Editorial [Hot Topic: New Ligands at 5-HT and DA Receptors for the Treatment of Neuropsychiatric Disorders (Guest Editor: Giuseppe Di Giovanni) ]

Decades ago, in the 1950s, dopamine (DA) and serotonin (5-hydroxytriptamine, 5-HT) were discovered in the mammalian central and peripheral nervous systems and successively their role as essential neurotransmitters was revealed. Advances in understanding the effect of DA and 5-HT have represented one of the success stories of neuropharmacology. In these years an enormous amount of experimental evidence has revealed the pivotal role of these biogenic amines in a bewildering diversity of behavioural and physiological processes. This is not surprising, considering the large distribution of DA- and 5-HT-containing axon terminals throughout the central nervous systems (CNS), although these monoamines are synthesized by a small group of neurons within the brain stem. There are 3 major DA systems in the brain. The nigrostriatal pathway originates from cell bodies which reside in the substantia nigra pars compacta (SNc) and project to the dorsal striatum (caudate-putamen). Degeneration of these neurones results in the motor deficits of Parkinson's disease (PD). The mesolimbic pathway originates in the ventral tegmental area (VTA) and project primarily to the ventral striatum/nucleus accumbens (NAc). The mesocortical pathway also originates in the VTA but projects to the prefrontal cortex where it is thought to regulate cognitive processes such as attention and working memory. Regarding the serotonergic system, this is one of the most diffusively organized projection systems of the mammalian brain. The majority of the neurons containing 5-HT generically called the raphe nuclei are located in the brainstem and in some regions of the reticular formation. Serotonergic neurones innervate virtually all regions of the CNS including both the SNc and the VTA and their terminal areas. Thus, at neuroanatomical levels there is a close relationship between 5-HT and DAcontaining neurones and this suggests that 5-HT could regulate the function of DA neurons via actions on midbrain DA cell bodies and on DA terminals. Recent receptor discoveries have permitted the identification and classification of up to seven families of 5-HT receptors (5- HT1-5-HT7) and five DA receptor sub-types have been classified to date (D1 through D5). All 5-HT receptors belong to the seven transmembrane domain G-protein-coupled receptor (GPCR) superfamily, except for the 5-HT3 receptor which is a ligand gated channel. The 5-HT1 receptor class is comprised of five receptor subtypes (5-HT1A, 5- HT1B, 5-HT1D, 5-HT1E and 5-HT1F), which, in humans, share 40-63% overall sequence identity and couple preferentially, although not exclusively, to Gi/o to inhibit cAMP formation. Among the multiple classes of 5-HT receptors described in the CNS, much attention has been devoted to the 5-HT2 receptor family since it has been shown by experimental and clinical observation to represent a possible therapeutic target for the development of drugs for a range of CNS disorders such as schizophrenia, depression, drug abuse, eating disorders, PD and epilepsy. Indeed, 5-HT2 receptors are major targets for a wide array of psychoactive drugs, ranging from non-classical antipsychotic drugs, anxiolytics and anti-depressants, which have a 5- HT2 antagonistic action, to hallucinogens, which are agonists of the 5-HT2 receptors. Furthermore, recently it has been shown that 5-HT2 receptors have a potential significance in brain development, and in experience-dependent plasticity in the visual cortex..........