Substance P inhibits GABA B receptor signalling in the ventral tegmental area

• Published in: The Journal of physiology 2010-05, Vol.588 (9), p.1541-1549
• Main Authors: Xia, Yan‐Fang, Margolis, Elyssa B., Hjelmstad, Gregory O.
• Format: Article
• Language: English
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2010.188367

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). The midbrain dopamine neurons of the ventral tegmental area play an important role in guiding motivated behaviours, and dysfunction in midbrain neural circuits may underlie addictive behaviours. The neuropeptide substance P, which acts at neurokinin receptors, is released into the midbrain by stress and has been shown to excite dopamine neurons. Thus, substance P may promote stress‐induced drug relapse. In this study, we investigate the interactions between substance P and the neurotransmitter GABA acting at GABA B receptors. We show that substance P inhibits GABA B receptor‐mediated transmission in the ventral tegmental area. These results suggest that drugs acting at neurokinin receptors may synergize with drugs acting at GABA B receptors to more effectively prevent drug relapse.