Serotonin-1A autoreceptor binding in the dorsal raphe nucleus of depressed suicides

Department of Psychiatry, Division of Neuroscience, Columbia University College of Physicians and Surgeons, New York State Psychiatric Institute, 1051 Riverside Drive, P.O. Box 42, New York, NY 10032, USA.
Journal of Psychiatric Research (Impact Factor: 3.96). 05/2008; 42(6):433-42. DOI: 10.1016/j.jpsychires.2007.05.004
Source: PubMed


Serotonergic dysfunction is present in mood disorders and suicide. Brainstem 5-HT1A somatodendritic autoreceptors regulate serotonin neuron firing but studies of autoreceptor binding in the dorsal raphe nucleus (DRN) in depressed suicides report conflicting results. We sought to determine: (1) the anatomical distribution of 5-HT1A receptor binding in the DRN in depressed suicides and psychiatrically normal controls; and (2) whether sex differences in 5-HT1A binding in the DRN contribute to differences between depressed suicides and controls. Previously collected quantitative receptor autoradiograms of [3H]8-hydroxy-2-(di-n-propyl)aminotetralin (3H-8-OH-DPAT) in postmortem tissue sections containing the DRN from drug-free suicide victims (n=10) and matched controls (n=10) were analyzed. Less total receptor binding (fmol/mg tissuexmm3) was observed in the entire DRN in depressed suicides compared with controls (p<0.05). Group differences along the rostrocaudal extent of the DRN were observed for cross-sectional 5-HT(1A) binding (fmol/mg tissue) and receptor binding (fmol/mgxmm3, p<0.05). Cross-sectional 5-HT1A DRN binding in depressed suicides compared with controls was higher rostrally and lower caudally. The differences between depressed suicides and controls were present in males and females, although females had more binding than males. Less autoreceptor binding in the DRN of depressed suicides may represent a homeostatic response to less serotonin release, increasing serotonin neuron firing. More autoreceptor binding in rostral DRN might contribute to deficient serotonin release in ventromedial prefrontal cortex by lower neuronal firing.

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Available from: Victoria Arango, Aug 13, 2014
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    • "Previous research has implicated the serotonergic system in MDD pathophysiology (Boldrini et al, 2008; Parsey et al, 2006; Sargent et al, 2000; Savitz et al, 2009; Stockmeier, 2003) and selective serotonin reuptake inhibitors (SSRIs) remain a first line treatment, further implicating serotonergic dysfunction in MDD (Blier et al, 1998; Parsey et al, 2010; Sullivan et al, 2009). Given its key role in MDD, the serotonergic system is a natural substrate in which to search for a biomarker (a characteristic that can be objectively measured and used as an indicator of either normal or pathogenic processes (Singh et al, 2009)) of depression. "
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    ABSTRACT: Multiple lines of research have implicated the serotonin 1A (5-HT1A) receptor in major depressive disorder (MDD). Despite this, quantification of 5-HT1A has yet to yield a clinically relevant MDD biomarker. One reason may that reported sex differences in the serotonergic system confound the comparison between diagnostic groups. Therefore, this study sought to determine whether differences in 5-HT1A binding between depressed and control subjects are affected by sex. Using Positron Emission Tomography (PET), serotonin 1A binding was quantified in 50 patients with MDD (34 female, 16 male) and 57 healthy controls (32 female, 25 male). The subjects' 5-HT1A density (BPF, equal to the product of the density of available receptors and tracer affinity), was determined using the PET tracer [carbonyl-C-11]-WAY-100635, a selective 5-HT1A antagonist. Results indicated that male MDD subjects had a 67.0% higher BPF across 13 brain regions compared to male controls (df=103, p<0.0001). The greatest difference between MDD subjects and controls was in the raphe (132%, p=0.000). Furthermore, using a threshold, male controls can be distinguished from depressed males with high sensitivity and specificity (both >80%). In females, the separation between diagnostic groups yields much lower sensitivity and specificity. This data therefore suggests a specific biosignature for MDD in males. Identification of such a biosignature could provide a deeper understanding of depression pathology, help identify those at highest risk and aid in the development of new therapies. Further, these findings suggest that combining male and female cohorts may not be optimal for some MDD studies.Neuropsychopharmacology accepted article preview online, 12 January 2015. doi:10.1038/npp.2015.15.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 01/2015; 40(7). DOI:10.1038/npp.2015.15 · 7.05 Impact Factor
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    • "5-HT 1A receptors are localized dendritically as inhibitory autoreceptors on serotonergic cells or in postsynaptic sites that are enriched in corticolimbic structures as the hippocampus and frontal cortex (Millan, 2000). Postmortem and neuroimaging studies suggest an increased density of 5-HT 1A autoreceptors in major depressive patients compared with control subjects (Boldrini et al., 2008; Parsey et al., 2002; Stockmeier et al., 1998). 5HT 1A and 5-HT 2A/2C receptors are of remarkable importance in the control of mood, motor behavior and appetite (Millan, 2005). "
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    • "Increases in 5-HT 1A autoreceptor density in the midbrain have been demonstrated in depressed suicide patients (Stockmeier et al. 1998). Boldrini et al. (2008) confirmed and extended this observation by using (H 3 ) 8-OH-DPAT autoradiography and reported an increase in rostral divisions of the dorsal raphe nuclei, which project to the prefrontal cortex, but decreased levels of 5-HT 1A autoreceptors in the caudal dorsal raphe nuclei. An increase in autoreceptor levels in rostral divisions might result in a decreased serotonin activity in projection areas by lowering firing rate. "
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