Antagonist Functional Selectivity: 5-HT2A Serotonin Receptor Antagonists Differentially Regulate 5-HT2A Receptor Protein Level In Vivo

Department of Pharmacology, University of North Carolina, Chapel Hill Medical School, Chapel Hill, North Carolina 27599, USA.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 07/2011; 339(1):99-105. DOI: 10.1124/jpet.111.183780
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Dysregulation of the 5-HT(2A) receptor is implicated in both the etiology and treatment of schizophrenia. Although the essential role of 5-HT(2A) receptors in atypical antipsychotic drug actions is widely accepted, the contribution of 5-HT(2A) down-regulation to their efficacy is not known. We hypothesized that down-regulation of cortical 5-HT(2A) receptors contributes to the therapeutic action of atypical antipsychotic drugs. To test this hypothesis, we assessed the effect of chronically administered antipsychotics (clozapine, olanzapine, and haloperidol) and several 5-HT(2A) antagonists [ketanserin, altanserin, α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol (M100907), α-phenyl-1-(2-phenylethyl)-4-piperidinemethano (M11939), 4-[(2Z)-3-{[2-(dimethylamino)ethoxy]amino}-3-(2-fluorophenyl)prop-2-en-1-ylidene]cyclohexa-2,5-dien-1-one (SR46349B), and pimavanserin], on the phencyclidine (PCP)-induced hyperlocomotor response and cortical 5-HT(2A) receptor levels in C57BL/6J mice. Clozapine and olanzapine, but not haloperidol, induced receptor down-regulation and attenuated PCP-induced locomotor responses. Of the selective 5-HT(2A) antagonists tested, only ketanserin caused significant receptor protein down-regulation, whereas SR46349B up-regulated 5-HT(2A) receptors and potentiated PCP-hyperlocomotion; the other 5-HT(2A) receptor antagonists were without effect. The significance of these findings with respect to atypical antipsychotic drug action is discussed.

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Available from: Martilias S Farrell, Dec 13, 2013
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    • "As seen in A (middle row), a profuse laminar distribution of 5-HT 2A R immunoreactivity was detected in the rat mPFC using the Immunostar 5-HT 2A R antibody from Neuromics (see Table 1). The strongest 5-HT 2A R immunoreactivity was seen in layer V. Though quite profuse, the 5-HT 2A R immunostaining produced by the antibody is typical for this cortical region (Weber and Andrade, 2010; Yadav et al., 2011b). Under higher magnification , a punctate 5-HT 2A R expression could be seen on the soma and initial segment of cells in the region (see sample cell in B, center and left photo). "
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    • "To investigate the 5-HT 2A receptor mechanism further we used ketanserin. Although widely used as a selective 5-HT 2A antagonist (Chen et al., 2003; De Paula et al., 2012; Yadav et al., 2011), ketanserin also exhibits a weaker affinity for the 5-HT 2C receptor (Alex and Pehek, 2007), which has been demonstrated as having an inhibitory effect on DA efflux in the NAc shell in vivo (Di Matteo et al., 2000). Unlike the phasic excitatory effect of 5-HT 2A receptors (Navailles and De Deurwaerdere, 2011), the 5-HT 2C subtype receptors exert both a tonic and phasic inhibitory control over DA efflux in the NAc shell with high constitutive activity (Navailles et al., 2006). "
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