Positron emission tomography studies of potential mechanisms underlying phencyclidine-induced alterations in striatal dopamine.
Positron emission tomography (PET), in combination with (11)C-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, (11)C-raclopride was administered at baseline and 30 min following intravenous PCP administration. In the second series of studies, gamma-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 min prior to a second scan. Finally, we explored the possible contributions of DAT blockade to PCP-induced increases in DA. By examining (11)C-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 (11)C-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 (11)C-raclopride binding). Finally, PCP (0.5 mg/kg) decreased (11)C-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.
Schiffer
Wynne K
WK
SUNY Stony Brook, Department of Neurobiology and Behavior, Stony Brook, NY 11973, USA. wynne@bnl.gov
Logan
Jean
J
Dewey
Stephen L
SL
D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D014150:Antipsychotic Agents / Q000493:pharmacokinetics; D002247:Carbon Isotopes / Q000493:pharmacokinetics; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D003042:Cocaine / Q000493:pharmacokinetics; D003342:Corpus Striatum / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D010215:Papio; D010622:Phencyclidine / Q000494:pharmacology*; D020891:Raclopride / Q000493:pharmacokinetics; D013997:Time Factors; D014055:Tomography, Emission-Computed; D020888:Vigabatrin / Q000494:pharmacology
D000927:Anticonvulsants; D014150:Antipsychotic Agents; D002247:Carbon Isotopes; D018691:Excitatory Amino Acid Antagonists; D020891:Raclopride; D020888:Vigabatrin; D003042:Cocaine; D010622:Phencyclidine; D004298:Dopamine