Discriminative stimulus properties of the selective norepinephrine reuptake inhibitor, reboxetine, in rats: a characterization with alpha/beta-adrenoceptor subtype selective ligands, antidepressants, and antagonists at neuropeptide receptors
by
Millan MJ, Dekeyne A.
Institut de Recherches Servier,
Centre de Recherches de Croissy,
Psychopharmacology Department,
Croissy-sur-Seine, Paris, France.
Int J Neuropsychopharmacol. 2006 Nov 1;:1-15

ABSTRACT

Although little information is available concerning discriminative stimulus (DS) properties of antidepressants, rats can be trained to recognize the selective norepinephrine (NE) reuptake inhibitor, reboxetine (2.5 mg/kg i.p.). By analogy to reboxetine (effective dose 50, 1.1), 'full' (>/=80%) substitution dose50 was obtained with the NE reuptake inhibitors, nisoxetine (4.9), nomifensine (0.5) and BW1555,U88 (1.0). Full substitution was also attained with the NE/serotonin (5-HT) reuptake inhibitors, S33005 (0.3), venlafaxine (4.8) and duloxetine (26.8), and the tricyclics, imipramine (2.5) and clomipramine (2.9). In contrast, the 5-HT reuptake inhibitors, citalopram, sertraline and paroxetine (all >2.5), and the 5-HT reuptake inhibitors/5-HT2 receptor antagonists, nefazodone and trazodone (both >10.0), did not substitute for reboxetine. The 'atypical' antidepressants, mirtazapine (>10.0) and mianserin (>2.5), similarly failed to substitute. DS properties of reboxetine were dose-dependently blocked by the alpha1-adrenoceptor (AR) antagonists, prazosin (inhibitory dose50, 0.3) and WB4101 (0.5), but resistant to the alpha2-AR antagonists, atipamezole (>0.63), idazoxan (>2.5) and RX821,002 (>0.08), and to the beta1-AR and beta2-AR antagonists, betaxolol (>2.5) and ICI118,551 (>10.0). Interestingly, the neurokinin-1 receptor antagonist, GR205,171, stereospecifically substituted for reboxetine (1.1) compared to its less active isomer, GR226,206 (>10.0). The corticotrophin-releasing factor-1 antagonists, DMP695 (>40), CP154,526 (>10.0) and SN003 (>40.0), and the melanin-concentrating hormone-1 antagonist, SNAP-7941 (>40.0), failed to substitute for reboxetine. In conclusion, DS properties of reboxetine are mimicked by antidepressants recognizing NE transporters, and require functionally intact alpha1-ARs for their expression. The neurokinin-1 antagonist, GR205,171, mimicks the interoceptive properties of reboxetine, possibly reflecting its elevation of extracellular levels of NE in corticolimbic structures.

Efficacy
Selectivity
Reboxetine
Desipramine
NARIs and SSRIs
Noradrenaline and mood
Catecholamine depletion
Selectivity or multiplicity?
Reboxetine and the elderly
Noradrenaline reuptake inhibition
Sexual function on reboxetine v paroxetine
Residual depressive symptoms: fluoxetine v reboxetine


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