disorder or schizophrenia have exhib- ited decreased CACNG2 DNA copy number (Wilson et al, 2006). Yet, increased stargazin mRNA expression has been found in the dorsolateral prefrontal cortex of brains from bipo- lar disorder patients suggesting a potential regio-specific action for star- gazin in this disorder (Silberberg et al, 2008). Furthermore, the PDE 11A knockout mouse, which shows multi- ple psychiatric illness-related pheno- types, possessed decreased hippo- campal expression of both g-2 and -8 proteins (Kelly et al, 2010). Recent research into neuropsychia- tric illnesses has shown an emer- ging pathological role for TARPs. As TARPs are differentially localized in neuron pathways, targeting indi- vidual isoforms may enable selective modulation of specific brain circuits without globally affecting synaptic transmission. However, the feasibility of uniquely targeting specific AMPA receptor complexes has not yet been established. Martin B Gill 1 and David S Bredt 1 1 Neuroscience Discovery Research, Eli Lilly and Company, Indianapolis, IN, USA E-mail: gill_martin_b@lilly.com DISCLOSURE Both MBG and DSB are employees of Eli Lilly and Company. ..................................................................... Beneyto M, Meador-Woodruff JH (2006). Lamina- specific abnormalities of AMPA receptor traffick- ing and signaling molecule transcripts in the prefrontal cortex in schizophrenia. Synapse 60: 585–598. Kelly MP, Logue SF, Brennan J, Day JP, Lakkaraju S, Jiang L et al (2010). Phosphodiesterase 11A in brain is enriched in ventral hippocampus and deletion causes psychiatric disease-related phenotypes. Proc Natl Acad Sci USA 107: 8457–8462. Martinez-Turrillas R, Del Rio J, Frechilla D (2007). Neuronal proteins involved in synaptic targeting of AMPA receptors in rat hippocampus by antide- pressant drugs. Biochem Biophys Res Commun 353: 750–755. Silberberg G, Levit A, Collier D, St Clair D, Munro J, Kerwin RW et al (2008). Stargazin involve- ment with bipolar disorder and response to lithium treatment. Pharmacogenet Genomics 18: 403–412. Tomita S, Byrd RK, Rouach N, Bellone C, Venegas A, O’Brien JL et al (2007). AMPA receptors and stargazin-like transmembrane AMPA receptor-reg- ulatory proteins mediate hippocampal kainate neurotoxicity. Proc Natl Acad Sci USA 104: 18784–18788. Wilson GM, Flibotte S, Chopra V, Melnyk BL, Honer WG, Holt RA (2006). DNA copy-number analysis in bipolar disorder and schizophrenia reveals aberrations in genes involved in glutamate signaling. Hum Mol Genet 15: 743–749. Neuropsychopharmacology Reviews (2011) 36, 362–363; doi: 10.1038/npp.2010.149 New Horizons for Selective 5-HT 2C Receptor Ligands in Psychiatric/Neurological Disorders The serotonin (5-HT) 5-HT 2C receptor is a key contributor to obesity, autism, psychiatric (eg, depression, schizophre- nia), and neurological diseases (eg, Parkinson’s disease). The diversity and regulation of the 5-HT 2C receptor signaling pathways are complex and provocatively suggest the importance of this receptor in an array of functions and indications. Therapeutic opportu- nities for both agonist and antagonist compounds that engage this receptor continue to emerge. The most advanced 5-HT 2C receptor agonist in development is lorcaserin, which has completed phase III clinical trials and has submitted an NDA for the treatment of obesity (Pauli and Abdelghany, 2010). In a 12-week obesity trial, approximately 30% of patients at 10 mg b.i.d. showed 45% weight loss with lorcaserin with mini- mal adverse events. Earlier in devel- opment is another 5-HT 2C receptor agonist vabicaserin for the treatment of psychiatric indications. Vabicaserin is a highly selective 5-HT 2C agonist (Dunlop et al, 2010) with a strong preclinical profile supporting multiple indications. Despite initial concerns regarding potential cardiovascular liabilities, selective 5-HT 2C agonists are proving to be devoid of these concerning side effects (Pauli and Abdelghany, 2010). Many different genetically modified animals have been created to improve understanding of the 5-HT 2C receptor. Much of the early work focused on the 5-HT 2C receptor knockout mouse that showed a hyperphagic obesity pheno- type. However, the 5-HT 2C receptor is subject to RNA editing leading to different forms of the receptor that are more (unedited) or less (fully edited) sensitive to the functional effects of 5-HT 2C agonists. Therefore, more recently, transgenic animals have been developed that lock the 5-HT 2C receptor into a fully edited (VGV) or an unedited (INI) isoform. Interestingly, animals locked into the fully edited VGV form of the receptor show failure to thrive, neonatal mus- cular hypotonia, decreased somatic growth, and reduced fat mass despite hyperphagia, characteristics consis- tent with Prader–Willi syndrome (Kawahara et al, 2008; Morabito et al, 2010). The link between Prader–Willi syndrome and the 5-HT 2C receptor has also been made through regulation of the splicing of the 5-HT 2C receptor by HBII-52, a small nucleolar RNA that affects 5-HT 2C receptor function (Kishore and Stam, 2006). Patients with Pra- der–Willi syndrome do not express HBII-52 that regulates alternative splicing of the 5-HT 2C receptor by binding to a silencing element in exon Vb (Kishore and Stam, 2006). More- over, these VGV mice have reduced G-protein-coupling efficiency and agonist binding but show enhanced behavioral sensitivity and serotonergic neurotransmission due to increased cell-surface expression of the 5-HT 2C receptor (Kawahara et al, 2008; Olaghere da Silva et al, 2010). Inter- estingly, both the nonedited INI mice and the fully edited VGV mice show anxiety-like phenotypes with the INI mice showing a depressant-like phe- notype and the VGV mice showing an antidepressant-like phenotype (Mom- bereau et al, 2010). Taken together, these transgenic models continue to show the complexity of the regulation of this receptor and the corresponding complexity of phenotypes. The multitude of ways that the 5-HT 2C receptor is regulated through different signaling pathways, RNA editing, and changes in receptor ............................................................................................................................................................... 363 HOT TOPICS .............................................................................................................................................. Neuropsychopharmacology