Modulation of anxiety by cortical serotonin 1A receptors

Abstract

Serotonin (5-HT) plays an important role in the modulation of behavior across animal species. The serotonin 1A receptor (Htr1a) is an inhibitory G-protein coupled receptor that is expressed both on serotonin and non-serotonin neurons in mammals. Mice lacking Htr1a show increased anxiety behavior suggesting that its activation by serotonin has an anxiolytic effect. This outcome can be mediated by either Htr1a population present on serotonin (auto-receptor) or non-serotonin neurons (hetero-receptor), or both. In addition, both transgenic and pharmacological studies have shown that serotonin acts on Htr1a during development to modulate anxiety in adulthood, demonstrating a function for this receptor in the maturation of anxiety circuits in the brain. However, previous studies have been equivocal about which Htr1a population modulates anxiety behavior, with some studies showing a role of Htr1a hetero-receptor and others implicating the auto-receptor. In particular, cell-type specific rescue and suppression of Htr1a expression in either forebrain principal neurons or brainstem serotonin neurons reached opposite conclusions about the role of the two populations in the anxiety phenotype of the knockout. One interpretation of these apparently contradictory findings is that the modulating role of these two populations depends on each other. Here we use a novel Cre-dependent inducible allele of Htr1a in mice to show that expression of Htr1a in cortical principal neurons is sufficient to modulate anxiety. Together with previous findings, these results support a hetero/auto-receptor interaction model for Htr1a function in anxiety.

Serotonin and brain function: a tale of two receptors

“…Related to the hypothesis that 5-HT functions to moderate aversive mental states ( Deakin and Graeff, 1991 ) and promote patience ( McDannald, 2015 ) is the notion that 5-HT plays an important role in negatively modulating anxiety ( Piszczek et al, 2015 ). Selective reductions of 5-HT in the forebrain have been found to enhance anxiety-related behaviours ( Pum et al, 2009 ; Tu et al, 2014 ), whereas chronically administered SSRIs have been found to reduce anxiety ( Blanco et al, 2013 ).…”

“…Selective reductions of 5-HT in the forebrain have been found to enhance anxiety-related behaviours ( Pum et al, 2009 ; Tu et al, 2014 ), whereas chronically administered SSRIs have been found to reduce anxiety ( Blanco et al, 2013 ). Like impulsivity and aggression, anxiety appears to be negatively modulated by 5-HT1AR stimulation ( Heisler et al, 1998 ; Parks et al, 1998 ; Schreiber and De Vry, 1993 ; Toth, 2003 ), and although there are some contradictory findings ( File et al, 1996 ), this effect appears to be mediated by postsynaptic 5-HT1AR signalling ( Celada et al, 2013a ; Gross et al, 2002 ; Piszczek et al, 2015 ; Stefanski et al, 1993 ; Tauscher et al, 2001 ; Tu et al, 2014 ; Zhou et al, 2008 , 2014 ).…”

Down‐regulation of HTR1A‐modulated ACC activation contributes to stress‐induced visceral hyperalgesia in rats

“…Stimulation of HTR1A within the hippocampus or amygdala was known to produce an anxiogenic effect, while HTR1A agonist injection into the dorsal raphe nucleus was anxiolytic . Findings from transgenic animals showed that overexpression of HTR1A in forebrain and even in cortical principal neurons could reverse the anxiety phenotype of HTR1A knockout mice . Therefore, we speculate that increasing HTR1A in ACC is likely associated with decreasing anxiety in rats, which need to be researched further.…”

“…6,31,32 Findings from transgenic animals showed that overexpression of HTR1A in forebrain and even in cortical principal neurons could reverse the anxiety phenotype of HTR1A knockout mice. 33,34 Therefore, we speculate that increasing HTR1A in ACC is likely associated with decreasing anxiety in rats, which need to be researched further.…”

Efeitos da corticosterona e do estrógeno na atividade do eixo HPA de ratas: comportamento e comprimento dos telômeros

“…As reported in other papers. (62)(63)(64) Activation of serotonin receptors may result in anxiolytic response (65), and estrogen may modulate this response (66). Other neurotransmitters and hormones may participate in this response.…”