Role of 5HT2C Receptors in the Regulation of Monoamine Neurotransmission

It is well established that monoamine systems play a central role in pathophysio-logy of affective disorders and in antidepressant response: Monoamine neurons densely innervate the limbic areas of the brain, modulate behavioral and emotional

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G. Di Giovanni et al. (eds.), 5-HT2C Receptors in the Pathophysiology of CNS Disease, 249 The Receptors 22, DOI 10.1007/978-1-60761-941-3_12, © Springer Science + Business Media, LLC 2011

functions, and serve as a primary target for all known antidepressant medication (Dremencov et al. 2002, 2003; Dremencov 2009; Tremblay and Blier 2006). Therefore, receptors regulating monoamine transmission might play an important role in the response to antidepressant drugs. 5-HT2C receptors have been demonstrated to modulate 5-HT, norepinephrine (NE) and dopamine (DA) transmission in the brain.

The effects of agonists and antagonists of 5-HT2C receptors on the firing activity of 5-HT, NE, and DA neurons are summarized in Table 12.1. It can be concluded that 5-HT2C receptors negatively regulate the firing activity of 5-HT and DA neurons in the dorsal raphe nucleus (DRN) and ventral tegmental area (VTA), respectively (Boothman et al. 2003, 2006; Di Giovanni et al. 2000, 2001; Di Matteo et al. 2000; Sotty et al. 2009; Millan 2006; Dremencov et al. 2009). 5-HT2C receptor agonists decrease the firing activity of 5-HT and DA neurons. This inhibition of firing of 5-HT and DA neurons and that produced by selective serotonin reuptake inhibitors (SSRIs) citalopram and escitalopram are reversed by 5-HT2C receptor antagonists. One study demonstrated that SB242084, a selective antagonist of 5-HT2C receptors, also increases DA neuronal firing activity on its own (Chenu et al. 2009).

A study by Millan et al. (2003) demonstrated that the mixed melatonin MT1/2 receptor agonist and 5-HT2C receptor antagonist agomelatine increases the firing activity of NE neurons and NE release in the prefrontal cortex (PFC). It was also shown that this effect of agomelatine was not reversed by selective melatonin antagonist, indicating that NE effect of agomelatine is mediated via 5-HT rather than the melatonin agonistic properties of this drug. However, a more recent study by Dremencov et al. (2007a) has shown that SB242084 has no effect on NE neuronal firing activity. It may therefore be suggested that 5-HT1A and/or 5-HT2A/2B antagonistic properties of agomelatine contribute to the stimulatory effect of this drug on NE neuronal firing activity (Millan et al. 2003).

The effects of agonists and antagonists of 5-HT2C receptors on the release of 5-HT, NE, and DA are summarized in Table 12.2. The antagonists of 5-HT2C receptors, administered individually, increase extracellular NE and DA levels in PFC but not in striatum and 5-HT levels in the nucleus accumbens (NAc), but not in hippocampus or PFC (Millan et al. 2003; Dremencov et al. 2005; Cremers et al. 2004, 2007; Alex et al. 2005). However, 5-HT2C receptor antagonists enhanced selective serotonin reuptake inhibitor (SSRI)-induced increase in extracellular 5-HT levels (Cremers et al. 2004, 2007). Since this effect was observed after both systemic (Cremers et al. 2004) and local (Cremers et al. 2007) administration of 5-HT2C receptor antagonists, it is possible that their potentiating effect on SSRI-induced increases in 5-HT levels is mediated via both the reversal of inhibition of 5-HT neurons in the DRN (Sotty et al. 2009) and local stimulation of 5-HT release from the neuronal terminals (Dremencov et al. 2005).

In general, it can be stated that 5-HT2C receptors negatively regulate monoamine transmission in the brain via the suppression of firing of monoamine neurons and/or via local inhibition of transmitter release from the terminals of monoamine neurons. The mechanism of 5-HT2C-mediated inhibition of 5-HT and DA neuronal firing

Table 12.1 Effects of agonists and antagonists of 5-HT receptors on 5-HT, NE, and DA neuronal firing activity





WAY161503 SB242084

SB242084 Agomelatine


R0600175 Agomelatine mCPP MK212

5-HT neuronal firing activity in the DRN

Boothman et al. (2003)

Decrease Decrease

No effect by its own Reverses WAY161,503-induced decrease of 5-HT neuronal activity

Diminishes citalopram-induced decrease of 5-HT neuronal activity

NE neuronal firing activity in the LC No effect Dremencov et al. (2007b)

Increase Millan et al. (2003)

DA neuronal firing activity in the VTA

Boothman et al. (2006) Sotty et al. (2009) Boothman et al. (2006)


No effect by its own; Reverses escitalopram-induced decrease of DA neuronal activity


Reverses R0600175-induced inhibition



Mixed S-HT^p agonist Selective 5-HT,c agonist Selective 5-HT antagonist

Mixed melatonin and



Chenu et al. 2009; Di Mascio et al. (1999) Dremencov et al. (2009)

Di Matteo et al. 2000; Millan et al. (2003) Mülan et al. (2003)

Di Giovanni et al. (2000) Di Giovanni et al. (2000)

Selective 5-HT antagonist

Mixed 5-HT,crB agonist Mixed 5-HT,c(,b agonist

Table 12.2 Effects of agonists and antagonists of 5-HT2C receptors on 5-HT, NE, and DA release in the rat brain


Brain area



Ketanserin (mixed 5-HT2A/2C antagonist, systemic administration)

SB242084 (local and systemic)

RS 102221 (local)

Agomelatine (systemic)

SB 206553 (mixed 5-HT2C/2B

reverse agonist, local) mCPP (mixed 5-HT2C/2B agonist, systemic)

Agomelatine (systemic) RS 102221 (local)

5-HT release Hippocampus No effect by its own

Potentiate citalopram, fluoxetine and sertraline-induced increase in 5-HT levels

Prefrontal cortex No effect on its own Potentiate citalopram-induced increase in 5-HT levels Hippocampus Potentiate citalopram-

induced increase in 5-HT levels Nucleus Increase accumbens

NE release Prefrontal cortex Increase Striatum No effect

DA release

Prefrontal cortex

Prefrontal cortex

Prefrontal cortex Striatum

Nucleus accumbens (Sprague-Dawley rats) Nucleus accumbens (FSL rats)

Increase Decrease

Reverse SB 206553-induced increase in DA levels Increase No effect Slight increase

Robust Increase

Cremers et al. (2004)

Cremers et al. (2007)

Dremencov et al. (2005)

Millan et al.

Millan et al.

(2003) Dremencov et al. (2005)

activity is not yet completely understood. 5-HT2C receptors are coupled to G and GI3 proteins (Cussac et al. 2002; McGrew et al. 2002; Theile et al. 2009; Westphal et al. 1995). The GQ11-mediated signal transduction pathway of 5-HT2C receptors is relatively well characterized. This pathway includes the activation of phospholipase C (PLC) and neuronal excitation due to the inositol triphosphate (IP3)-induced Ca2+ influx into the neuronal cytoplasm (Bockaert et al. 2006). However, it was shown that 5-HT2C receptors stimulate the firing activity of y-aminobutyric acid (GABA) interneurons in the Vental tegmental area VTA (Di Giovanni et al. 2001). It is thus possible that the inhibitory effect of 5-HT2C receptors on DA neuronal firing activity is mediated, at least in part, via GABA neurons and GABAa and/or GABAb receptors (Alex and Pehek 2007; Dremencov et al. 2006). The study by Cremers et al. (2007) demonstrated that phaclofen, a GABAB-receptor agonist, enhanced the citalopram-induced increase in hippocampal 5-HT levels in the same way as SB242084, a 5-HT2C receptor antagonist. It suggests that the inhibitory effect of 5-HT2C receptors on 5-HT neuronal firing activity is also mediated, at least in part, via GABA interneurons and GABAB receptors.

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