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The Journal of Neuroscience, January 23, 2008, 28(4):808-815; doi:10.1523/JNEUROSCI.4876-07.2008

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Cellular/Molecular
Glutamate Spillover Modulates GABAergic Synaptic Transmission in the Rat Midbrain Periaqueductal Grey via Metabotropic Glutamate Receptors and Endocannabinoid Signaling

Geoffrey M. Drew, Vanessa A. Mitchell, and Christopher W. Vaughan

Pain Management Research Institute, Kolling Institute of Medical Research, Northern Clinical School, The University of Sydney at Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia

Correspondence should be addressed to Dr. Geoffrey M. Drew, Pain Management Research Institute, Northern Clinical School, Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia. Email: gdrew{at}med.usyd.edu.au

Glutamate spillover regulates GABAergic synaptic transmission at several CNS synapses via presynaptic ionotropic and metabotropic glutamate receptors (mGluRs). We have previously demonstrated that activation of group I–III mGluRs inhibits GABAergic transmission in the midbrain periaqueductal gray (PAG), a region involved in organizing behavioral responses to threat, stress, and pain. Here, we examined the role of glutamate spillover in the modulation of GABAergic transmission in the PAG. Using whole-cell recordings from rat PAG slices, we found that evoked IPSCs were reduced by the nonspecific glutamate transport blockers DL-threo-β-benzyloxyaspartic acid (TBOA) and L-trans-pyrrolidine-2,4-dicarboxylic acid, but not by the glial GLT1-specific blocker dihydrokainate. In contrast, TBOA had no effect on evoked IPSCs when glutamate uptake into the postsynaptic neuron was selectively impaired. TBOA increased the paired-pulse ratio of evoked IPSCs and reduced the rate but not the amplitude of spontaneous miniature IPSCs. The effect of TBOA on evoked IPSCs was abolished by the broad-spectrum mGluR antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (100 µM), reduced by the mGluR5-specific antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) and mimicked by the mGluR1/5 agonist (RS)-3,5-dihydroxyphenylglycine (DHPG). Furthermore, the effects of both TBOA and DHPG were reduced by the cannabinoid CB1 receptor antagonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (AM251). Finally, although MPEP and AM251 had no effect on single evoked IPSCs, they increased evoked IPSCs during repetitive stimulation. These results indicate that neuronal glutamate transporters limit mGluR5 activation and endocannabinoid signaling, but may be overwhelmed during conditions of elevated glutamate release. Thus, neuronal glutamate transporters play a key role in regulating endocannabinoid-mediated cross talk between glutamatergic and GABAergic synapses within the PAG.

Key words: glutamate transporters; metabotropic glutamate receptor; GABA; cannabinoid; periaqueductal grey; analgesia

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Received May 25, 2007; revised Nov. 28, 2007; accepted Dec. 1, 2007.

Correspondence should be addressed to Dr. Geoffrey M. Drew, Pain Management Research Institute, Northern Clinical School, Royal North Shore Hospital, St. Leonards, New South Wales 2065, Australia. Email: gdrew{at}med.usyd.edu.au

This article has been cited by other articles:

				G. M. Drew, B. K. Lau, and C. W. Vaughan Substance P Drives Endocannabinoid-Mediated Disinhibition in a Midbrain Descending Analgesic Pathway J. Neurosci., June 3, 2009; 29(22): 7220 - 7229. [Abstract] [Full Text] [PDF]

				V. A. Mitchell, H. Kawahara, and C. W. Vaughan Neurotensin inhibition of GABAergic transmission via mGluR-induced endocannabinoid signalling in rat periaqueductal grey J. Physiol., June 1, 2009; 587(11): 2511 - 2520. [Abstract] [Full Text] [PDF]

				M. Kano, T. Ohno-Shosaku, Y. Hashimotodani, M. Uchigashima, and M. Watanabe Endocannabinoid-Mediated Control of Synaptic Transmission Physiol Rev, January 1, 2009; 89(1): 309 - 380. [Abstract] [Full Text] [PDF]

				B. K. Lau and C. W. Vaughan Muscarinic Modulation of Synaptic Transmission via Endocannabinoid Signalling in the Rat Midbrain Periaqueductal Gray Mol. Pharmacol., November 1, 2008; 74(5): 1392 - 1398. [Abstract] [Full Text] [PDF]

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