α2-adrenoceptors modulating neuronal serotonin release:: a study in α2-adrenoceptor subtype-deficient mice

1 The release-inhibiting alpha (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 alpha (2A D)-, the alpha (2B)-, the alpha (2C)- or both the alpha (2A D)- and the alpha (2C)-adrenoceptor, and from mice sharing the genetic background of the receptor-deficient animals (WT) were preincubated with [H-3]-serotonin and then superfused and stimulated electrically, in most experiments by trains of 8 pulses at 100 Hz. 2 The concentration-response curves of the alpha (2)-adrenoceptor agonist medetomidine were virtually identical in hippocampal slices from NMRI and WT mice, with maximally 70% inhibition and an EC50 of about 2 nm. In hippocampal slices from NMRI mice. phentolamine and rauwolscine were equipotent antagonists against medetomidine. 3 The effect of medetomidine was greatly reduced, with maximally 20% inhibition, in hippocampal slices from alpha (2A) (D)-adrenoceptor-deficient mice; was slightly reduced, with maximally 59% inhibition, in hippocampal slices from alpha (2C)-adrenoceptor-deficient mice: was not changed in hippocampal slices from alpha (2B)-adrenoceptor-deficient mice; and was abolished in hippocampal slices from mice lacking both the alpha (2A D)- and the alpha (2C)-adrenoceptor. 4 Similar results were obtained in: (i) occipito-parietal slices from NMRI and alpha (2A D)-adrenoceptor-deficient mice and (ii) hippocampal slices that were preincubated with [H-3]-serotonin in the presence of oxaprotiline to rule out cross-labelling of noradrenergic axons. 5 The serotoninergic axons of the mouse brain possess both alpha (2A D)-hereroreceptors, which predominate, and alpha (2C)-heteroreceptors but lack alpha (2B)-adrenoceptors. The situation resembles the coexistence of alpha (2A D)- and alpha (2C)-autoreceptors but lack of alpha (2B)-autoreceptors at the noradrenergic axons of mice.