title: Distinct mechanisms of presynaptic inhibition at GABAergic synapses of the rat substantia nigra pars compacta.
abstract: We investigated the mechanisms of presynaptic inhibition of GABAergic neurotransmission by group III metabotropic glutamate receptors (mGluRs) and GABA(B) receptors, in dopamine (DA) neurons of the substantia nigra pars compacta (SNc). Both the group III mGluRs agonist L-(+)-2-amino-4-phosphonobutyric acid (AP4, 100 microM) and the GABA(B) receptor agonist baclofen (10 microM) reversibly depressed the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) to 48.5 +/- 2.7 and 79.3 +/- 1.6% (means +/- SE) of control, respectively. On the contrary, the frequency of action potential-independent miniature IPSCs (mIPSCs), recorded in tetrodotoxin (TTX, 1 microM) and cadmium (100 microM) were insensitive to AP4 but were reduced by baclofen to 49.7 +/- 8.6% of control. When the contribution of voltage-dependent calcium channels (VDCCs) to synaptic transmission was boosted with external barium (1 mM), AP4 became effective in reducing TTX-resistant mIPSCs to 65.4 +/- 3.9% of control, thus confirming a mechanism of presynaptic inhibition involving modulation of VDCCs. Differently from AP4, baclofen inhibited to 58.5 +/- 6.7% of control the frequency mIPSCs recorded in TTX and the calcium ionophore ionomycin (2 microM), which promotes Ca2+-dependent, but VDCC-independent, transmitter release. Moreover, in the presence of alpha-latrotoxin (0.3 nM), to promote a Ca2+-independent vesicular release of GABA, baclofen reduced mIPSC frequency to 48.1 +/- 3.2% of control, while AP4 was ineffective. These results indicate that group III mGluRs depress GABA release to DA neurons of the SNc through inhibition of presynaptic VDCCs, while presynaptic GABA(B) receptors directly impair transmitter exocytosis.
authors.affiliation: Centro Europeo di Ricerca sul Cervello Fondazione Santa Lucia Istituto di Ricovero e Cura a Carattere Scientifico, Via del Fosso di Fiorano, 64, 00143 Rome, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Giustizieri
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bernardi
authors.forename: Nicola B
authors.initials: NB
authors.lastname: Mercuri
authors.forename: Nicola
authors.initials: N
authors.lastname: Berretta
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000613:Aminobutyrates / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001418:Baclofen / Q000494:pharmacology; D019256:Cadmium Chloride / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D018408:Patch-Clamp Techniques / Q000379:methods; D010721:Phosphinic Acids / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology*; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013111:Spider Venoms / Q000494:pharmacology; D013378:Substantia Nigra / Q000166:cytology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D013779:Tetrodotoxin / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000613:Aminobutyrates; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018755:GABA Agonists; D018756:GABA Antagonists; D007476:Ionophores; D010721:Phosphinic Acids; D011412:Propanolamines; D026941:Sodium Channel Blockers; D013111:Spider Venoms; C104331:cyclopropyl-4-phosphonophenylglycine; C085075:CGP 55845A; D013779:Tetrodotoxin; D005680:gamma-Aminobutyric Acid; D015759:Ionomycin; C020763:alpha-latrotoxin; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D001418:Baclofen; C012729:2-amino-4-phosphonobutyric acid; D019256:Cadmium Chloride; D005998:Glycine; D004298:Dopamine