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Vol. 295, Issue 3, 1206-1222, December 2000
2-Adrenoceptors: II. Influence on Monoaminergic
Transmission, Motor Function, and Anxiety in Comparison with
Dexmedetomidine and Clonidine
Psychopharmacology Department (M.J.M., F.L., A.G., M.B., A.A.,
C.B., J.-M.R., A.D.), Institut de Recherches Servier, Centre de
Recherches de Croissy, Croissy/Seine, Paris, France; and Chemistry C
Department (J.-M.L., A.C.), Institut de Recherches Servier, Centre de
Recherches de Suresnes, Suresnes, Paris, France
The 
2-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
2-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 2- versus 1-AR antagonists,
atipamezole and BRL-44408 (a preferential 2A-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
1- versus 2-AR antagonist (which also
preferentially blocks 2B/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 2-ARs, S18616 potently inhibits corticolimbic adrenergic, serotonergic, and (frontocortical) dopaminergic transmission in parallel with the expression of its anxiolytic and sedative properties.
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