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Long-lasting modulation of glutamatergic transmission in VTA dopamine neurons after a single dose of benzodiazepine agonists.
Neuropsychopharmacology 2009; 34(2):290-8N

Abstract

Initial effects of drugs of abuse seem to converge on the mesolimbic dopamine pathway originating from the ventral tegmental area (VTA). Even after a single dose, many drugs of abuse are able to modulate the glutamatergic transmission activating the VTA dopamine neurons, which may represent a critical early stage in the development of addiction. Ligands acting on the benzodiazepine site of the inhibitory gamma-aminobutyric acid type A (GABA(A)) receptors are known to be rewarding in animal models and have abuse liability in humans, but notably little evidence exists on the involvement of the mesolimbic dopamine system in their effects. Here we report that single in vivo doses of benzodiazepine-site agonists, similar to morphine and ethanol, induce a modulation in the glutamatergic transmission of VTA dopamine neurons. This is seen 24 h later as an increase in the ratio between alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor-mediated excitatory currents using whole-cell patch-clamp configuration in mouse VTA slices. The effect was due to increased frequency of spontaneous miniature AMPA receptor-mediated currents. It lasted at least 3 days after the injection of diazepam, and was prevented by coadministration of the benzodiazepine-site antagonist flumazenil or the NMDA receptor antagonist dizocilpine. A single injection of the GABA(A) receptor alpha1 subunit-preferring benzodiazepine-site ligand zolpidem also produced an increase in the AMPA/NMDA ratio in VTA dopamine neurons. These findings suggest a role for the mesolimbic dopamine system in the initial actions of and on neuronal adaptation to benzodiazepines.

Authors+Show Affiliations

Institute of Biomedicine, Pharmacology, University of Helsinki, Helsinki, Finland.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18563060

Citation

Heikkinen, Anne E., et al. "Long-lasting Modulation of Glutamatergic Transmission in VTA Dopamine Neurons After a Single Dose of Benzodiazepine Agonists." Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, vol. 34, no. 2, 2009, pp. 290-8.
Heikkinen AE, Möykkynen TP, Korpi ER. Long-lasting modulation of glutamatergic transmission in VTA dopamine neurons after a single dose of benzodiazepine agonists. Neuropsychopharmacology. 2009;34(2):290-8.
Heikkinen, A. E., Möykkynen, T. P., & Korpi, E. R. (2009). Long-lasting modulation of glutamatergic transmission in VTA dopamine neurons after a single dose of benzodiazepine agonists. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, 34(2), pp. 290-8. doi:10.1038/npp.2008.89.
Heikkinen AE, Möykkynen TP, Korpi ER. Long-lasting Modulation of Glutamatergic Transmission in VTA Dopamine Neurons After a Single Dose of Benzodiazepine Agonists. Neuropsychopharmacology. 2009;34(2):290-8. PubMed PMID: 18563060.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Long-lasting modulation of glutamatergic transmission in VTA dopamine neurons after a single dose of benzodiazepine agonists. AU - Heikkinen,Anne E, AU - Möykkynen,Tommi P, AU - Korpi,Esa R, Y1 - 2008/06/18/ PY - 2008/6/20/pubmed PY - 2009/2/24/medline PY - 2008/6/20/entrez SP - 290 EP - 8 JF - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology JO - Neuropsychopharmacology VL - 34 IS - 2 N2 - Initial effects of drugs of abuse seem to converge on the mesolimbic dopamine pathway originating from the ventral tegmental area (VTA). Even after a single dose, many drugs of abuse are able to modulate the glutamatergic transmission activating the VTA dopamine neurons, which may represent a critical early stage in the development of addiction. Ligands acting on the benzodiazepine site of the inhibitory gamma-aminobutyric acid type A (GABA(A)) receptors are known to be rewarding in animal models and have abuse liability in humans, but notably little evidence exists on the involvement of the mesolimbic dopamine system in their effects. Here we report that single in vivo doses of benzodiazepine-site agonists, similar to morphine and ethanol, induce a modulation in the glutamatergic transmission of VTA dopamine neurons. This is seen 24 h later as an increase in the ratio between alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor-mediated excitatory currents using whole-cell patch-clamp configuration in mouse VTA slices. The effect was due to increased frequency of spontaneous miniature AMPA receptor-mediated currents. It lasted at least 3 days after the injection of diazepam, and was prevented by coadministration of the benzodiazepine-site antagonist flumazenil or the NMDA receptor antagonist dizocilpine. A single injection of the GABA(A) receptor alpha1 subunit-preferring benzodiazepine-site ligand zolpidem also produced an increase in the AMPA/NMDA ratio in VTA dopamine neurons. These findings suggest a role for the mesolimbic dopamine system in the initial actions of and on neuronal adaptation to benzodiazepines. SN - 1740-634X UR - https://www.unboundmedicine.com/medline/citation/18563060/Long_lasting_modulation_of_glutamatergic_transmission_in_VTA_dopamine_neurons_after_a_single_dose_of_benzodiazepine_agonists_ L2 - http://dx.doi.org/10.1038/npp.2008.89 DB - PRIME DP - Unbound Medicine ER -