Peripheral GABA B agonists stimulate gastric acid secretion in mice

We characterized the effects of intravenous GABA and preferential GABA A (muscimol), GABA B ( R ‐baclofen and SKF‐97541) and GABA C agonists (imidazole‐4‐acetic acid) on gastric acid secretion in urethane‐anesthetized mice implanted with a gastric cannula, and determined the role of vagal cholinergic mechanisms, and gastrin and somatostatin by using peptide immunoneutralization, the SSTR2 antgonist, PRL‐2903, and SSTR2 knockout mice. The selective GABA B agonists R ‐baclofen (0.1–3 mg kg −1 , i.v.) and SKF‐97541 (0.01–0.3 mg kg −1 , i.v.) induced a dose‐related stimulation of gastric acid secretion. SKF‐97541 was about 10 times more potent than R ‐baclofen stimulating gastric acid secretion. Neither GABA (0.1–100 mg kg −1 , i.v.) nor muscimol (0.1–3 mg kg −1 ) nor imidazole‐4‐acetic acid (0.1–10 mg kg −1 ) affected basal gastric acid secretion. Stimulatory effects of SKF‐97541 (0.1 mg kg −1 , i.v.) were blocked by the selective GABA B antagonist, 2‐hydroxysaclofen, cholinergic blockade with atropine, subdiaphragmatic vagotomy or gastrin immunoneutralization. Somatostatin immunoneutralization or SSTR2 blockade with PRL‐2903 enhanced the secretory response to SKF‐97541 (0.1 mg kg −1 , i.v.) by 78 and 105%, respectively. In SSTR2 knockout mice, SKF‐97541 (0.1 mg kg −1 , i.v.) increased basal gastric acid secretion by 48%. Neither GABA nor muscimol nor imidazole‐4‐acetic acid modified basal gastric acid secretion in SSTR2 knockout mice. These results indicate that, in mice, stimulation of GABA B receptors increases gastric acid secretion through vagal‐ and gastrin‐dependent mechanisms. Somatostatin implication might be secondary to the release of gastrin and the increase in gastric luminal acidity.British Journal of Pharmacology (2004) 142 , 1038–1048. doi: 10.1038/sj.bjp.0705876