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Functional characterization of α1 adrenergic receptor in the rat locus coeruleus in vitro
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1  University of the Basque Country

Abstract:

α1-adrenoceptor (α1AR) is involved in the physiopathology of the central nervous system (CNS) and could constitute a therapeutic target for neurological disorders such as drug addiction or Alzheimer´s disease. α1AR mainly couples to Gq/11 protein, which activation leads to stimulation of phospholipase C (PLC) and subsequent activation of protein kinase C (PKC). However, other G proteins (Gi, Gs) have also been described to be coupled to α1AR receptors. The locus coeruleus (LC), the main noradrenergic nucleus in the CNS, has been shown to express α1AR, but to date functional role of α1AR in the adult rat brain LC remains unclear. The aim of this study was to characterize, by single-unit extracellular recordings of LC neurons, the role of α1AR in the regulation of the firing rate (FR) of LC neurons in adult rat brain in vitro. For that purpose, we first characterize the effect of the α1/α2AR agonist noradrenaline (NA) in the presence and absence of the α2AR antagonist RS 79948 (0.1 µM). Then, we investigated the signalling pathway involved in the effect of NA. Perfusion with NA (100 µM) inhibited the FR of LC neurons through activation of α2AR. However, in the presence of the α2-adrenoceptor (α2AR) antagonist RS 79948 (0.1 µM) perfusion with NA increased the FR of NA neurons (stimulatory effect = 114%). The stimulatory effect of NA (100 µM) was blocked by the α1AR antagonist WB 4101 (0.5 µM). Administration of the PKC inhibitor Go 6976 (1 µM), the G protein-coupled inwardly-rectifying potassium channel (GIRK) blocker BaCl2 (300 µM) or PKA inhibitor H-89 (10 µM) failed to change the stimulatory effect of NA. However, NA (100 µM) induced stimulation was reduced by 64% in the presence of the Gi/o protein inactivator pertussis toxin (PTX) (500 ng·ml-1). In conclusion, α1AR activation stimulates the FR of NA neurons in the adult rat LC through a signalling pathway that involves activation of the Gi/o protein. It remains to be studied the mechanism by which Gi/o proteins stimulates the FR of LC neurons via α1AR activation.

Keywords: locus coeruleus; electrophysiology; in vitro; α1-adrenoceptor; noradrenaline
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