Dopamine transporter-related effects of modafinil in rhesus monkeys.
BACKGROUND
Modafinil is currently used as a treatment for daytime sleepiness.


OBJECTIVE
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).


CONCLUSIONS
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.
Andersen
Monica L
ML
Yerkes National Primate Research Center, Emory University, 954 Gatewood Rd, Atlanta, GA 30329, USA.
Kessler
Eileen
E
Murnane
Kevin S
KS
McClung
Jessica C
JC
Tufik
Sergio
S
Howell
Leonard L
LL
D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D002421:Caudate Nucleus / Q000187:drug effects / Q000378:metabolism; D019970:Cocaine-Related Disorders / Q000378:metabolism; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D005260:Female; D008253:Macaca mulatta; D008297:Male; D000077408:Modafinil; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology*; D012890:Sleep / Q000187:drug effects / Q000502:physiology
D001559:Benzhydryl Compounds; D050483:Dopamine Plasma Membrane Transport Proteins; D000077408:Modafinil
J Clin Psychiatry. 2006 Apr;67(4):554-66
16669720
Drug Alcohol Depend. 2009 Sep 1;104(1-2):133-9
19560290
Psychopharmacology (Berl). 2003 Jul;168(1-2):3-20
12402102
Psychopharmacology (Berl). 2006 Apr;185(2):142-9
16425059
Psychopharmacology (Berl). 1991;103(1):28-32
1672457
Nature. 2001 Jul 12;412(6843):141-2
11449260
J Pharmacol Exp Ther. 2002 Mar;300(3):831-7
11861788
Am J Psychiatry. 2006 Jun;163(6):1109
16741217
Lab Anim. 2005 Apr;39(2):169-77
15901360
Neuropsychopharmacology. 2008 Mar;33(4):761-8
17568397
Addiction. 2005 Jan;100(1):96-106
15598197
Psychopharmacology (Berl). 2003 Jul;168(1-2):21-30
12695875
Psychopharmacology (Berl). 1996 Aug;126(4):286-92
8878344
Addiction. 2007 Dec;102(12):1871-87
18031423
J Pharmacol Exp Ther. 2006 Nov;319(2):561-9
16885432
J Pharmacol Exp Ther. 2001 Jul;298(1):1-6
11408518
Synapse. 2002 Jan;43(1):78-85
11746736
Psychopharmacology (Berl). 2002 Jun;161(4):387-95
12073166
J Pharmacol Exp Ther. 2009 May;329(2):738-46
19197004
Psychopharmacology (Berl). 2009 Aug;205(2):237-47
19365621
Drug Alcohol Depend. 2003 May 1;70(1):29-37
12681523
Eur J Pharmacol. 2003 Oct 31;479(1-3):93-106
14612141
J Pharmacol Exp Ther. 1989 Mar;248(3):1010-7
2703961
Synapse. 2002 Jun 15;44(4):203-10
11984856
Pharmacol Biochem Behav. 2007 Jan;86(1):45-54
17258302
Neuropsychopharmacology. 2008 Jun;33(7):1477-502
17712350
Psychopharmacology (Berl). 2005 Oct;182(1):186-93
15986191
Behav Brain Res. 2009 Dec 1;204(1):250-3
19482046
Nucl Med Biol. 2000 Jan;27(1):1-12
10755640
Biochem Pharmacol. 2008 Jan 1;75(1):196-217
17825265
J Pharmacol Exp Ther. 2004 Jun;309(3):959-69
14982963
Neuropsychopharmacology. 2005 Jan;30(1):205-11
15525998
J Psychopharmacol. 2000 Mar;14(1):53-60
10757254
J Neurosci. 2002 Jul 15;22(14):6247-53
12122083
Clin Pharmacol Ther. 2009 Mar;85(3):296-304
19037200
Synapse. 2005 Dec 15;58(4):220-8
16206183
J Pharmacol Exp Ther. 2007 Feb;320(2):757-65
17105829
JAMA. 2009 Mar 18;301(11):1148-54
19293415
Pharmacol Biochem Behav. 2008 Sep;90(3):453-62
18468667
Psychopharmacology (Berl). 2003 Jan;165(3):260-9
12417966
Ann Clin Psychiatry. 2004 Apr-Jun;16(2):101-9
15328903
Psychopharmacology (Berl). 2000 Feb;148(3):299-306
10755743