Substance P inhibits GABA_B receptor signalling in the ventral tegmental area

Abstract

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).

Alcohol dependence potentiates substance P/neurokinin-1 receptor signaling in the rat central nucleus of amygdala

“…Here, we sought to determine potential alterations in (i) the expression of SP and NK-1R in the CeM of dependent compared to naïve rats and (ii) the modulation of GABA transmission by the (10,24). SP/NK-1R interaction has also been associated with noncanonical signaling pathways including activation of AC (22,25), phospholipase A2 (26), or G protein-independent phosphotyrosine kinase-mediated mechanisms (27).…”

“…Thus, to determine the intracellular mechanism(s) involved in mediating SP-induced GABA release, we assessed SP (100 nM) effects on sIPSCs in the presence of pharmacological blockers of PLC [5 M U73122 for phosphatidylcholine-specific PLC (PC-PLC) (24) or 10 M D609 for phosphatidylinositol-specific PLC (PI-PLC) ( on CeA GABA transmission (data are summarized in table S1), indicating that SP-induced CeM GABA release is primarily mediated via an interaction with GIRK channels.…”

Calcium Release from Stores Inhibits GIRK

“…Typically modulation has been studied on the order of minutes (Xia et al, 2010) to days (Arora et al, 2011). The data presented here show that release of calcium from stores inhibits GIRK currents in milliseconds and reverses in seconds, a dynamic process that can modulate on the timescale of GIRK-dependent synaptic transmission.…”

“…The most commonly proposed mechanism(s) involve protein kinase C (PKC) (Mao et al, 2004). PKC-dependent inhibition has been reported to be either calcium-independent (Stevens et al, 1999; Leaney et al, 2001) or calcium-dependent (Hill and Peralta, 2001; Xia et al, 2010). The inhibition of GIRK by phospholipase C (PLC) has also been shown to be directly (Kobrinsky et al, 2000) and indirectly involved (Keselman et al, 2007).…”

Reversal of inhibition of putative dopaminergic neurons of the ventral tegmental area: Interaction of GABAB and D2 receptors

“…Others have shown that activation of GPCRs like NK1 can result in reduction of GABA B responsiveness of VTA neurons via PKC (Xia, et al, 2010). The present report is the first to show that such interaction (in this case between GPCRs that both activate GIRKs), can be long-lasting (30 min).…”