Chronic administration of most somatic treatments for depression downregulates or reduces the density of B -adrenergic binding sites in the brain (Bergstrom and Kellar 1979). These treatments include traditional NE-specific and mixed uptake inhibitors (Charney et al. 1981). However, results with the SSRIs have been less consistent (Johnson 1991). Despite its in vitro 5-HT selectivity, fluoxetine has been observed, with autoradiography, to induce ^-adrenergic receptor downregulation. It has also been shown in at least one study to increase extracellular NE concentrations in rat prefrontal cortex after acute systemic administration; this effect was not observed with other SSRIs tested (Bymaster et al. 2002). Fluoxetine has also been demonstrated to potentiate the noradrenergic effects of bupropion (Li et al. 2002).

Most studies with SSRIs have not shown a consistent change in ^-adrenergic binding or &-adrenergic-stimulated cyclic adenosine monophosphate (cAMP) production. However, Baron et al. (1988) reported that fluoxetine, when it was coadministered with desipramine, augmented the reduction in cortical (^-adrenergic receptors expected with desipramine alone. In contrast, investigations with fluvoxamine, paroxetine, and citalopram have not yielded consistent results. In general, the greater the 5-HT selectivity of a compound, the less in vitro evidence for 3 -adrenergic downregulation has been seen. Thus, (^-adrenergic downregulation may not be essential for clinical efficacy.

Current data do not support a significant effect on a-adrenergic receptor affinity or density by the SSRIs. Studies using radiolabeling to investigate fluoxetine (Wong et al. 1985) have shown relative inactivity at this site. Fluoxetine has been reported to reduce desipramine-induced release of growth hormone after 4 weeks of treatment (O'Flynn et al. 1991). This effect suggests a possible indirect activity at the 1^2-adrenergic receptor.

In summary, although relative differences in adrenoreceptor affinity exist across the SSRI class, and fluoxetine may have more adrenergic activity than some of the other SSRIs, the clinical significance of these differences appears to be negligible.

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