Differential effects of acute and repeated citalopram in mouse models of anxiety and depression

Abstract

Clinically, SSRIs are widely prescribed in the treatment of several anxiety disorders, though very few pre-clinical studies have observed a beneficial effect of this class of drugs in animal models of anxiety. Furthermore, the biphasic pattern observed clinically, an exacerbation of anxiety followed by beneficial effects, is rarely observed in animal studies. In the present study we document this clinical phenomenon in several behavioral paradigms. While a single injection of citalopram induced anxiogenic effects, three administrations of citalopram were sufficient to elicit anxiolytic effects. Congruent with these data, we observed that short-term repeated administration with citalopram was accompanied by an increase activation of CREB in hippocampus and a desensitization of 5-HT1A receptors, two phenomenon well associated with chronic (2-3 week) rather than acute effects of antidepressants. Moreover, anxiolytic effects of citalopram were abolished in CREB αΔ mutant animals in elevated zero maze and tail suspension test, but not in novelty-induced hypophagia or 5-HT1A receptors desensitization. The significance of the elevated-zero maze and TST paradigms in predicting therapeutic efficacy is well known while effects in NIH and 5-HT1A sensitization are less well-established. These data demonstrate that behavioral response to citalopram is dependent on frequency of acministration which is associated with differences in CREB requirements.

Differential role of AMPA receptors in mouse tests of antidepressant and anxiolytic action

“…The pronounced anxiolytic-like action of citalopram observed in the EZM contrasts with earlier reports in mice. Previous studies reported either anxiogenic-like or no effects of acute SSRI treatment in the mouse EPM and EZM (Borsini et al, 2002;Kurt et al, 2000;Mombereau et al, 2010). To our knowledge this is the first demonstration of anxiolytic-like action of acute SSRI treatment in the mouse EZM or EPM.…”

Chronic modulation of serotonergic neurotransmission with sertraline attenuates the loudness dependence of the auditory evoked potential in healthy participants

“…Preskorn 1996;Anderson et al 2002), in contrast to acute and subchronic studies (e.g. Aznavour et al 2006;Beyer and Cremers 2008;Mombereau et al 2010). Further, chronic administration of an SSRI in healthy participants leads to changes in behaviour, mood, personality and brain function, consistent with augmented serotonergic function (e.g.…”

“…However, there is evidence that this is not the case (e.g. Jensen et al 1999;Burghardt et al 2004;Beyer and Cremers 2008;Mombereau et al 2010).…”

Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala

“…SSRIs represent one of the most widely used classes of drugs for psychiatric disorders. One limitation of SSRIs is that acute administration can lead to negative behavioral states1,2, a finding that is recapitulated in rodent models3,16–20. Importantly, the BNST has been demonstrated to be an anatomical site of action for some of the aversive actions of SSRIs in rodents4.…”