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 GBR12909 on DAT and dopamine D(2) receptors were evaluated in the brains under awake and isoflurane-anesthetized monkeys using high-resolution positron emission tomography (PET) in combination with microdialysis. The striatal DAT availability and dopamine D(2) receptor binding were assayed with [11C]beta-CFT (WIN35,428) and [11C]raclopride, respectively. Cocaine or GBR12909 at a dose of 2 mg/kg was administered intravenously 30 min prior to the injection of labeled compounds. In the awake state, the in vivo binding of [11C]beta-CFT to DAT was significantly decreased by administration of cocaine or GBR12909 at a dose of 2 mg/kg. In contrast, [11C]raclopride binding to dopamine D(2) receptors was decreased only by GBR12909. Under isoflurane anesthesia, dopamine concentration in the striatal extracellular fluid (ECF), as measured by microdialysis, was markedly increased by cocaine or GBR12909 compared to the awake state. Isoflurane anesthesia more markedly enhanced the binding of [11C]beta-CFT in the saline-injected animals, and the degrees of reduction by cocaine and GBR12909 were more marked than those observed in the awake state. Under isoflurane anesthesia, the binding of [11C]raclopride was reduced not only by GBR12909 but also by cocaine which did not affect the binding in the awake state. Taken together, these observations indicated that isoflurane anesthesia enhanced not only the direct inhibitory effects of cocaine and GBR12909 on DAT, but also their indirect effects on dopamine D(2) receptors.