Amantadine and dextromethorphan suppress levodopa (L-DOPA)-induced dyskinesia in Parkinson's disease patients and abnormal involuntary movements (AIM) in the 6-hydroxydopamine (6-OHDA) rat model. These medications have been hypothesized to exert their therapeutic effects by a noncompetitive N-methyl-D-aspartate (NMDA) antagonist mechanism, but they also have known serotonin (5-HT) indirect agonist effects that could suppress AIM. This raised the possibility that NMDA antagonists lacking 5-HTergic effects would not have the antidyskinetic action predicted by previous investigators. To test this hypothesis, we investigated MK-801, the most widely-studied NMDA antagonist. We found that chronic low-dose MK-801 (0.1 mg/kg) had no effect on development of AIM or contraversive rotation. In addition, in L-DOPA primed rats, low-dose MK-801 (0.1 mg/kg) had no effect on expression of AIM, contraversive rotation, or sensorimotor function. Conversely, higher doses of MK-801 (0.2-0.3 mg/kg) suppressed expression of AIM. However, as we show for the first time, anti-dyskinetic doses of MK-801 also suppressed L-DOPAinduced contralateral rotation and impaired sensorimotor function, likely due to non-specific interference of MK-801 with L-DOPA-induced behavior. We conclude that noncompetitive NMDA antagonists are unlikely to suppress dyskinesia clinically without worsening parkinsonism.

The current study examined whether modafinil would reinstate an extinguished cocaine conditioned place preference (CPP). Following extinction of a cocaine CPP, rats were administered modafinil (128mg/kg), cocaine (5mg/kg) or vehicle and given a 60-min reinstatement test. While the effect of cocaine was transient, modafinil robustly reinstated a cocaine CPP following extinction, suggesting that modafinil may induce relapse or increase the vulnerability of addicts to the reinforcing effects of environmental triggers. Keywords modafinil; cocaine; conditioned place preference; reinstatement Modafinil [(±)2-(benzydryl-sulfinyl)acetamide] is a psychostimulant that promotes wakefulness, and as such is FDA-approved for the treatment of excessive daytime sleepiness associated with narcolepsy, shift-work sleep disorder, and obstructive sleep apnea in humans. Modafinil has also been investigated for use in other neuropsychiatric disorders, such as cocaine addiction [12,17], and thus it has been important to determine whether the neurochemical and behavioral effects of modafinil are similar to those of other psychostimulants, such as cocaine and amphetamine.Preclinical work has found that modafinil may partially exert its effects on arousal by interacting with the dopamine transporter (DAT) [15] and subsequently enhancing dopaminergic neurotransmission, similar-but with lower affinity [16]-to the pharmacological action of cocaine [22]. Modafinil's lower affinity for DAT in vitro [16] and conflicting behavioral profile [7,21] as compared to conventional pychostimulants [16] was believed to confer on modafinil less abuse potential [7,8,16]. However, Madras et al. [15] reported that modafinil or an active metabolite had a high affinity interaction with the DAT of monkey brain in vivo, and inhibited dopamine uptake via DAT in human embryonic kidney (HEK) cells in vitro. Fuerthermore, DAT knock-out mice showed decreased responsiveness *To whom correspondence and requests for reprints should be addressed: Oregon Health & Science University, Department of Behavioral Neuroscience, Mail Code L470, 3181 SW Sam Jackson Park Rd., Portland, OR 97239, Phone: 503-220-8262 x51827, Fax: 503-494-6877, E-mail: bernardi@ohsu.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Given the central role hypothesized for dopamine in reinforcement mechanisms [reviewed in 1], these findings of modafinil's dopaminergic effects necessitate the study of its reinforcing properties. Preclinically, Deroche-Gamonet et al. [5] reported that modafinil failed to produce a conditioned place preference, induce sel...