Positron emission tomography (PET), in combination with 11C-raclopride, was used to examine the effects of phencyclidine (PCP) on dopamine (DA) in the primate striatum. In addition, we explored the hypotheses that GABAergic pathways as well as molecular targets beyond the N-methyl-D-aspartate (NMDA) receptor complex (ie dopamine transporter proteins, DAT) contribute to PCP's effects. In the first series of experiments. 11C-raclopride was administered at baseline and 30min following intravenous PCP administration. In the second series of studies, γ-vinyl GABA (GVG) was used to assess whether enhanced GABAergic tone altered NMDA antagonist-induced changes in DA. Animals received an initial PET scan followed by pretreatment with GVG (300 mg/kg), then PCP 30 mm prior to a second scan. Finally, we explored the possible contributions of DAT blockade to PCP-induced increases in DA. By examining 11C-cocaine binding a paradigm in which PCP was coadministered with the radiotracer, we assessed the direct competition between these two compounds for the DAT. At 0.1, 0.5, and 1.0 mg/kg, PCP decreased 11C-raclopride binding by 2.1, 14.9 ± 2.2 and 8.18 ± 1.1%, respectively. These effects were completely attenuated by GVG (3.38 ± 3.1% decrease in 11C-raclopride binding). Finally, PCP (0.5 mg/ kg) decreased 11C-cocaine binding by 25.5 ± 4.3%, while at 1.0 mg/kg this decrease was 13.5%, consistent with a competitive interaction at the DAT. These results suggest that PCP may be exerting some direct effects through the DAT and that GABA partially modulates NMDA-antagonist-induced increases in striatal DA.
Bibliographical noteFunding Information:
We gratefully acknowledge J Fowler, P Vaska, D Alexoff, D Schlyer, P King, P Carter, N Pappas, M Gerasimov, C Shea, V Garza, and R Ferrieri. Hoescht Marion Roussel and ChiroTech supplied the GVG. This research was carried out at Brookhaven National Laboratory under contract with the US Department of Energy Office of Biological and Environmental Research (USDOE/OBER DE-AC02-98CH10886), and partially funded by NIH awards to WKS (F31-DA15874) and SLD (DA015041).
- NMDA antagonist
- Positron emission tomography (PET)