Tags

Type your tag names separated by a space and hit enter

Nanomolar propofol stimulates glutamate transmission to dopamine neurons: a possible mechanism of abuse potential?
J Pharmacol Exp Ther 2008; 325(1):165-74JP

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 alpha-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 D(1) 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 D(1) 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 D(1) 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.

Authors+Show Affiliations

Department of Anesthesiology, New Jersey Medical School, 185 South Orange Ave., Newark, NJ 07103-2714, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18216287

Citation

Li, Ke-Yong, et al. "Nanomolar Propofol Stimulates Glutamate Transmission to Dopamine Neurons: a Possible Mechanism of Abuse Potential?" The Journal of Pharmacology and Experimental Therapeutics, vol. 325, no. 1, 2008, pp. 165-74.
Li KY, Xiao C, Xiong M, et al. Nanomolar propofol stimulates glutamate transmission to dopamine neurons: a possible mechanism of abuse potential? J Pharmacol Exp Ther. 2008;325(1):165-74.
Li, K. Y., Xiao, C., Xiong, M., Delphin, E., & Ye, J. H. (2008). Nanomolar propofol stimulates glutamate transmission to dopamine neurons: a possible mechanism of abuse potential? The Journal of Pharmacology and Experimental Therapeutics, 325(1), pp. 165-74. doi:10.1124/jpet.107.132472.
Li KY, et al. Nanomolar Propofol Stimulates Glutamate Transmission to Dopamine Neurons: a Possible Mechanism of Abuse Potential. J Pharmacol Exp Ther. 2008;325(1):165-74. PubMed PMID: 18216287.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nanomolar propofol stimulates glutamate transmission to dopamine neurons: a possible mechanism of abuse potential? AU - Li,Ke-Yong, AU - Xiao,Cheng, AU - Xiong,Ming, AU - Delphin,Ellise, AU - Ye,Jiang-Hong, Y1 - 2008/01/23/ PY - 2008/1/25/pubmed PY - 2008/4/23/medline PY - 2008/1/25/entrez SP - 165 EP - 74 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 325 IS - 1 N2 - 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 alpha-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 D(1) 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 D(1) 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 D(1) 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. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/18216287/Nanomolar_propofol_stimulates_glutamate_transmission_to_dopamine_neurons:_a_possible_mechanism_of_abuse_potential L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=18216287 DB - PRIME DP - Unbound Medicine ER -