Rosa-Neto P, Diksic M, Okazawa H, Leyton M, Ghadirian N, Mzengeza S et al. Measurement of brain regional alpha-[11C]methyl-L-tryptophan trapping as a measure of serotonin synthesis in medication-free patients with major depression. Arch Gen Psychiatry 61: 556-563

Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada.
Archives of General Psychiatry (Impact Factor: 13.75). 06/2004; 61(6):556-63. DOI: 10.1001/archpsyc.61.6.556
Source: PubMed

ABSTRACT The serotonin hypothesis of depression invokes a relative or absolute deficit of serotonin neurotransmission. Reduced synthesis of serotonin in the brain pathways mediating the expression of mood (ie, the limbic cortex) is a plausible candidate mechanism.
To measure and compare, using the alpha-[(11)C]methyl-l-tryptophan/positron emission tomography method, the brain trapping constant of alpha-[(11)C]methyl-l-tryptophan (K*, milliliters per gram per minute), an index of serotonin synthesis, in brain areas involved in the regulation of mood in patients with major depression (MD) and age- and sex-matched controls.
Between-group comparison.
Department of Psychiatry and Montreal Neurological Institute, McGill University.
Seventeen medication-free outpatients with a current episode of MD (9 women: mean +/- SD age, 41 +/- 11 years; 8 men: mean +/- SD age, 41 +/- 11 years) and 17 controls (9 women: mean +/- SD age, 37 +/- 15 years; 8 men: mean +/- SD age, 32.5 +/- 9.9 years). Main Outcome Measure Normalized K*, normalized to the global mean, was measured in the dorsolateral prefrontal, anterior cingulate, and mesial temporal cortices; the thalamus; and the caudate nucleus.
Compared with age- and sex-matched controls, normalized K* was significantly decreased bilaterally in female patients with MD in the anterior cingulate cortex, in the left anterior cingulate cortex in male patients with MD, and in the left mesial temporal cortex in male and female patients with MD (P<.001 for all). Exploratory analyses identified additional patient-control differences for normalized K* (eg, inferior frontal gyrus and superior parietal lobule), most of which, once corrected for 38 multiple comparisons, lost their significance. Morphometric measurements of the cingulate cortex divisions confirmed that the reduction of normalized K* in depressed patients was not attributable to a reduction in gray matter volume. Normalized K* in the anterior cingulate cortex did not correlate with ratings of depression severity collected at the time of scan.
Reduction of normalized K*, an index of serotonin synthesis, in parts of the limbic and paralimbic cortices may contribute to the biochemical alterations associated with MD.

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Available from: Mirko Diksic, Aug 26, 2015
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    • "Taken together, the results, as well as previous reports, suggest that the regional imbalance in the synthesis and/or 5-HT regional concentration may be the most important factors in the manifestation and subsequent alleviation of depressive symptoms. It has been suggested previously that probably the most important factor in depression and the action of antidepressants is the relative imbalance in synthesis between different brain regions, rather than the absolute values of the synthesis as such (Rosa-Neto et al. 2004; Berney et al. 2008). Mayberg et al. (2000) showed regional specific changes produced in glucose utilization by antidepressant treatment. "
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    ABSTRACT: The influence of citalopram on regional 5-hydroxytryptamine (serotonin, 5-HT) synthesis, one of the most important presynaptic parameters of serotonergic neurotransmission, was studied. Sprague-Dawley (SPD) rats were used as the controls, and Flinders Resistant Line (FRL) rats were used as auxiliary controls, to hopefully obtain a better understanding of the effects of citalopramon Flinders Sensitive Line (FSL; "depressed") rats. Regional 5-HT synthesis was evaluated using a radiographic method with a labelled tryptophan analog tracer. In each strain of rats, the animals were treated with citalopram (10 mg/(kg day)) or saline for 14 days. The groups consisted of between fourteen and twenty rats. There were six groups of rats with citalopram (CIT) and saline (SAL) groups in each of the strains (SPD-AL, SPD-IT, FRL-AL, FRL-IT, FSL-AL and FSL-IT). A two-factor analysis of variance was used to evaluate the effect of the treatment c., SPD-SAL relative to SPD-CIT) followed by planned comparisons to evaluate the effect in each brain region. In addition, the planned comparison with appropriate contrast was used to evaluate a relative effects in SPD relative to FSL and FRL, and FSL relative to FRL groups. A statistical analysis was first performed in the a priori selected regions, because we had learned, from previous work, that it was possible to select the brain regions in which neurochemical variables had been altered by the disorder and subsequent antidepressant treatments. The results clearly show that citalopram treatment does not have an overall effect on synthesis in the control SPD rats; there was no significant (p > 0.05) difference between the SPD-SAL and SPD-CIT rats. In "depressed" FSL rats, citalopram produced a significant (p < 0.05) elevation of synthesis in seventeen out of thirty-four regions, with a significant (p < 0.05) reduction in the dorsal and median raphe. In the FRL rats, there was a significant (p < 0.05) elevation in the synthesis in twenty-two out of thirty-four brain regions, with a reduction in the dorsal raphe. In addition to these regions magnus raphe was different in the SPD and FSL groups, but it was on the statistical grounds identified as an outlier. There were significant changes produced in the FSL and FRL rats in thirteen out of seventeen a priori selected brain regions, while in the SPD rats, citalopram produced significant changes in only four out of seventeen a priori selected regions. The statistical evaluation also revealed that changes produced by citalopram in the FSL and FRL rats were significantly greater than those in the SPD rats and that there was no significant difference between the effect produced in the FSL and FRL rats. The presented results suggest that in "depressed" FSL rats, the antidepressant citalopram elevates 5-HT synthesis, which probably in part relates to the reported improved in behaviour with citalopram.
    Neurochemistry International 05/2009; 54(5-6):363-71. DOI:10.1016/j.neuint.2009.01.005 · 2.65 Impact Factor
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    • "5-HT synthesis) after acute treatment with antidepressants. The clinical importance of assessing 5-HT synthesis is emphasized by the finding that 5-HT synthesis is abnormal in depressed humans (Rosa-Neto et al., 2004). Similarly in a recent study using positron emission tomography and 11 C-labelled a-MTrp, it has been shown that pindolol augmentation, in a region-specific manner, affects 5- HT synthesis in depressed subjects treated with citalopram (Berney et al., 2008). "
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    ABSTRACT: 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.
    Neurochemistry International 12/2008; 54(3-4):161-71. DOI:10.1016/j.neuint.2008.08.012 · 2.65 Impact Factor
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    • "For example, 5-HT turnover is significantly elevated in the frontal cortex of olfactory bulbectomized rats (Zhou et al., 1998), and both 5-HT and 5-HIAA content are elevated in the PFC of Flinders sensitive line (FSL) rats, a genetic rat model of depression (Zangen et al., 1997). Additionally, the present findings suggest that the perinatal DHAdeficient rat has face and construct validity as a model of depression because patients with major depression also exhibit PFC DHA deficits (McNamara et al., 2007), elevated central 5- HIAA content (Barton et al., 2008), and reduced indices of 5-HT synthesis (Rosa-Neto et al., 2004). Furthermore, chronic SSRI treatment decreases central 5-HIAA content in patients with major depression (Barton et al., 2008; Lundmark et al., 1994; Potter et al., 1985; Sheline et al., 1997), and decrease both 5-HT and 5-HIAA content in the rat PFC (Unceta et al., 2007). "
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    ABSTRACT: A dysregulation in central serotonin neurotransmission and omega-3 fatty acid deficiency have been implicated in the pathophysiology of major depression. To determine the effects of omega-3 fatty acid deficiency on indices of serotonin neurotransmission in the adult rat brain, female rats were fed diets with or without the omega-3 fatty acid precursor alpha-linolenic acid (ALA) during perinatal (E0-P90), post-weaning (P21-P90), and post-pubescent (P60-130) development. Ovariectomized (OVX) rats and OVX rats with cyclic estrogen treatment were also examined. Serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) content, and fatty acid composition were determined in the prefrontal cortex (PFC), and tryptophan hydroxylase-2 (TPH-2), serotonin transporter, and 5-HT(1A) autoreceptor mRNA expression were determined in the midbrain. ALA deficiency during perinatal (-62%, p=0.0001), post-weaning (-34%, p=0.0001), and post-pubertal (-10%, p=0.0001) development resulted in a graded reduction in adult PFC docosahexaenoic acid (DHA, 22:6n-3) composition. Relative to controls, perinatal DHA-deficient rats exhibited significantly lower PFC 5-HT content (-65%, p=0.001), significant greater 5-HIAA content (+15%, p=0.046), and a significant greater 5-HIAA/5-HT ratio (+73%, p=0.001). Conversely, post-weaning DHA-deficient rats exhibited significantly greater PFC 5-HT content (+12%, p=0.03), no change in 5-HIAA content, and a significantly smaller 5-HIAA/5-HT ratio (-9%, p=0.01). Post-pubertal DHA-deficient and OXV rats did not exhibit significant alterations in PFC 5-HT or 5-HIAA content. Only perinatal DHA-deficient rats exhibited a significant reduction in midbrain TPH-2 mRNA expression (-29%, p=0.03). These preclinical data support a causal link between perinatal omega-3 fatty acid deficiency and reduced central serotonin synthesis in adult female rats that is independent of ovarian hormones including estrogen.
    Journal of Psychiatric Research 12/2008; 43(6):656-63. DOI:10.1016/j.jpsychires.2008.09.011 · 4.09 Impact Factor
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