Acute effects of combining citalopram and pindolol on regional brain serotonin synthesis in sham operated and olfactory bulbectomized rats

Dec 17, 2008Neurochemistry international

Short-term effects of combining citalopram and pindolol on serotonin production in specific brain areas of normal and smell-loss rats

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Abstract

Acute citalopram treatment increased serotonin synthesis in sham rats, while decreasing it in olfactory bulbectomized (OBX) rats by approximately 45%.

In sham rats, citalopram (20mg/kg) elevated serotonin synthesis in nearly all terminal regions but slightly reduced it in cell body regions.
Combining pindolol (10mg/kg) with citalopram further enhanced serotonin synthesis in sham rats compared to citalopram alone.
In OBX rats, citalopram decreased serotonin synthesis at several terminal regions and significantly at the dorsal and median raphe.
The combination of pindolol with citalopram in OBX rats substantially increased serotonin synthesis across nearly all regions compared to citalopram alone.
Findings indicate that serotonin autoreceptor feedback is stronger in OBX rats, which may delay the effects of SSRIs in both OBX rats and human depression.

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The olfactory bulbectomized (OBX) rat is considered to be a good model of the pathology of human depression and also of the functional actions of antidepressant drug therapy. It has been proposed that antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) can be accelerated by blocking 5-HT(1A/B) autoreceptors with pindolol. The underlying mechanism is thought to involve acute unrestricting of 5-HT release and, consequently, relatively enhanced 5-HT turnover throughout the forebrain serotonergic networks. The effect of this combination on 5-HT turnover in sham operated or OBX rats can be assessed at the level of 5-HT synthesis, a very important presynaptic step in serotonergic neurotransmission, using the alpha-[(14)C]methyl-l-tryptophan autoradiography method. In sham rats, acute citalopram (20mg/kg) treatment increased synthesis at almost all serotonergic terminal regions but slightly decreased synthesis at serotonergic cell body regions (i.e. dorsal and median (not significant) raphe; approximately 16%). Combining pindolol (10mg/kg) with citalopram further increased synthesis at many regions in sham rats (relative to treatment with only citalopram). In OBX rats, citalopram decreased synthesis at a few terminal regions and greatly decreased synthesis at the dorsal and median raphe ( approximately 45%; relative to OBX rats treated with saline). Combining pindolol with citalopram greatly increased synthesis at almost all regions in OBX rats (relative to treatment with only citalopram). These results suggest that acute citalopram effects result in elevated terminal 5-HT synthesis, but these effects are restrained by 5-HT(1A/B) autoreceptor feedback to different degrees in sham and OBX rats. Moreover, 5-HT(1A/B) autoreceptor feedback is stronger in OBX rats and may underlie the delay of SSRI effects in OBX rats and, correspondingly, in human depression. Pindolol acceleration and augmentation of SSRI antidepressant therapy for human depression may be mediated by attenuation of 5-HT(1A/B) autoreceptor feedback, permitting unhindered SSRI effects on serotonergic terminals.

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Acute effects of combining citalopram and pindolol on regional brain serotonin synthesis in sham operated and olfactory bulbectomized rats

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