However, this mechanism has not been explored in AP-treated patients. Furthermore, APs may affect bone health independently of their effect on prolactin. In fact, APs, particularly second-generation

APs, modulate serotoninergic and adrenergic receptors [Richelson and Souder, 2000]. A number of functional serotonin receptors [e.g. 5-hydroxytryptamine 1A (5-HT1A), 5-HT1B, 5-HT2A, Inhibitors,research,lifescience,medical 5-HT2B] along with the serotonin transporter have been identified in bone cells [Bliziotes et al. 2001; Westbroek et al. 2001; Yadav et al. 2008]. This has recently stimulated great interest in understanding the role of serotonin in bone metabolism [Warden et al. 2010]. In fact, circulating serotonin has been implicated in reduced bone formation [Yadav et al. 2008; Modder et al. 2010], by activating the 5-HT1B receptor on osteoblasts [Yadav et al. 2008]. This activation reduces the expression of the transcription factor cyclic adenosine monophosphate response element binding protein, which in Inhibitors,research,lifescience,medical turn decreases the expression of cyclin D1, reducing osteoblast proliferation [Yadav et al. 2008]. Consistent with this finding, 5-HT1B

knockout mice display increased Inhibitors,research,lifescience,medical bone formation and bone mass [Yadav et al. 2008]. While the affinity for the 5-HT1B receptor of commonly used APs is generally low, it does vary across the different compounds [Roth et al. 2004]. Therefore, it is conceivable that some APs may promote bone formation by blocking the 5-HT1B receptor. The skeletal effect of blocking the 5-HT2A receptor, which most APs have a high affinity for [Roth et al. 2004], is less clear. This receptor is expressed on osteoblasts [Bliziotes et al. 2001] but 5-HT2A receptor knockout mice display normal bone formation and resorption and no deficit Inhibitors,research,lifescience,medical in osteoblast proliferation [Yadav et al. 2008]. In contrast, 5-HT2B receptor knockout mice exhibit impaired osteoblast recruitment and proliferation resulting in deficient cortical and trabecular BMD [Locker et al. 2006; Collet et al. 2008; Baudry et al. 2010]. Inhibitors,research,lifescience,medical Thus, APs may also interfere with bone mineralization by blocking the 5-HT2B receptor [Bymaster

et al. 1999]. However, by blocking the 5-HT2C receptors in neurons of the ventromedial hypothalamus, APs may attenuate the inhibition of the sympathetic nervous system by serotoninergic buy Everolimus signaling from the raphe nuclei [Ducy, 2011]. This, in turn, activates skeletal β2-adrenergic receptors, which negatively impact bone metabolism [Karsenty and Ducy, 2006]. Of note is that most APs have a very low affinity for much β-adrenergic receptors [Leysen et al. 1992]. However, several APs have high affinity for α1A- and α1B-adrenergic receptors [Roth et al. 2004]. Human osteoblasts express α1A-adrenergic receptors and stop proliferating when treated with α1 antagonists [Huang et al. 2009]. Expression of α1B-adrenergic receptor mRNA has also been demonstrated in human osteoclasts [Togari, 2002], suggesting that these receptors may have a role in osteoclast regulation.