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 α1-adrenoceptor (AR) antagonists, prazosin (inhibitory dose50, 0.3) and WB4101 (0.5), but resistant to the α2-AR antagonists, atipamezole (>0.63), idazoxan (>2.5) and RX821,002 (>0.08), and to the β1-AR and β2-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 α1-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.

The norepinephrine transporter (NET) has a major role in terminating the neurochemical signal established by the neurotransmitter norepinephrine (NE) in the synaptic cleft. The NET is also the initial site of action for therapeutic antidepressants, and drugs such as cocaine and amphetamines. Polymorphisms in the NET gene have been identified, and associations with several disorders such as depression have been proposed but not established. However, evidence of a direct association between a genetic mutation of the NET and an autonomic clinical syndrome has recently emerged. A patient and her identical twin were evaluated for typical symptoms of orthostatic intolerance (OI), a disorder mainly characterised by elevated heart rate on standing, and both were found to have clinical and laboratory signs of abnormal uptake of NE. Sequence analysis of the patients' NET gene identified a mutation that resulted in more than 98% loss of function as compared with the wild-type gene. This article reconsiders the important role of the NET protein in the regulation of the nervous and cardiovascular systems, reviews the literature for its polymorphisms and their suggested clinical manifestations, and finally focuses on the effects of its defect on the pathophysiology of OI, the only confirmed direct association between a genetic mutation of the NET and a clinical syndrome.

At the onset of their migration into the embryo, many neural crest cells are pluripotent in the sense that they have the capacity to generate progeny that consist of more than one cell type. More recently, we have found that there are pluripotent neural crest cell-derived cells even at sites of terminal differentiation. These findings support the notion that cues originating from the microenvironment, at least in part, direct neural crest cell type specification. Based on the rationale that growth factors that are known to support survival of neural crest cell derivatives may have additional functions in progenitor cell development, we have examined the action of pertinent growth factors. Trophic, mitogenic, antiproliferative and differentiation promoting activities were found. Stem cell factor (SCF) is trophic for pluripotent neural crest cells. Contrary to expectation, SCF plus a neurotrophin, rather than SCF alone, is trophic for committed melanogenic cells. Basic fibroblast growth factor (bFGF) is mitogenic both for pluripotent cells and committed melanogenic cells. However, the cells become dependent on another factor for survival. Whereas any neurotrophin tested can rescue bFGF-activated pluripotent neural crest cells, the factor that rescues melanogenic cells remains to be determined. Transforming growth factor β1 (TGF-β1) is a powerful antimitotic signal for all neural crest cells that overrides the bFGF/neurotrophin proliferative signal. Furthermore, SCF promotes differentiation of neural crest cells into cells of the sensory neuron lineage. Neurotrophin-3 (NT-3) specifically promotes high affinity uptake of norepinephrine by neural crest cells and is thus thought to play a critical role in the differentiation of sympathetic neuroblasts. In summary, our data indicate that neurotrophins and other pertinent growth factors affect survival, proliferation and differentiation of neural crest cells at multiple levels and in different lineages. Moreover, our findings emphasise the importance of the concerted action of combinations of growth factors, rather than of individual factors.