149 ISSN 1758-2008 10.2217/NPY.11.12 © 2011 Future Medicine Ltd Neuropsychiatry (2011) 1(2), 149–164 † NeuroAct Communication, 25 rue des Généraux Ricard, 81100 Castres, France; Tel.: +33 563 596 037; adrian.newman.tancredi@neuroact.com REVIEW Adrian Newman-Tancredi † Biased agonism at serotonin 5-HT 1A receptors: preferential postsynaptic activity for improved therapy of CNS disorders Practice points  Serotonin or 5-hydroxytryptamine (5-HT) 1A receptors are attractive targets for pharmacotherapy of pathologies associated with dysfunctional serotonergic neurotransmission, including anxiety, depression, Parkinson’s disease, pain and schizophrenia.  5-HT 1A receptors are expressed both as presynaptic autoreceptors on serotonergic cell bodies in the raphe and as postsynaptic heteroreceptors in multiple brain regions including the cortex, hippocampus, septum and hypothalamus.  The signaling cascades elicited by 5-HT 1A receptor activation difer between brain regions: diferent G-protein subtypes, diferent second messengers and diferent neurochemical read-outs.  The concept of ‘biased agonism’ or ‘functional selectivity’ asserts that agonists can preferentially direct receptor signaling to specifc intracellular responses. This opens the possibility of targeting receptors in specifc cellular environments or brain regions.  F15599 is a selective 5-HT 1A receptor agonist that exhibits biased agonism, preferentially activating Gai versus Gao G-protein subtypes. F15599 preferentially activates ERK1/2 phosphorylation more than G-protein, receptor internalization or adenylyl cyclase inhibition.  F15599 stimulates rat medial prefrontal cortex pyramidal neuron electrical activity and dopamine release (controlled by postsynaptic 5-HT 1A receptors) at low doses that do not inhibit raphe serotonergic neuron electrical activity or hippocampal 5-HT release (controlled by presynaptic 5-HT 1A receptors).  F15599 preferentially stimulates c-Fos expression and ERK1/2 phosphorylation in rat prefrontal cortex, with less pronounced efects in the raphe. This preferential postsynaptic activity is not observed with other 5-HT 1A agonists.  In rats F15599 exhibits potent antidepressant-like activity in the forced swim test, inhibits stress-induced ultrasonic vocalization and attenuates phencyclidine-induced cognitive impairments in reversal learning, in novel object recognition and in a hole-board test.  At ‘antidepressant’ doses in rats, F15599 does not induce serotonin syndrome, does not disrupt attentional performance, does not impair working memory and does not inhibit prepulse inhibition of startle response.