Acute NMDA receptor antagonism induces biphasic striatal utilization of L‐[β‐11C]DOPA: PET studies in the conscious monkey brain

N-methyl-D-aspartate (NMDA) receptor inhibitors, ketamine, phencyclidine (PCP), and dizocilpine (MK801), were reported to bind to the PCP recognition site in the Ca2þchannels of the NMDA receptor and to inhibit its functions uncompetitively (Willetts et al., 1990; Yamamura et al., 1990). NMDA receptors are known to interact with the central dopamine (DA) system (Roberts and Anderson, 1979; Carter et al., 1988; Krebs et al., 1991; Morari et al., 1993; Youngren et al., 1993; Tsukada et al., 2000b, 2001). The blockade of NMDA receptors produced locomotor hyperactivity, stereotyped behavior, and ataxia (Donzanti and Uretsky, 1984; Raffa et al., 1989; Schmidt, 1986), suggesting that the psychotomimetic behaviors induced by ketamine might be caused by the increased DA neurotransmission in the striatum. To image the effects of ketamine on DA neuronal system with positron emission tomography (PET), [C]raclopride, a D2 receptor ligand with moderate affinity, has been applied (for review see Laruelle, 2000). Ketamine administration induced the decreased striatal binding of [C]raclopride to D2 receptors (Smith et al., 1997; Tsukada et al., 2000b), suggesting the increased striatal DA concentration by ketamine. However, the results of microdialysis studies were inconsistent in that ketamine and MK-801 increased (Verma and Moghaddam, 1996), decreased (Koshikawa et al., 1988), or did not affect (Bacopoulos et al., 1979; Onoe et al., 1994) DA concentration in the striatum. Our previous results in combined with L-[b-C]DOPA and [C]b-CFT suggested that the striatal synaptic DA concentration, as measured by microdialysis, might not be the exclusive factor of ketamine-induced alterations of the in vivo binding of [C]raclopride in the striatum (Tsukada et al., 2000b). To evaluate presynaptic dopaminergic function in vivo with PET, F-labeled L-6-fluorodopa ([F]FDOPA) has been used. Previous results indicated the different affinity between [b-C]L-DOPA and [F]fluorodopa for the metabolic enzymes, especially the peripheral formation rate of 3-O-methyldopa, showing a much higher rate of 3-O-methyl-6FDOPA formation in plasma than that of 3-O-methylL-DOPA (Melega et al., 1990; Tsukada et al., 1996; Torstenson et al., 1999). Since 3-O-methyl metabolites are known to pass the blood-brain barrier, extensive 3-O-methyl-6-fluorodopa could obscure the delectability of functional changes in striatal utilization of tracer when using a reference tissue model for calculation (Torstenson et al., 1999). The aim of the present study was to determine whether the index of L-[b-C]DOPA utilization was actually suitable to clarify the interactive mechanism between the acute uncompetitive NMDA receptor antagonism and the DA neuronal system. Three young-adult male rhesus monkeys (Macaca mulatta) weighing from 6.5 to 8.0 kg were subjects for the study. Monkeys were maintained and handled in accordance with recommendations of the US National Institutes of Health and also the guidelines of the Central Research Laboratory, Hamamatsu Photonics. During PET scans, heart rate, respiration rate, and body temperature were continuously monitored with a life monitor, and the levels of carbon dioxide (PaCO2), blood oxygen (PaO2), pH, and blood pressure