The effect of modafinil on psychostimulant-evoked [³H]dopamine release from rat striatal slices

Abstract

[ACCESS RESTRICTED TO THE UNIVERSITY OF MISSOURI AT AUTHOR'S REQUEST.] Modafinil is a novel wake-promoting compound currently marketed as a stimulant that lacks the side effects and addictive potential of typical psychostimulants. Despite these claims, the true mechanism(s) of action for modafinil has yet to be determined. Since modafinil and nicotine share many behavioral, cognitive, and reinforcing effects, this study examined the extent that their pharmacodynamics would also be similar. [³H]Dopamine (DA) overflow (i.e., a measure of DA release) from rat striatal slices preloaded with [³H]DA was used to provide an assessment of whether modafinil, like nicotine, is mediated by nicotinic acetylcholine receptors (nAChRs) or, like amphetamine and cocaine, is mediated by the dopamine transporter (DAT). By observing modafinilevoked [³H]DA overflow in the presence and absence of a variety of nAChR or DAT agonists and antagonists/inhibitors, these experiments examined the degree to which modafinil is mediated by nAChRs or the DAT. Results indicated that modafinil (100-300 µM) evoked [³H]DA overflow in a concentration-dependent manner, but was less potent and efficacious than nicotine, amphetamine, and cocaine. Modafinil-evoked overflow was not altered by the nAChR antagonist mecamylamine and modafinil did not alter nicotine-evoked [³H]DA overflow, making it unlikely that nAChRs are important for modafinil's mechanism of action. The DAT inhibitor nomifensine (10 µM) attenuated (~50%) modafinil-evoked [³H]DA overflow, and concentrations that did not have intrinsic activity attenuated amphetamine (1 and 3 µM) - evoked [³H]DA overflow. Thus, modafinil is pharmacologically similar to, but less potent than, amphetamine and cocaine; however, the behavioral effects are likely mediated through, but not exclusively influenced by, interactions with the DAT.