Role of 5HT2A and 5HT2C Receptors in the Regulation of the Behavioral State

Several approaches have been followed to characterize the role of the 5-HT2A and 5-HT2C receptors in the regulation of sleep and W. They include

Table 20.1 Distribution of the 5-HT2A receptor in rat brain (From Mengod et al. 1990; Abramowski et al. 1995; Duxon et al. 1997; Cornea-Hebert et al. 1999; Clemett et al. 2000)

Telencephalon

5-HT2A receptor Diencephalon

1. Cerebral cortex

2. Olfactory system

3. Limbic system

4. Basal forebrain

Basal ganglia

1. Thalamus

2. Hypothalamus

Mesencephalon Rhombencephalon

^ Frontal ^ Parietal ^ Occipital ^ Piriform ^Olfactory bulb

^ Medial and lateral septal nuclei ^ Hippocampal formation ^ Amygdala

^ Nucleus of the diagonal band of Broca ^ Ventral pallidum ^ Nucleus accumbens ^ Caudate-putamen ^ Globus pallidus ^ Subthalamic nucleus

^ Medial, lateral, habenular, reticular, intralaminar, reuniens, anterior ^ Medial and lateral preoptic area ^ Anterior and lateral hypothalamic areas ^ Ventromedial nucleus ^ Mammillary nucleus ^ Central gray

^ Substantia nigra - pars compacta ^ Ventral tegmental area

^ Laterodorsal and pedunculopontine tegmental nuclei

^ Dorsal raphe nucleus and median raphe nuclei ^ Locus coeruleus ^ Medial pontine reticular formation ^ Gigantocellular reticular nucleus

1. Characterization of the changes occurring in serotonin 5-HT2A and 5-HT2C receptor deficient mice

2. Determination of the changes that follow the administration of selective and nonselective 5-HT2A and 5-HT2C receptor agonists and antagonists to laboratory animals and man

20.1.1.1 Sleep Patterns in Mutant Mice That Do Not Express 5-HT2A or 5-HT2C Receptors

Popa et al. (2005) investigated the role of the 5-HT2A receptor on non-rapid-eye-movement (NREM) sleep and W regulation using wild-type and knockout mice that do not express the 5-HT2A receptor. 5-HT2A receptor knockout mice showed a significant increase of W and a reduction of NREM sleep. Values of REM sleep

Table 20.2 Distribution of the 5-HT2C receptor in the rat brain (From Mengod et al. 1990; Abramowski et al. 1995; Duxon et al. 1997; Cornea-Hébert et al. 1999; Clemett et al. 2000)

Telencephalon

1. Cerebral cortex

^ Frontal ^ Parietal ^ Occipital ^ Piriform ^ Cingulate

2. Olfactory system

^ Olfactory bulb

3. Limbic system

^ Lateral septal nucleus ^ Hippocampal formation ^ Amygdala

4. Basal forebrain

^ Nucleus of the diagonal band of Broca ^ Ventral pallidum ^ Bed nucleus of the stria terminalis

5. Basal ganglia

^ Nucleus accumbens ^ Caudate-putamen ^ Globus pallidus ^ Subthalamic nucleus

5-HT2C receptor

Diencephalon

1. Thalamus

^ Medial, lateral, reuniens, habenular, lateral, and geniculate nuclei

2. Hypothalamus

^ Medial preoptic area ^ Ventromedial nucleus ^ Dorsomedial nucleus ^ Mammillary nucleus

Mesencephalon

^ Substantia nigra pars compacta

Rhombencephalon

^ Laterodorsal and pedunculopontine tegmental nuclei

^ Dorsal raphe nucleus and median raphe nucleus

were not significantly different from those found in the wild-type mice. Systemic administration of the selective 5-HT2A receptor antagonist MDL 100907 {R-(+)-a-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine-methanol} significantly augmented NREM sleep and decreased W and REM sleep in the wild-type mice only.

Sleep has been characterized also in 5-HT2C receptor knockout mice (Frank et al. 2002). Mice lacking the 5-HT2C receptor had significantly less NREM sleep and greater amounts of W compared with the wild-type animals. In contrast, REM sleep values remained unchanged in the mutant mice. Since 5-HT2A and 5-HT2C receptors are positively coupled to PLC via G proteins and mobilize intracellular Ca2+, a reduction of W and an increase of NREM sleep should have been expected in the mutants. In other words, opposite effects of gene deletion versus acute pharmacological activation of the same protein with selective 5-HT2A and 5-HT2C receptor agonists (to be dealt with in the next section) should have been expected on W and NREM sleep. Adrian (2008) has proposed that the discrepancy might depend, at

Fig. 20.1 5-HT2A/2C receptor binding sites in neuroanatomical structures involved in the regulation of sleep and waking: basal forebrain, thalamus, preoptic area, and hypothalamus. AHA anterior hypothalamic area, HDB nucleus of the horizontal limb of the diagonal band, LA lateroanterior hypothalamic nucleus, LPO lateral preoptic area, MnPO median preoptic nucleus, MPA median preoptic area, MS medial septal nucleus, Re reuniens thalamic nucleus, Rt reticular thalamic nucleus (Modified from Paxinos and Watson 2005)

Fig. 20.1 5-HT2A/2C receptor binding sites in neuroanatomical structures involved in the regulation of sleep and waking: basal forebrain, thalamus, preoptic area, and hypothalamus. AHA anterior hypothalamic area, HDB nucleus of the horizontal limb of the diagonal band, LA lateroanterior hypothalamic nucleus, LPO lateral preoptic area, MnPO median preoptic nucleus, MPA median preoptic area, MS medial septal nucleus, Re reuniens thalamic nucleus, Rt reticular thalamic nucleus (Modified from Paxinos and Watson 2005)

least in part, on compensatory mechanisms in constitutive mutants. On the other hand, Frank et al. (2002) have posed that the greater amounts of W in the 5-HT2C receptor knockout mice could be related to the increase of catecholaminergic neurotransmission involving mainly the noradrenergic and dopaminergic systems.

It has been established that acetylcholine (ACh), 5-HT, noradrenaline (NA), dopamine (DA), histamine (HA), orexin (OX), and glutamate function to promote W (Pace-Schott and Hobson 2002; Jones 2003). The results obtained from studies aimed at determining the role of the 5-HT2A and 5-HT2C receptors in the modulation of ACh release are inconsistent. Thus, 5-HT and the 5-HT2A/2C receptor agonist 2,5-dimethoxy-4-bromo-amphetamine ( DOB) inhibited ACh release of superfused rat neocortical slices, and this effect was attenuated by ketanserin, a predominantly 5-HT2A receptor antagonist (Muramatsu et al. 1990). On the other hand, systemic administration of the 5-HT2A/2C agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) increased ACh release in the prefrontal cortex and the hippocampus of the rat, and this effect was prevented by LY-53857 {4-isopropyl-7-methyl-9-(2-hydroxy-1-methyl-propoxycarbonyl)-4,6A,7,8,9,10,10A-octahydro-indolo[4,3-FG]quinolone maleate}, a 5-HT2A/2C receptor antagonist (Nair and Gudelsky 2004). Fink and Gothert (2007) have

Fig. 20.2 5-HT2A/2C receptor binding sites in neuroanatomical structures involved in the regulation of sleep and waking: hippocampus, preoptic area, hypothalamus, and pons. CA2 CA2 field of the hippocampus, DRN dorsal raphe nucleus, LC locus coeruleus, LDT laterodorsal tegmental nucleus, LM lateral mammillary nucleus, ML medial mammillary nucleus, lateral part, MM medial mammillary nucleus, medial part, MRN median raphe nucleus, PPT pedunculopontine tegmental nucleus, PRF pontine reticular formation, Py pyramidal cells, SNCD substantia nigra pars compacta, VTAR ventral tegmental area (Modified from Paxinos and Watson 2005)

Fig. 20.2 5-HT2A/2C receptor binding sites in neuroanatomical structures involved in the regulation of sleep and waking: hippocampus, preoptic area, hypothalamus, and pons. CA2 CA2 field of the hippocampus, DRN dorsal raphe nucleus, LC locus coeruleus, LDT laterodorsal tegmental nucleus, LM lateral mammillary nucleus, ML medial mammillary nucleus, lateral part, MM medial mammillary nucleus, medial part, MRN median raphe nucleus, PPT pedunculopontine tegmental nucleus, PRF pontine reticular formation, Py pyramidal cells, SNCD substantia nigra pars compacta, VTAR ventral tegmental area (Modified from Paxinos and Watson 2005)

proposed that the 5-HT2 receptors mediating ACh release in the prefrontal cortex of the rat are located on cholinergic axon terminals.

As regards the involvement of 5-HT2A and 5-HT2C receptors in the release of DA, it has been found that systemically injected or locally applied MDL 100907 increases DA release in the medial prefrontal cortex (mPFC) of the rat (Schmidt and Fadayel 1995). On the other hand, administration of the 5-HT2C receptor agonist RO 60-0175 [(S)-2-(chloro-5-fluoro-indol-1-yl)-1-methylethylamine] by the intraperitoneal (IP) route decreases DA release in the nucleus accumbens of the rat, and this effect is prevented by the selective 5-HT2C antagonist SB 242084 [1-(1-methylindol-5-yl)-3-(3-pyridyl) urea] (Di Matteo et al. 2000). Fink and Gothert (2007) have suggested that the 5-HT2A and 5-HT2C receptors responsible for the inhibition of DA release are expressed by inhibitory GABA-ergic interneurons and that activation of these receptors indirectly inhibits the neurotransmitter release. With respect to the participation of 5-HT2A and 5-HT2C receptors in the release of NE, it has been reported that systemic administration of DOB and DOI inhibits the release of the catecholamine in the rat hippocampus and that this effect is prevented by ketanserin (Done and Sharp 1994). The inhibitory effect of the 5-HT2 receptors on NE release has been ascribed also to the activation of GABA-ergic interneurons. The evidence in favor of the involvement of 5-HT2A and 5-HT2C receptors in the release of HA is scanty. It has been reported that 5-HT excites histaminergic tubero-mammillary neurons by activation of 5-HT2C receptors and Na+/Ca2+ exchange (Eriksson et al. 2001). However, no attempts have been made to quantify HA levels at postsynaptic sites in animals treated with 5-HT2A and 5-HT2C ligands. Muraki et al. (2004) examined the effect of 5-HT on orexin neurons using hypothalamic slices from orexin-enhanced green fluorescent protein transgenic mice in which the protein was expressed exclusively in orexin neurons. 5-HT hyperpolarized orexin neurons in a concentration-dependent manner. In this study the authors proposed that this inhibitory 5-HT input to the orexin cells was predominantly dependent on the activation of the 5-HT1A receptor. However, no attempts have been made to elucidate the role of 5-HT2 receptors in the functional activity of orexin neurons. It has been observed that most glutamatergic cells in layers II to IV of human and monkey prefrontal cortex express 5-HT2A receptor messenger ribonucleic acid (mRNA) (de Almeida and Mengod 2007). In addition, it has been established that amino-hydroxy-methyl-isoxazole propionic acid (AMPA) and kainate receptors mediate the 5-HT-induced excitatory postsynaptic potentials recorded from layer V pyramidal cells in the rat mPFC and that this effect is suppressed by a selective AMPA receptor antagonist (Zhang and Marek 2008). However, further studies are needed to determine whether glutamate participates in the 5-HT2A receptor-induced increase of W and decrease of NREM sleep. Thus, the limited available evidence tends to suggest that the increase of W and reduction of NREM sleep in 5-HT2A and 5-HT2C receptor knockout mice is related, at least in part, to the increased release of NA and DA. With respect to the mechanisms involved, it can be speculated that the reduction of GABA release at critical sites in the central nervous system (CNS) of 5-HT2A and 5-HT2C receptor knockout mice would be indirectly responsible for the increased availability of NA and DA. However, further studies are needed to resolve this issue.

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