@article {Millan1206, author = {Mark J. Millan and Fran{\c c}oise Lejeune and Alain Gobert and Mauricette Brocco and Agn{\'e}s Auclair and Catherine Bosc and Jean-Michel Rivet and Jean-Michel Lacoste and Alex Cordi and Anne Dekeyne}, title = {S18616, a Highly Potent Spiroimidazoline Agonist at α2-Adrenoceptors: II. Influence on Monoaminergic Transmission, Motor Function, and Anxiety in Comparison with Dexmedetomidine and Clonidine}, volume = {295}, number = {3}, pages = {1206--1222}, year = {2000}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {The α2-adrenoceptor (AR) agonist, S18616 {(S)-spiro[(1-oxa-2-amino-3-azacyclopent-2-ene)-4,2'-(8'-chloro-1',2',3',4'-tetrahydronaphthalene)] accompanying article}, suppressed electrical activity of adrenergic neurons in the locus ceruleus, an action reversed by the α2-AR antagonist, idazoxan, which itself enhanced their firing rate. Electrical activity of serotonergic neurons in the dorsal raphe nucleus was similarly suppressed, an action likewise blocked by idazoxan, which did not, itself, influence firing. In freely moving rats, S18616 decreased extracellular levels of norepinephrine (NE), serotonin (5-HT), and dopamine (DA) in frontal cortex and hippocampus. The selective α2- versus α1-AR antagonists, atipamezole and BRL-44408 (a preferential α2A-AR antagonist), elevated levels of NE and DA but not 5-HT. In their presence, the influence of S18616 on frontocortical levels of NE, DA, and 5-HT was blocked. In contrast, prazosin, a selective α1- versus α2-AR antagonist (which also preferentially blocks α2B/2C-ARs) dose dependently decreased levels of 5-HT, but not NE and DA, and failed to modify the actions of S18616. Ultrasonic vocalizations elicited by rats in an aversive environment were inhibited by S18616, which also suppressed aggressive and marble-burying behaviors in mice. Furthermore, S18616 (biphasically) enhanced punished responses in the Vogel conflict test and active social interaction tests in rats. At higher doses, S18616 displayed sedative/hypnotic properties. Both anxiolytic and motor actions of S18616 were inhibited by atipamezole and BRL-44408 but not prazosin. Dexmedetomidine mimicked the actions of S18616 at higher doses except for more potent sedative/hypnotic properties. Clonidine also mimicked S18616, but only at markedly higher doses. In conclusion, via activation of α2-ARs, S18616 potently inhibits corticolimbic adrenergic, serotonergic, and (frontocortical) dopaminergic transmission in parallel with the expression of its anxiolytic and sedative properties. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0022-3565}, URL = {https://jpet.aspetjournals.org/content/295/3/1206}, eprint = {https://jpet.aspetjournals.org/content/295/3/1206.full.pdf}, journal = {Journal of Pharmacology and Experimental Therapeutics} }