α 2 ‐Adrenoceptors modulating neuronal serotonin release: a study in α 2 ‐adrenoceptor subtype‐deficient mice

The release‐inhibiting α 2 ‐adrenoceptors of cerebral serotoninergic axons were studied in mice. Slices of the hippocampus or the occipito‐parietal cortex from NMRI mice, from mice lacking the α 2A/D ‐, the α 2B ‐, the α 2C ‐ or both the α 2A/D ‐ and the α 2C ‐adrenoceptor, and from mice sharing the genetic background of the receptor‐deficient animals (WT) were preincubated with [ 3 H]‐serotonin and then superfused and stimulated electrically, in most experiments by trains of 8 pulses at 100 Hz. The concentration‐response curves of the α 2 ‐adrenoceptor agonist medetomidine were virtually identical in hippocampal slices from NMRI and WT mice, with maximally 70% inhibition and an EC 50 of about 2 n M . In hippocampal slices from NMRI mice, phentolamine and rauwolscine were equipotent antagonists against medetomidine. The effect of medetomidine was greatly reduced, with maximally 20% inhibition, in hippocampal slices from α 2A/D ‐adrenoceptor‐deficient mice; was slightly reduced, with maximally 59% inhibition, in hippocampal slices from α 2C ‐adrenoceptor‐deficient mice; was not changed in hippocampal slices from α 2B ‐adrenoceptor‐deficient mice; and was abolished in hippocampal slices from mice lacking both the α 2A/D ‐ and the α 2C ‐adrenoceptor. Similar results were obtained in: (i) occipito‐parietal slices from NMRI and α 2A/D ‐adrenoceptor‐deficient mice and (ii) hippocampal slices that were preincubated with [ 3 H]‐serotonin in the presence of oxaprotiline to rule out cross‐labelling of noradrenergic axons. The serotoninergic axons of the mouse brain possess both α 2A/D ‐heteroreceptors, which predominate, and α 2C ‐heteroreceptors but lack α 2B ‐adrenoceptors. The situation resembles the coexistence of α 2A/D ‐ and α 2C ‐autoreceptors but lack of α 2B ‐autoreceptors at the noradrenergic axons of mice.British Journal of Pharmacology (2001) 132 , 925–933; doi: 10.1038/sj.bjp.0703882