GABA_B receptor-mediated tonic inhibition of noradrenergic A7 neurons in the rat

Abstract

Noradrenergic (NAergic) A7 neurons that project axonal terminals to the dorsal horn of the spinal cord to modulate nociceptive signaling are suggested to receive tonic inhibition from local GABAergic interneurons, which are under the regulation of descending analgesic pathways. In support of this argument, we presently report GABA(B) receptor (GABA(B)R)-mediated tonic inhibition of NAergic A7 neurons. Bath application of baclofen induced an outward current (I(Bac)) in NAergic A7 neurons that was blocked by CGP 54626, a GABA(B)R blocker. The I(Bac) was reversed at about -99 mV, displayed inward rectification, and was blocked by Ba(2+) or Tertipian-Q, showing it was mediated by G protein-activated inward-rectifying K(+) (GIRK) channels. Single-cell RT-PCR results suggested that GIRK1/3 heterotetramers might dominate functional GIRK channels in NAergic A7 neurons. Under conditions in which GABA(A) and glycine receptors were blocked, bath application of GABA inhibited the spontaneous firing of NAergic A7 neurons in a dose-dependent manner. Interestingly, CGP 54626 application not only blocked the effect of GABA but also increased the firing rate to 126.9% of the control level, showing that GABA(B)Rs were constitutively active at an ambient GABA concentration of 2.8 μM and inhibited NAergic A7 neurons. GABA(B)Rs were also found at presynaptic excitatory and inhibitory axonal terminals in the A7 area. Pharmacological activation of these GABA(B)Rs inhibited the release of neurotransmitters. No physiological role was found for GABA(B)Rs on excitatory terminals, whereas those on the inhibitory terminals were found to exert autoregulatory control of GABA release.

GABAB receptor‐mediated tonic inhibition regulates the spontaneous firing of locus coeruleus neurons in developing rats and in citalopram‐treated rats

“…For example, since ambient GABA levels in the LC are significantly higher during REM/non-REM sleep than during wakefulness (Nitz & Siegel, 1997;Nelson et al 2002), our results suggest that GABA B R-mediated tonic inhibition may play an important role in regulating the SFR of LC neurons, and thus the wakefulness/arousal level of the brain. In addition to postsynaptic regulation, GABA B Rs at presynaptic sites have been shown to regulate glutamate and GABA release in many brain areas (Wu et al 2011;Wang et al 2013), perhaps including the LC neurons, as our EM study showed presynaptic location of GABA B Rs in the LC. As GABA B R signalling and the activity of GABA transporters in many physiological and pathological processes can be regulated by various transmitter/receptor systems, such as the activation of 5-HT 1A receptors during chronic exposure to SSRIs, our results suggest that tonic inhibition and presynaptic regulation of transmitter release mediated by peri/extrasynaptic GABA B Rs on LC neurons could be important players in the development of normal and abnormal behaviours/brain functions that are associated with the LC-NA system.…”

“…We refer to this GABA B R antagonist‐induced current as the GABA B R‐mediated standing current (GABA B R‐ I Stand ) (see Wu et al . ). Since CGP54626 and SCH50911 both function as inverse agonists of GABA B Rs (Grünewald et al .…”

“…4Aa and c). We refer to this GABA B R antagonist-induced current as the GABA B R-mediated standing current (GABA B R-I Stand ) (see Wu et al 2011). Since CGP54626 and SCH50911 both function as inverse agonists of GABA B Rs (Grünewald et al 2002), a neutral antagonist, CGP35348, was used to examine whether the GABA B R-I Stand resulted from activation of GABA B Rs by ambient GABA or from constitutive activity of the receptor.…”

“…Interestingly, recent reports have shown that GABA tonic inhibition in A6 (the LC) and A7 catecholamine cells in the pons (Wu et al . ; Wang et al . ) and layer 2/3 pyramidal neurons in the medial prefrontal cortex (Wang et al .…”

“…Interestingly, recent reports have shown that GABA tonic inhibition in A6 (the LC) and A7 catecholamine cells in the pons (Wu et al 2011;Wang et al 2012) and layer 2/3 pyramidal neurons in the medial prefrontal cortex (Wang et al 2010) is mediated by GABA B Rs, but not GABA A Rs. Since GABA is important for regulating LC neuron activity, the aims of the present study were to fully characterize the GABA B R-mediated tonic inhibition of LC neurons and determine the functional outcome of manipulations that increase or decrease it.…”