Early-Life Blockade of 5-HT1A Receptors Alters Adult Anxiety Behavior and Benzodiazepine Sensitivity

Developmental Effects of Serotonin 1A Autoreceptors on Anxiety and Social Behavior

“…Specifically, autoreceptor knockdown during post-natal development increases anxiety and decreases levels of social engagement but does not alter stress coping. These findings support and refine previous pharmacological and transgenic work suggesting that the effects of 5-HT1A autoreceptors on anxiety are a developmentally mediated phenotype (Bortolozzi et al, 2012;Lo Iacono and Gross, 2008;Richardson-Jones et al, 2011;Vinkers et al, 2010) and provide insights into how perturbations to the 5-HT1A autoreceptor system during post-natal life can impact more complex social phenotypes, an area that has not been extensively explored in previous literature. Importantly, this work addresses a number of limitations of previous studies.…”

“…Because 5-HT1A activation directly impacts the firing of raphe neurons, we hypothesized that decreased autoreceptor levels during post-natal development may have a longterm impact on neural physiology within the raphe (Vinkers et al, 2010). In order to test this hypothesis, we examined electrophysiological properties of serotonin-producing neurons in KD and WT littermates late in life (4P270).…”

“…Clinically, the 5-HT1A agonist, buspirone, decreases anxiety levels and acts as a mild anti-depressant (Loane and Politis, 2012). Further, developmental blockade of 5-HT1A with WAY-100,635 from post-natal day (P)0 to P21 or from P13 to P34 recapitulates the increased anxiety phenotype, whereas similar antagonism during adulthood does not (Lo Iacono and Gross, 2008;Vinkers et al, 2010). However, it is unclear whether the increased anxiety phenotype is due to alteration of serotonin levels via the direct actions of the 5-HT1A autoreceptor on raphe neurons or through the altered response to released serotonin acting at 5-HT1A heteroreceptors in the limbic system.…”

“…A separate cohort of control and knockdown mice were also exposed to daily bouts of unpredictably timed restraint stress from P14 to P21. This represents the period of overlap in studies that found long-term increases in anxiety when administering the 5-HT1A antagonist, WAY100635, from P0 to P21 (Vinkers et al, 2010) and from P13 to P34 (Lo Iacono and Gross, 2008). Thus we sought to ask whether concurrent stress might interact with receptor knockdown to shape behavior later in life.…”

Mirtazapine exerts an anxiolytic-like effect through activation of the median raphe nucleus-dorsal hippocampal 5-HT pathway in contextual fear conditioning in rats

“…It should to be noted that although WAY-100635 has been widely employed as a 5-HT 1A antagonist in the scientific literature (e.g., Berrocoso and Mico, 2009;Horiguchi and Meltzer, 2012;Hunt et al, 2011;Vicente et al, 2008;Vinkers et al, 2010), WAY-100635 also has dopamine D 4 receptor agonist activity (Chemel et al, 2006).…”