Nanomolar propofol stimulates glutamate transmission to dopamine neurons

A possible mechanism of abuse potential?

Ke Yong Li, Cheng Xiao, Ming Xiong, Ellise S. Delphin, Jiang Hong Ye

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Anesthesiologists among physicians are on the top of the drug abuse list, and the mechanism is unclear. Recent studies suggest occupation-related second-hand exposure to i.v. drugs, including propofol, may play a role. Growing evidence indicates that propofol is one of the choices of drugs being abused. In this study, we show that propofol at minute concentrations increases glutamatergic excitatory synaptic transmission and discharges of dopamine neurons in the ventral tegmental area (VTA). We found that acute application of propofol (0.1-10 nM) to the VTA in midbrain slices of rats increased the frequency but not the amplitude of spontaneous excitatory postsynaptic currents (EPSCs) mediated by α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. We observed that propofol increased the amplitude but decreased the paired-pulse ratio of EPSCs evoked by stimulation in the absence and the presence of gabazine (SR 95531), a GABAA receptor antagonist. Moreover, the propofol-induced facilitation of EPSCs was mimicked by 6-phenyl-4-azabicyclo[5.4.0]undeca-7,9,11-triene-9,10-diol (SKF38393), an agonist of dopamine D1 receptor, and by 1-[2-(diphenylmethoxy)ethyl]- 4-(3-phenylpropyl)piperazine dihydrochloride (GBR 12935), a dopamine reuptake inhibitor, but blocked by (±)-7-bromo-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine hydrochloride (SKF83566), a D1 antagonist, or by depleting dopamine stores with reserpine. Finally, 1 nM propofol increased the spontaneous discharge rate of dopamine neurons. These findings suggest that propofol at minute concentrations enhances presynaptic D1 receptor-mediated facilitation of glutamatergic synaptic transmission and the excitability of VTA dopamine neurons, probably by increasing extracellular dopamine levels. These changes in synaptic plasticity in the VTA, an addiction-related brain area might contribute to the development of propofol abuse and the increased susceptibility to addiction of other drugs.

Original languageEnglish (US)
Pages (from-to)165-174
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume325
Issue number1
DOIs
StatePublished - Apr 2008
Externally publishedYes

Fingerprint

Dopaminergic Neurons
Propofol
Glutamic Acid
Ventral Tegmental Area
Excitatory Postsynaptic Potentials
Synaptic Transmission
Substance-Related Disorders
Dopamine
Dopamine Uptake Inhibitors
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine
Presynaptic Receptors
GABA-A Receptor Antagonists
Dopamine D1 Receptors
Neuronal Plasticity
Reserpine
Mesencephalon
Occupations
Pharmaceutical Preparations
Hand
Physicians

ASJC Scopus subject areas

  • Pharmacology

Cite this

Nanomolar propofol stimulates glutamate transmission to dopamine neurons : A possible mechanism of abuse potential? / Li, Ke Yong; Xiao, Cheng; Xiong, Ming; Delphin, Ellise S.; Ye, Jiang Hong.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 325, No. 1, 04.2008, p. 165-174.

Research output: Contribution to journalArticle

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AU - Delphin, Ellise S.

AU - Ye, Jiang Hong

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