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

doi:10.1016/S0006-8993(99)02018-1

Brain Research

Volume 849, Issues 1–2, 4 December 1999, Pages 85-96

https://doi.org/10.1016/S0006-8993(99)02018-1 Get rights and content

Abstract

The effects of the dopamine transporter (DAT) inhibitors cocaine and GBR12909 on DAT and dopamine D₂ 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 D₂ receptor binding were assayed with [ $^{11} C$ ]β-CFT (WIN35,428) and [ $^{11} C$ ]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 [ $^{11} C$ ]β-CFT to DAT was significantly decreased by administration of cocaine or GBR12909 at a dose of 2 mg/kg. In contrast, [ $^{11} C$ ]raclopride binding to dopamine D₂ 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 [ $^{11} C$ ]β-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 [ $^{11} C$ ]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 D₂ receptors.

Introduction

Cocaine binds to dopamine transporter (DAT) located on the presynaptic dopaminergic nerve terminals 19, 28, 46and blocks dopamine re-uptake into presynaptic terminals. Acute cocaine administration leads to an immediate and dose-dependent increase in extracellular dopamine level 3, 8, 27, 31, 32, 33, as well as the increased locomotor activity [43]. Cocaine produces its reinforcing effects by increasing dopaminergic neurotransmission in the dopamine neuronal synaptic cleft 25, 39, 42, 51. GBR12909 (1-[2-[bis (4-fluorophenyl) methoxy] ethyl]-4-[3-phenylpropyl]-piperazine) also binds to DAT and induces the elevation of dopamine in the extracellular fluid (ECF). Cocaine induces a rapid and short-lived elevation of dopamine level, whereas GBR12909 causes a slow onset of the effect and longer elevation of dopamine in the ECF [1]. GBR12909 did not evoke psychomotor stimulant effects when administered orally to normal healthy human volunteers [49].

Positron emission tomography (PET) enables the direct and noninvasive measurement of components (receptors, transporters, biosynthesis and degradation) of the dopamine system in the living brain (for review see Ref. [54]). Dopamine receptors are present both pre- and post-synoptically at dopamine synapses. At the pre-synaptic side, they modulate the synthesis, release and re-uptake of dopamine, and at the post-synaptic side they function in cell-to-cell communication using released dopamine as a transmitter. PET has been used in psychopharmacological research to investigate dopamine drugs used in the treatment of Parkinson's disease and of schizophrenia as well as to investigate the effects of drugs of abuse on the dopamine systems.

PET has been applied to assess the effects of dopamine itself 5, 12, 22, 53and also those of another neurotransmitters 11, 13, 14, 47, 53on the striatal post-synaptic binding of [ $^{11} C$ ]raclopride, a dopamine D₂ receptor antagonist. These studies demonstrated that the changes in dopamine concentration in the striatal synaptic cleft could be measured non-invasively with PET and [ $^{11} C$ ]raclopride. [ $^{11} C$ ]Raclopride has more moderate affinity for dopamine D₂ receptors than [ $^{11} C$ ]N-methylspiperone 45, 56. The synaptic dopamine might compete with the ligand on the dopamine D₂ receptor, if the affinity of the ligand is relatively low. The in vivo binding of [ $^{3} H$ ]raclopride, the affinity of which is lower than that of [ $^{3} H$ ]N-methylspiperone, might be altered by the endogenous dopamine concentration in the synaptic cleft 23, 45, 53, 56. The synaptic dopamine concentrations can be modulated by the administration of DAT inhibitors (e.g., cocaine and GBR12909). PET study with DAT-specific ligands, such as [ $^{11} C$ ]β-CFT (2β-carbomethoxy-3β-(4-fluorophenyl) tropane, WIN 35,428) [10], is also useful for evaluation of the pharmacological aspects of the DAT inhibitors from the neurochemical view point.

In PET experiments with animals, selection of anesthetic agent for the sedation and fixation of animals is critical aspect. We demonstrated that ketamine significantly increased the in vivo binding of [ $^{11} C$ ]N-methylspiperone in the monkey brain when compared to the awake state [37]. Isoflurane decreased the in vivo binding of [ $^{11} C$ ]raclopride to a much lesser extent than that of [ $^{11} C$ ]N-methylspiperone [24]. In addition, it has been suggested that isoflurane or halothane anesthesia modulated not only the post-synaptic receptor binding but also the pre-synaptic DAT availability as measured ECF dopamine level by microdialysis 16, 38.

In the present study, the effects of isoflurane on DAT and dopamine D₂ receptors were evaluated in the monkey brain with PET. [ $^{11} C$ ]β-CFT and [ $^{11} C$ ]raclopride were used to assess the DAT availability and D₂ receptor binding, respectively. Microdialysis was also applied to confirm the effects of cocaine and GBR12909 on dopamine release in the awake state and under isoflurane anesthesia.

Section snippets

Animals and drugs

Four young-adult male rhesus monkeys (Macaca mulatta) weighing from 4 to 6 kg were used for PET measurements. Monkeys were maintained and handled in accordance with recommendations by the US National Institutes of Health and also the guidelines of Central Research Laboratory, Hamamatsu Photonics. They were trained to sit on a chair twice a week over a period of more than 3 months. The magnetic resonance images (MRI) of all monkeys were obtained with a TOSHIBA MRT-50A/II (0.5 T) under anesthesia

Results

As shown in the PET images in Fig. 1, in the awake state, marked accumulation of radioactivity associated with [ $^{11} C$ ]β-CFT or [ $^{11} C$ ]raclopride was observed in the striatal regions, whereas levels of radioactivity in the cerebellum were much lower compared to those in the striatum in both cases (Fig. 1). [ $^{11} C$ ]β-CFT and [ $^{11} C$ ]raclopride showed relatively low uptake of radioactivity in the neocortex (Fig. 1).

In plasma, the curve of total radioactivity associated with [ $^{11} C$ ]β-CFT and [ $^{11} C$ ]raclopride

Discussion

This is the first study to demonstrate how isoflurane anesthesia affects DAT inhibition and the resulting dopamine D₂ receptor binding using high-resolution animal PET combined with microdialysis in the monkey brain.

In the awake state, cocaine administration (2 mg/kg) significantly elevated the striatal ECF dopamine concentration showing peak values within 15 min, returning to the basal level 90 min after cocaine administration. GBR12909 increased the striatal ECF dopamine (peak at around 45

Acknowledgements

We gratefully acknowledge the excellent support by Drs. M. Iyo and Y. Sekine in the quantitative analysis of [ $^{11} C$ ]β-CFT in vivo and the technical assistance by Mr. D. Fukumoto. This work was supported in part by the Special Coordination Funds for Promoting Science and Technology of the Science and Technology Agency of the Japanese Government.

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

Abstract

Introduction

Section snippets

Animals and drugs

Results

Discussion

Acknowledgements

Neuroscience

TINS

Neurochem. Int.

Eur. J. Pharmacol.

Neuroscience

Brain Res.

Eur. J. Pharmacol.

Brain Res.

Neurosci. Lett.

Brain Res.

Brain Res.

GBR12909 attenuate cocaine-induced activation of mesolimbic dopamine neurons in the rat

J. Pharmacol. Exp. Ther.

Nitric oxide mediates glutamate-linked enhancement of cGMP levels in the cerebellum

Proc. Natl. Acad. Sci. U.S.A.

Quantification of amphetamine-induced changes in [11C]raclopride binding with continuous infusion

J. Cereb. Blood Flow Metab.

Neuromodulatory actions of dopamine in the neostriatum are depend upon the excitatory amino acid receptor subtypes activated

Proc. Natl. Acad. Sci. U.S.A.

Dopamine receptor binding: Differentiation of agonist and antagonist states with [3H]dopamine and [3H]haloperidol

Life Sci.

Synthesis of a radiotracer for studying dopamine uptake site in vivo using PET: (2β-carbomethoxy-3β-(p-fluorophenyl)-[N-11C-methyl]tropane) ([11C]CFT or [11C]WIN 35,428)

J. Labeled Comp. Radiopharm.

GABAergic inhibition of endogenous dopamine release measured in vivo with 11C-raclopride and positron emission tomography

J. Neurosci.

Striatal binding of the PET ligand 11C-raclopride is altered by drugs that modify synaptic dopamine levels

Synapse

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Proc. Natl. Acad. Sci. U.S.A.

Serotonergic modulation of striatal dopamine measured with positron emission tomography (PET) and in vivo microdialysis

J. Neurosci.

Quantitative analysis of D2-dopamine receptor binding in the living human brain by positron emission tomography

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Halothane anesthesia enhances the effect of dopamine uptake inhibition on interstitial levels of striatal dopamine

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Quantitative measurement of regional cerebral blood flow and oxygen metabolism in man using 15O and positron emission tomography: theory, procedure and normal value

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Nature

Cloning, pharmacological characterization, and chromosome assignment of the human dopamine transporter

Mol. Pharmacol.

What is the correct value for the brad–brain partition coefficient for water?

J. Cereb. Blood Flow Metab.

Neuroreceptor assay with positron emission tomography; equilibrium versus dynamic approach

J. Cereb. Blood Flow Metab.

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

Quantification of amphetamine-induced changes in [ $^{11} C$ ]raclopride binding with continuous infusion

Dopamine receptor binding: Differentiation of agonist and antagonist states with [ $^{3} H$ ]dopamine and [ $^{3} H$ ]haloperidol

Synthesis of a radiotracer for studying dopamine uptake site in vivo using PET: (2β-carbomethoxy-3β-(p-fluorophenyl)-[N- $^{11} C$ -methyl]tropane) ([ $^{11} C$ ]CFT or [ $^{11} C$ ]WIN 35,428)

GABAergic inhibition of endogenous dopamine release measured in vivo with $^{11} C$ -raclopride and positron emission tomography

Striatal binding of the PET ligand $^{11} C$ -raclopride is altered by drugs that modify synaptic dopamine levels

Quantitative analysis of D₂-dopamine receptor binding in the living human brain by positron emission tomography

Quantitative measurement of regional cerebral blood flow and oxygen metabolism in man using $^{15} O$ and positron emission tomography: theory, procedure and normal value