110 Desensitization is not restricted to metabotropic receptors. Indeed desensitization of 5-HT3 receptor channels following PH-797804 concentration sustained stimulation may

play a critical physiological role in the regulation of neuronal excitability via this receptor.111 Intriguingly, homodimerization between 5-HT receptors (eg, 5-HT2A, 5-HT2C, 5-HT4 receptors) or even heterodimerization, an aggregate of two unrelated receptors, such as a 5-HT2A/ metabotropic glutamate receptor 2 dimerized complexes integrating both 5-HT and glutamate signaling, were reported in the human cortex.112 Furthermore, this complex could Inhibitors,research,lifescience,medical increase the affinity of 5-HT2A receptors for hallucinogenic compounds such as LSD.113 It was also recently reported that the internalization of CRF1 receptors by a CRF agonist enhances Inhibitors,research,lifescience,medical 5-HT2A signaling and anxiety-related

behavior by recycling this receptor to the plasma membrane from an intracellular pool.114,115 Finally, a variety of proteins including (3-arrestins, serine/threonine protein kinases, protein phosphatase and tensin homolog, calpactin, and PDZ proteins interact with 5-HT receptor subtypes, modifying Inhibitors,research,lifescience,medical their functional activity105,116 They represent putative new targets for treatment of mood disorders and addiction. Thus, the status and function of 5-HT receptors in the brain depend on a multiplicity of factors including crosstalk with other Inhibitors,research,lifescience,medical homologous and heterologous receptors.106 As illustrated in (Figure 2) 5-HT availability in the extracellular space and target receptor functions are regulated at multiple levels, some of them being closely linked (eg, 5-HT1A, 5-HT1B/1D feedback mechanisms). Figure 2. The serotonergic neurotransmission depends on serotonin (5-HT) levels present in the extracellular space and Inhibitors,research,lifescience,medical on membrane receptors triggering functional changes in neighbouring neuronal

elements. 5-HT synthesis, release and reuptake are regulated by several … Anatomical organization of 5-HT circuitries in the brain Morphological approaches in the brain The respective scales of morphological approaches in the brain are called in Figure 3. Thus, imaging of the human living brain provides nowadays an incredible amount of information on functionally linked regions unless and, according to the availability of selective radiotracers, on millimetric clusters of binding sites. Morphological approaches including immunohistochemistry, in situ hybridization histochemistry and autoradiography allow to visualize a nucleus like the dorsal raphe, as well as a single labeled neuronal element of approximately one micrometer in diameter (eg, an axon varicosity) in brain tissue sections (Figure 3). Electron microscopy studies in the human brain and, more often, in other mammalian species give ultrastructural details (eg, junctions between neuronal elements or 5-HT1A receptor internalization).117 Figure 3.