The 5HT2 Receptor Family

5-HT2 receptors form a closely related subgroup of G-protein-coupled receptors, are functionally linked to the phosphatidylinositol hydrolysis pathway, and are currently classified as 5-HT2A, 5-HT2B, and 5-HT2C subtypes, based on their close structural homology and pharmacology (Hoyer et al. 1994; Barnes and Sharp 1999; Boess and Martin 1994). There is a high sequence homology (>80% in the transmembrane regions) between the mouse, rat, and human 5-HT2C receptors (Barnes and Sharp 1999), and it is not surprising that many compounds bind with high affinity to all three receptor subtypes. 5-HT2C receptors are widely distributed throughout the brain and have been proposed as the main mediators of the different actions of 5-HT in the CNS (Hoyer et al. 1994; Barnes and Sharp 1999; Boess and Martin 1994). High levels of 5-HT2C mRNA or protein expression have been found in the choroid plexus, the frontal cortex, in limbic structures such as hippocampus, septum, and hypothalamus and in the striatum, nucleus accumbens, rhombencephalon, and spinal cord. The presence of these receptors has also been demonstrated on DA and non-DA cells in the VTA, the SNc, and the SNr (Grace and Bunney 1985; Molineaux et al. 1989; Wright et al. 1995; Sharma et al. 1997; Clemett et al. 2000; Bubar and Cunningham 2007). The regional and cellular distribution of 5-HT2C receptors was also investigated in the human brain. The main sites of mRNA 5-HT2C receptors or protein expression were the choroid plexus, cerebral cortex, hippocampus, amygdala, some components of the basal ganglia, and other limbic structures (Abramowski et al. 1995; Pasqualetti et al. 1999), suggesting that this receptor might be involved in the regulation of different human brain function and might play a role in the pathophysiology of several mental disorders (Jenck et al. 1998; Di Matteo et al. 2001; Higgins and Fletcher 2003; Giorgetti and Tecott 2004; Kennett 1993; Baxter et al. 1995; Alex and Pehek 2007).

There is now evidence that the 5-HT2C receptor is mainly located postsynapti-cally within dopaminergic, GABA-ergic, cholinergic, substance P, dynorphin, and other systems (Barnes and Sharp 1999; Bubar and Cunningham 2007; Ward and Dorsa 1996; Eberle-Wang et al. 1997). Interestingly, the studies by Eberle-Wang et al. (1997) showed the presence of 5-HT2C mRNA within inhibitory GABA-ergic interneurons making direct synaptic contact with SNc and VTA dopaminergic cell bodies. Other immunohistochemical and electrophysiological studies demonstrated an important role of 5-HT2C receptors, localized on non-DA neurons, presumably GABA-ergic, in the regulation of DA cells in the VTA (Bubar and Cunningham 2007; Van Bockstaele and Pickel 1995; Steffensen et al. 1998), in the medial prefrontal cortex (Liu et al. 2007), and in the SNc (Di Giovanni et al. 2001; Invernizzi et al. 2007).

Recent studies found a somatodentritic localization of 5-HT2A receptors on DA neurons in both the parabrachial and paranigral subdivisions of the VTA (Doherty and Pickel 2000; Nocjar et al. 2002), which project mainly to the prefrontal cortex and nucleus accumbens, respectively. In addition, 5-HT2A immunoreactivity was also expressed on non-DA cells in the VTA, providing a potential anatomical basis for the modulation of DA neurons in the VTA either directly by 5-HT2A receptors localized on DA cell or indirectly through receptors present on non-DA (presumably GABA-ergic) neurons (Doherty and Pickel 2000; Nocjar et al. 2002). These receptors were also found at high concentrations in various cortical regions (Doherty and Pickel 2000; Wright et al. 1995). It is likely that 5-HT2A receptors could affect DA function by acting at the level of dopaminergic nerve terminals, although no direct evidence for the presence of 5-HT2A receptors on such terminals has been provided so far.

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Defeat Drugs and Live Free

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