) to study the extent and effect of lateral diffusion of the CPO on its in vitro transungual permeation. The permeation flux of CPO decreased as the surface area of the toenail increased. There was a positive correlation between the concentrations of CPO and MR in the area of application and in the peripheral area of the toenails of the three surface areas, confirming the findings in the suspended nail experiment. Profound lateral diffusion of CPO was demonstrated and shown to reduce the in vitro passive transungual drug permeation and prolong the lag-time in human toenails. The study data implies that during passive in vitro transungual permeation experiments, the peripheral nail around the area of drug application has to be kept to a minimum, in order to get reliable data which mimics the in vivo situation.
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