title: In vivo neurochemical evidence that newly synthesised GABA activates GABA(B), but not GABA(A), receptors on dopaminergic nerve endings in the nucleus accumbens of freely moving rats.
abstract: GABA released from accumbal GABAergic interneurons plays an inhibitory role in the regulation of dopamine efflux through GABA(B) and GABA(A) receptors located on accumbal dopaminergic nerve endings. The cytosolic newly synthesised GABA alters vesicular GABA levels and, accordingly, the amount of GABA released from the neuron. Therefore, we hypothesised that glutamic acid decarboxylase (GAD) which generates GABA in accumbal GABAergic neurons, at least partly determines the GABA receptor subtype-mediated GABAergic tonus. To (in)validate this hypothesis, in vivo microdialysis was used to study the effects of an intra-accumbal infusion of the GAD inhibitor l-allylglycine (allylglycine) on the accumbal dopamine efflux of freely moving rats. The intra-accumbal infusion of allylglycine (50.0, 250.0 and 500.0 nmol) dose-dependently increased the accumbal dopamine levels. The co-administration of tetrodotoxin (720 pmol) suppressed the allylglycine (500.0 nmol)-induced dopamine efflux. The intra-accumbal infusion of GABA(B) receptor agonist baclofen (2.5 and 5.0 nmol) inhibited the allylglycine (500.0 nmol)-induced dopamine efflux. The baclofen's effects were counteracted by GABA(B) receptor antagonist saclofen (10.0 nmol). Neither GABA(A) receptor agonist (muscimol: 25.0 and 250.0 pmol) nor antagonist (bicuculline: 50.0 pmol) altered the allylglycine (250.0 and 500.0 nmol)-induced dopamine efflux. The present study provides in vivo neurochemical evidence that newly synthesised GABA that exerts an inhibitory tonus on the accumbal dopaminergic activity, acts at the level of GABA(B) receptors, but not GABA(A) receptors. The present study also shows that there is an allylglycine-insensitive GABA pool that release GABA exerting an inhibitory control of the accumbal dopaminergic activity, at the level of GABA(A) receptors. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.
authors.affiliation: Department of Pharmacology, Nihon University School of Dentistry, 1-8-13, Kanda-Surugadai, Chiyoda-ku, Tokyo 101-8310, Japan. saigusa@dent.nihon-u.ac.jp
authors.forename: Tadashi
authors.initials: T
authors.lastname: Saigusa
authors.forename: Yuri
authors.initials: Y
authors.lastname: Aono
authors.forename: Reiko
authors.initials: R
authors.lastname: Sekino
authors.forename: Takuya
authors.initials: T
authors.lastname: Uchida
authors.forename: Koji
authors.initials: K
authors.lastname: Takada
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Oi
authors.forename: Noriaki
authors.initials: N
authors.lastname: Koshikawa
authors.forename: Alexander R
authors.initials: AR
authors.lastname: Cools
mesh_terms: D000501:Allylglycine / Q000494:pharmacology; D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D018756:GABA Antagonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists / Q000494:pharmacology; D058786:GABA-B Receptor Agonists / Q000494:pharmacology; D008297:Male; D017551:Microdialysis; D009118:Muscimol / Q000494:pharmacology; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists; D058786:GABA-B Receptor Agonists; D011963:Receptors, GABA-A; D018080:Receptors, GABA-B; D000501:Allylglycine; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; D001418:Baclofen; D004298:Dopamine