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*N. S. BURGHARDT1, D. E. A. BUSH1, B. S. MCEWEN2, J. E. LEDOUX1;
SSRIs are effective in treating a range of anxiety disorders, although
symptoms of anxiety are often exacerbated during early stages of treatment.
We previously reported that acute treatment with the SSRI citalopram enhances
the acquisition of auditory fear conditioning, which is consistent with
the anxiogenic effects found clinically. Here, we extend our findings
by testing the effects of acute SSRI treatment on the expression of previously
acquired conditioned fear. Rats underwent fear conditioning drug-free.
Tone-evoked fear responses were tested after drug treatment the following
day. This paradigm more closely resembles the clinical setting than pre-conditioning
treatment, since it evaluates the effects of treatment on a pre-existing
fear, rather than on the formation of a new fear memory. We found that
a single pre-testing injection of the SSRIs citalopram or fluoxetine significantly
increased fear expression. There was no effect of the antidepressant tianeptine,
or the norepinephrine reuptake inhibitor tomoxetine, indicating that this
effect is specific to SSRIs. The SSRI-induced enhancement in fear expression
was not blocked by systemically administered tropisetron, a 5-HT3 receptor
antagonist, but was blocked by systemically administered SB 242084, a
specific 5-HT2C receptor antagonist. Therefore, enhanced activation of
5-HT2C receptors may be a mechanism for the anxiogenic effects of SSRIs
observed initially during treatment. Given the important role of the amygdala
in auditory fear conditioning, it is possible that the 5-HT2C receptors
located in this brain region may be involved. Our findings suggest that
co-administration of 5-HT2C receptor antagonists with SSRIs may help prevent
the increase in anxiety often reported during early stages of treatment..
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