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NEUROPHARMACOLOGY

Nanomolar Propofol Stimulates Glutamate Transmission to Dopamine Neurons: A Possible Mechanism of Abuse Potential?

Departments of Anesthesiology (K.-Y.L., C.X., M.X., E.D., J.-H.Y.) and Physiology and Pharmacology (J.-H.Y.), University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey

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 -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 GABA_A 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.

Address correspondence to: Dr. Jiang-Hong Ye, Department of Anesthesiology, New Jersey Medical School, 185 South Orange Ave., Newark, NJ 07103-2714. E-mail: ye{at}umdnj.edu