RATIONALE: Modafinil is currently used as a treatment for daytime sleepiness. OBJECTIVES: The objectives of this study were to explore the dopamine transporter (DAT)-related effects of modafinil on behavior and in vivo neurochemistry in rhesus monkeys (Macaca mulatta). METHODS: The effects of modafinil (3.0-10 mg/kg, i.v.) were evaluated on locomotor activity, reinstatement of cocaine-maintained behavior, extracellular dopamine levels in the caudate nucleus, and DAT occupancy in the dorsal striatum. Eight subjects were fitted with a collar-mounted activity monitor to evaluate sleep-activity cycles, with 4 days of baseline recording preceding an injection of saline or modafinil (3.0-10 mg/kg). The effects of modafinil (3.0-10 mg/kg) and cocaine (0.3 mg/kg) on reinstatement of behavior that was previously maintained under a second-order schedule of i.v. cocaine delivery were tested in a separate group of subjects (n = 6). Finally, the effects of modafinil (3.0-10 mg/kg) on extracellular dopamine levels and DAT occupancy in vivo were characterized using microdialysis and positron emission tomography, respectively, in a within-subjects design (n = 4). RESULTS: Modafinil significantly increased nighttime locomotor activity and reinstated cocaine-maintained behavior but did not affect daytime locomotor activity. Modafinil significantly increased striatal extracellular dopamine levels at a dose that resulted in DAT occupancy of 64.4% (putamen) and 60.2% (caudate). CONCLUSION: The behavioral and in vivo dopaminergic effects of modafinil are consistent with the profile of a low potency DAT inhibitor and may indicate potential for abuse at high doses.
RATIONALE: Modafinil is currently used as a treatment for daytime sleepiness. OBJECTIVES: The objectives of this study were to explore the dopamine transporter (DAT)-related effects of modafinil on behavior and in vivo neurochemistry in rhesus monkeys (Macaca mulatta). METHODS: The effects of modafinil (3.0-10 mg/kg, i.v.) were evaluated on locomotor activity, reinstatement of cocaine-maintained behavior, extracellular dopamine levels in the caudate nucleus, and DAT occupancy in the dorsal striatum. Eight subjects were fitted with a collar-mounted activity monitor to evaluate sleep-activity cycles, with 4 days of baseline recording preceding an injection of saline or modafinil (3.0-10 mg/kg). The effects of modafinil (3.0-10 mg/kg) and cocaine (0.3 mg/kg) on reinstatement of behavior that was previously maintained under a second-order schedule of i.v. cocaine delivery were tested in a separate group of subjects (n = 6). Finally, the effects of modafinil (3.0-10 mg/kg) on extracellular dopamine levels and DAT occupancy in vivo were characterized using microdialysis and positron emission tomography, respectively, in a within-subjects design (n = 4). RESULTS:Modafinil significantly increased nighttime locomotor activity and reinstated cocaine-maintained behavior but did not affect daytime locomotor activity. Modafinil significantly increased striatal extracellular dopamine levels at a dose that resulted in DAT occupancy of 64.4% (putamen) and 60.2% (caudate). CONCLUSION: The behavioral and in vivo dopaminergic effects of modafinil are consistent with the profile of a low potency DAT inhibitor and may indicate potential for abuse at high doses.
Authors: Bertha K Madras; Zhihua Xie; Zhicheng Lin; Amy Jassen; Helen Panas; Laurie Lynch; Ryan Johnson; Eli Livni; Thomas J Spencer; Ali A Bonab; Gregory M Miller; Alan J Fischman Journal: J Pharmacol Exp Ther Date: 2006-08-02 Impact factor: 4.030
Authors: Leonard L Howell; F Ivy Carroll; John R Votaw; Mark M Goodman; Heather L Kimmel Journal: J Pharmacol Exp Ther Date: 2006-11-14 Impact factor: 4.030
Authors: Richard W Foltin; Margaret Haney; Eric Rubin; Stephanie C Reed; Nehal Vadhan; Rebecca Balter; Suzette M Evans Journal: Pharmacol Biochem Behav Date: 2015-04-28 Impact factor: 3.533
Authors: Jianjing Cao; Thomas E Prisinzano; Oluyomi M Okunola; Theresa Kopajtic; Matthew Shook; Jonathan L Katz; Amy Hauck Newman Journal: ACS Med Chem Lett Date: 2010-10-10 Impact factor: 4.345