5-Hydroxytryptamine2C Receptor Contribution to m-Chlorophenylpiperazine and N-Methyl-β-carboline-3-carboxamide-Induced Anxiety-Like Behavior and Limbic Brain Activation

Abstract

Activation of 5-hydroxytryptamine2C (5-HT 2C ) receptors by the 5-HT 2 receptor agonist m-chlorophenylpiperazine (m-CPP) elicits anxiety in humans and anxiety-like behavior in animals. We compared the effects of m-CPP with the anxiogenic GABA A receptor inverse agonist N-methyl-␤-carboline-3-carboxamide (FG-7142) on both anxiety-like behavior and regional brain activation using functional magnetic resonance imaging (fMRI) in the rat. We also determined whether the selective 5-HT 2C receptor antagonist SB 242084 [6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxyamide dihydrochloride] would blunt m-CPP or FG-7142-induced neuronal activation. Both m-CPP (3 mg/kg i.p.) and FG-7142 (10 mg/kg i.p.) elicited anxiety-like behavior when measured in the social interaction test, and pretreatment with SB 242084 (1 mg/kg i.p.) completely blocked the behavioral effects of both anxiogenic drugs. Regional brain activation in vivo in response to anxiogenic drug challenge was determined by blood oxygen level-dependent (BOLD) fMRI using a powerful 9.4T magnet. Region of interest analyses revealed that m-CPP and FG-7142 significantly increased BOLD signals in brain regions that have been linked to anxiety, including the amygdala, dorsal hippocampus, and medial hypothalamus. These BOLD signal increases were blocked by pretreatment with SB 242084. In contrast, injection of m-CPP and FG-7142 resulted in BOLD signal decreases in the medial prefrontal cortex that were not blocked by SB 242084. In conclusion, the brain activation signals produced by anxiogenic doses of both m-CPP and FG-7142 are mediated at least partially by the 5-HT 2C receptor, indicating that this receptor is a key component in anxiogenic neural circuitry.The 5-hydroxytryptamine 2C (5-HT 2C ) receptor has been implicated in mood and anxiety disorders and is a target for development of novel anxiolytic drugs (Wood, 2003). Selective and nonselective 5-HT 2C receptor antagonists reduce anxiety-like behavior in several animal models of anxiety (Stutzmann et al., 1991;Kennett et al., 1995;Griebel et al., 1997). (Charney et al., 1987;Lowy and Meltzer, 1988;Kahn and Wetzler, 1991;Gatch, 2003;de Mello Cruz et al., 2005). For example, m-CPP administration to mice resulted in less time spent on the open arms of an elevated plus maze (Benjamin et al., 1990), and in rats, anxiety-like behavior has been reported in the This study was supported by National Institutes of Health Grants T32 GM07628, RO1 MH34007, and R01 EB02326 and a predoctoral fellowship from the PhRMA foundation (to E.A.H.).Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.106.113357. 2C , 5-hydroxytryptamine2C; m-CPP, m-chlorophenylpiperazine; FG-7142, N-methyl-␤-carboline-3-carboxamide; SB 242084, 6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxyamide dihydrochloride; fMRI, functional magnetic resonance imaging; BOLD, blood oxygen level-dependent;...

Anxiety-like behaviors produced by acute fluoxetine administration in male Fischer 344 rats are prevented by prior exercise

“…The current results are consistent with prior work indicating that an acute increase in 5-HT is associated with anxiety (Abrams et al 2005;Graeff et al 1996;Hackler et al 2007;Lowry et al 2005) and can interfere with escape behaviors (Brown et al 1982). Additionally, anxiety-like behaviors have been reported following a single administration of an SSRI in several other animal models of anxiety including social interaction (Bagdy et al 2001;, the elevated plus maze (Kurt et al 2000), and the free-exploration test (Belzung et al 2001).…”

“…Anxiety-like behavioral effects of anxiogenic drugs such as the 5-HT 2 receptor agonist m-chlorophenylpiperazine and the GABA A receptor partial inverse agonist Nmethyl-beta-carboline-3-carboxamide correspond with activation of DRN 5-HT neurons (Abrams et al 2005;Singewald and Sharp 2000) and can be blocked by 5-HT 2C receptor antagonists (Bagdy et al 2001;Hackler et al 2007). Similarly, although selective-5-HT reuptake inhibitors (SSRIs) can reduce clinical symptoms in the spectrum of depression and anxiety disorders following several weeks of treatment (Feighner and Boyer 1991;Kent et al 1998), SSRIs rapidly increase extracellular 5-HT in the DRN (Rutter et al 1995), and symptom exacerbation, especially an increase in anxiety, is often reported during the onset of clinical treatment with SSRIs (Feighner and Boyer 1991;Goldstein and Goodnick 1998;Masand and Gupta 1999;Nutt and Glue 1989;Pohl et al 1988).…”

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“…Santos et al, 2006. The ability of SB 242084 to antagonize the anxiogeniclike effects of mCPP were associated with a significant attenuation of neural activation in the amygdala (as well as the hippocampus and hypothalamus, but not mPFC) (Hackler et al, 2007). Finally, the aforementioned anxiety-like phenotype in SERT knockout mice is associated with a significant increase in 5-HT2C-R binding density in the amygdala (Li et al, 2003).…”

“…Treatment with the non-specific serotonin receptor agonist mchlorophenylpiperazine (mCPP) has potent anxiogenic effects in rodent and man alike (Griebel, 1995;Menard and Treit, 1999;Millan, 2003;Murphy et al, 1986). Selective blockade of 5-HT2C-Rs with compounds such as SB 242084, either systemically or in the amygdala, is sufficient to prevent mCPP-induced (and in some cases, spontaneous or stress-induced) rodent anxiety-like behavior (Campbell and Merchant, 2003;Cornelio and Nunes-de-Souza, 2007;Graeff et al, 1996;Griebel, 1995;Hackler et al, 2007;Harada et al, 2006Harada et al, , 2007Kennett et al, 1996;Martin et al, 2002;Millan, 2003). Systemic treatment with SB 242084 also blocks the enhancement of conditioned fear produced by acute SRI treatment (Burghardt et al, 2004) (cf.…”

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“…mirtazapine or agomelatine (Cremers et al 2004;see Millan 2003), possibly by stimulating neurogenesis, as well as that of atypical antipsychotics Herrick Davis et al 2000). 5-HT2CR are expressed in the amygdala, and fMRI data have demonstrated that 5-HT 2C R agonists lead to its neuronal activation (Hackler et al 2007). Other therapeutic indications relate to obesity and possibly epilepsy Brennan et al 1997;Heisler et al 1998;2007a; as observed in the first series of receptor transgenic mice and later with 5-HT2CR selective ligands (Venzi et al 2016;Bagdy et al 2007;Jakus et al 2003;Isaac 2005).…”