Isoflurane anesthesia enhances the inhibitory effects of cocaine and GBR12909 on dopamine transporter: PET studies in combination with microdialysis in the monkey brain

The effects of the dopamine transporter (DAT) inhibitors cocaine and GBR129 09 on DAT and dopamine D-2 receptors were evaluated in the brains under awa ke and isoflurane-anesthetized monkeys using high-resolution positron emiss ion tomography (PET) in combination with microdialysis. The striatal DAT av ailability and dopamine D-2 receptor binding were assayed with [C-11]beta-C FT (WIN35,428) and [C-11]raclopride, respectively. Cocaine or GBR12909 at a dose of 2 mg/kg was administered intravenously 30 min prior to the injecti on of labeled compounds. In the awake state, the in vivo binding of [C-11]b eta-CFT to DAT was significantly decreased by administration of cocaine or GBR12909 at a dose of 2 mg/kg. In contrast, [C-11]raclopride binding to dop amine D-2 receptors was decreased only by GBR12909. Under isoflurane anesth esia, dopamine concentration in the striatal extracellular fluid (ECF), as measured by microdialysis, was markedly increased by cocaine or GBR12909 co mpared to the awake state. Isoflurane anesthesia more markedly enhanced the binding of [C-11]beta-CFT in the saline-injected animals, and the degrees of reduction by cocaine and GBR12909 were more marked than those observed i n the awake state. Under isoflurane anesthesia, the binding of [C-11]raclop ride was reduced not only by GBR12909 but also by cocaine which did nor aff ect the binding in the awake state. Taken together, these observations indi cated that isoflurane anesthesia enhanced not only the direct inhibitory ef fects of cocaine and GBR12909 on DAT, but also their indirect effects on do pamine D-2 receptors, (C) 1999 Elsevier Science B.V. All rights reserved.