title: 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.
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 dose50, 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, mimics the interoceptive properties of reboxetine, possibly reflecting its elevation of extracellular levels of NE in corticolimbic structures.
authors.affiliation: Institut de Recherches Servier, Centre de Recherches de Croissy, Psychopharmacology Department, Croissy-sur-Seine, Paris, France. mark.millan@fr.netgrs.com
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Millan
authors.forename: Anne
authors.initials: A
authors.lastname: Dekeyne
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects*; D004192:Discrimination, Psychological / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D008297:Male; D009025:Morpholines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000077593:Reboxetine; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000502:physiology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000928:Antidepressive Agents; D009025:Morpholines; D000077593:Reboxetine; D018013:Receptors, Neuropeptide; D017367:Selective Serotonin Reuptake Inhibitors