Substance P inhibits GABAB receptor signalling in the ventral tegmental area.
Substance P (SP) and its receptors are involved in anxiety-related behaviours and regulate the intake of drugs of abuse and alcohol. Within the midbrain ventral tegmental area (VTA), a region that is clearly involved in the control of these behaviours, SP is released by stress and has been shown to trigger relapse. SP activates neurokinin (NK) receptors, which excites midbrain dopamine (DA) neurons and leads to increased DA in target regions. In this study, we have investigated the mechanisms underlying SP actions in the VTA, specifically investigating interactions between SP and GABA(B) receptors. We show that in VTA neurons, NK receptor activation closes an inwardly rectifying potassium channel, and moreover inhibits GABA(B) receptor-mediated transmission through an interaction that depends upon phospholipase C (PLC), intracellular calcium and protein kinase C (PKC).
Ernest Gallo Clinic and Research Center, 5858 Horton Street, Suite 200, Emeryville, CA 94608, USA.
Yan-Fang
YF
Xia
Elyssa B
EB
Margolis
Gregory O
GO
Hjelmstad
D000818:Animals; D001418:Baclofen / Q000494:pharmacology; D002614:Chelating Agents / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004594:Electrophysiology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000187:drug effects; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists; D058788:GABA-B Receptor Antagonists; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018040:Receptors, Neurokinin-1 / Q000187:drug effects; D018041:Receptors, Neurokinin-2 / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects*; D013373:Substance P / Q000494:pharmacology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D017557:Ventral Tegmental Area / Q000187:drug effects*
D002614:Chelating Agents; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D018755:GABA Agonists; D018756:GABA Antagonists; D058788:GABA-B Receptor Antagonists; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D013373:Substance P; D004533:Egtazic Acid; D014446:Tyrosine 3-Monooxygenase; D011493:Protein Kinase C; D001418:Baclofen; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D004298:Dopamine