Serotonin 5-HT2C Receptors: Chemical Neuronatomy in the Mammalian Brain

Serotonin 5-HT 2C receptors belong to the 5-HT 2 family, which includes 5-HT 2A and 5-HT 2B receptors. All three share similarities in their molecular structure, pharmacology, and signal transduction pathways (Barnes and Sharp 1999; Hoyer et al. 1994). Initially named 5-HT 1C, based on the conventions for naming serotonin receptors at the time of its discovery, it was later renamed 5-HT 2C receptors after the cloning of its gene and that of 5-HT 2A (Pazos et al. 1984a; Prichett et al. 1988; Julius et al. 1988, 1990; Hoyer et al. 1985; Lubbert et al. 1987; Pazos and Palacios 1985) (see also Palacios et al., Chap. 1, this volume). Chemical neuroanatomical techniques were pivotal in the discovery of 5-HT 2C receptors, which were first identified by autoradiography after labeling of rat brain sections with the 5-HT 2A and dopamine D 2 receptor ligand mesulergine. This was followed by a thorough pharmacological characterization performed in pig brain choroid plexus, and the binding site was differentiated from the 5-HT 2A receptor. The combined use of membrane receptor binding/pharmacology and brain slice autoradiography allowed its differentiation from 5-HT 1A , 5-HT 1B , and 5-HT 2A receptors; it was then named 5-HT 1C . The pharmacology and distribution of the new site differed from the existing knowledge about other receptors (Pazos et al. 1984a, b; Hoyer et al. 1985). The 5-HT 1C receptor was cloned soon thereafter (Julius et al. 1988). The knowledge of the messenger ribonucleic acid (mRNA) sequence and the derived protein sequence of these receptors allowed the development of new important tools for the study of their chemical neuroanatomy. The autoradiographic localization of 5-HT 2C receptors had suffered from the lack of selective ligands. While mesulergine remains the ligand of choice, 5HT 2C sites can also be labeled by other ligands such as 5-HT self, LSD (lysergic acid diethylamide), and DOI (1-(2,5-dimethoxy-4-iodophenyl-2-aminopropane), but