GABA(B) receptor-mediated tonic inhibition regulates the spontaneous firing of locus coeruleus neurons in developing rats and in citalopram-treated rats

摘要

Noradrenaline (NA)-releasing neurons in the locus coeruleus (LC) provide NA to the forebrain. Their activity is believed to be a key factor regulating the wakefulness/arousal level of the brain. In this study, we found that the activity of NA-releasing neurons in the LC (LC neurons) was subject to -aminobutyric acid (GABA) tonic inhibition through GABA(B) receptors (GABA(B)Rs), but not GABA(A) receptors. The intensity of GABA(B)R tonic inhibition was found to depend on ambient GABA levels, as it was dramatically increased by blockade of GABA reuptake. It also varied with the function of GABA(B)Rs. The GABA(B)R activity on LC neurons was found to increase with postnatal age up to postnatal days 8-10, resulting in increased tonic inhibition. Interestingly, there was no significant difference in the spontaneous activity of LC neurons at different postnatal ages unless GABA(B)R tonic inhibition was blocked. These results show that, during postnatal development, there is a continuous increase in GABA(B)R tonic inhibition that maintains the activity of LC neurons at a proper level. In male, but not female, rats, chronic perinatal treatment with citalopram, a selective serotonin reuptake inhibitor, reduced GABA(B)R activity and tonic inhibition, which might result in the significantly higher spontaneous activity of LC neurons seen in these animals. In conclusion, our results show that GABA(B)R-mediated tonic inhibition has a direct impact on the spontaneous activity of LC neurons and that the extent of the effect varies with ambient GABA levels and functionality of GABA(B)R signalling.