Antidepressant-like action of intracerebral 6-fluoronorepinephrine, a selective full α-adrenoceptor agonist.
The present study examined the ability of 6-fluoronorepinephrine (6FNE), a full selective α-adrenoceptor agonist, to produce antidepressant-like effects in mice. The drug, administered in the 4th ventricle, produced marked anti-immobility effects at mid-dose range in the acute forced swim, tail suspension and repeated open-space forced swim tests with minimal effect on open-field motor activity and also reversed anhedonia following lipopolysaccharide administration. Its antidepressant effects were equal to or greater than that of an established systemic antidepressant, desmethylimipramine, given subacutely. Experiments with α-adrenoceptor antagonists indicated that the drug acts primarily via the α2-receptor in contrast to endogenous catecholamines which appear to control depressive behaviour primarily via the α1-receptor. Antidepressant activity declined at higher doses signifying a possible pro-depressant effect of one of the α-adrenoceptor subtypes. Compared to the selective α2-agonist, dexmedetomidine, 6FNE showed equivalent antidepressant action in the tail suspension test but appeared to have a greater efficacy or speed of action in the repeated open-space forced swim test which produces a more sustained depression. Studies of regional brain Fos expression induced during the antidepressant tests showed that 6FNE tended to inhibit neural activity in two stress-responsive regions (locus coeruleus and paraventricular hypothalamus) but to enhance activity in two areas involved in motivated behaviour (nucleus accumbens shell and lateral septal nucleus) producing a neural pattern consistent with antidepressant action. It is concluded that 6FNE elicits a rapid and effective antidepressant and anti-stress response that may compare favourably with available antidepressants.
Stone
Eric A
EA
Department of Psychiatry, New York University Langone School of Medicine, New York, NY 10016, USA. eric.stone@nyumc.org
Lin
Yan
Y
Sarfraz
Yasmeen
Y
Quartermain
David
D
D058647:Adrenergic alpha-2 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects; D003863:Depression / Q000188:drug therapy*; D003891:Desipramine / Q000494:pharmacology*; D019417:Hindlimb Suspension; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009638:Norepinephrine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D057181:Pleasure / Q000187:drug effects; D011897:Random Allocation; D013550:Swimming
D058647:Adrenergic alpha-2 Receptor Agonists; D000928:Antidepressive Agents; C024884:6-fluoronorepinephrine; D003891:Desipramine; D009638:Norepinephrine