Besides changes within the central serotonergic system, chronic treatment with citalopram also changed several peripheral markers. The chronically treated animals had significantly lower plasma levels of adrenaline and noradrenaline, ACTH and corticosterone, suggesting a decreased activity of the HPA-axis. This is in agreement with the observation that chronic treatment with antidepressants restores HPA-axis hyperactivity in depressive patients (Barden et al., 1995; Inder et al., 2001) and that it reduces basal levels of corticosteroids and ACTH in rodents (Reul et al., 1993). Cortisol release in humans can be regulated by activation of 5-HT1A receptors. This response is blunted following chronic antidepressant therapy (Berlin et al., 1998; Lerer et al., 1999), which indicates a strong interaction between the serotonergic system and HPA axis activity and thus further supports our results.
Levels of corticosterone and catecholamines found in the subchronic treatment group are 10-fold higher than baseline levels reported in literature (Gomez et al., 1998; Reul et al., 1993), and comparable with a restraint stress induced response (Ginsberg et al., 2003). The termination procedure used in the present study induced acute stress in all animals, which likely explains the high plasma levels of stress hormones. Interestingly, stress hormone levels were significantly reduced in the chronic treatment group. Our results are in line with the observation that rats chronically treated with an SSRI have a blunted corticosterone response to citalopram (Jensen et al., 1999), as well as a reduced HPA-axis activation in response to acute stress (Reul et al., 1993). In short, the present study confirms that control of stress hormone release is affected by chronic SSRI treatment.
It can be concluded that as 5-HT1B receptor function remains unaltered following chronic citalopram treatment, this receptor is not involved in the observed reduction of the stress hormone release. The notion that 5-HT1B receptors do not desensitize in presence of citalopram suggests that the therapeutic effect of long-term antidepressant treatment could be improved by co-administration of a 5-HT1B receptor antagonist. Further research should reveal how HPA-axis attenuation might play a role in achieving the therapeutic effect of SSRIs.
SSRI treatment, 5-HT1B receptor sensitivity and HPA-axis activity
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