Ivan Skelin

Gender differences in α-[11C]MTrp brain trapping, an index of serotonin synthesis, in medication-free individuals with major depressive disorder: A positron emission tomography study

Women are at higher risk than men for developing major depressive disorder (MDD), but the mechanisms underlying this higher risk are unknown. Here, we report proportionally normalized alpha-[(11)C]methyl-L-tryptophan brain trapping constant (alpha-[(11)C]MTrp K*(N)), an index of serotonin synthesis, in 25 medication-free individuals with MDD and in 25 gender- and age-matched healthy subjects who were studied using positron emission tomography (PET). Comparisons of alpha-[(11)C]MTrp K*(N) values between the men and women were conducted at the voxel and cluster levels using Statistical Parametric Mapping 2 (SPM2) analysis. In addition, the alpha-[(11)C]MTrp K*(N) values on both sides of the brain were extracted and compared to identify the left to right differences, as well as the gender differences. Women with MDD displayed higher alpha-[(11)C]MTrp K*(N) than men in the inferior frontal gyrus, anterior cingulate cortex (ACC), parahippocampal gyrus, precuneus, superior parietal lobule, and occipital lingual gyrus. In a matched group of normal subjects the gender differences were opposite from those found in MDD patients. Significant hemispheric differences in fronto-limbic structures between men and women with MDD were also observed. The K*(N) extracted from the volumes identified in MDD patients and in male and female normal subjects suggested no significant differences between males and females. In conclusion, depressed women have higher serotonin synthesis in multiple regions of the prefrontal cortex and limbic system involved with mood regulation, as compared with depressed men. Gender differences in brain serotonin synthesis may be related to higher risk for MDD in women.

Reduced metabotropic glutamate receptor 5 in the Flinders Sensitive Line of rats, an animal model of depression: An autoradiographic study

Depression is a brain disorder and there is still only a partial understanding of its underlying pathophysiology. Antidepressant medications with a fast onset have not yet been developed. In addition to the monoaminergic systems, the brain glutaminergic system has been implicated in the etiology of depression. Animal studies of depression have gained importance because they permit a more invasive manipulation of the subjects than human studies. In the present study, we measured the densities of the brain regional metabotropic glutaminergic receptor 5 (mGluR5) in the Flinders Sensitive Line (FSL) rat model of depression and two groups of control rats, the Flinders Resistant Line (FRL) and Sprague Dawley (SPD), the parent strain for both the FSL and FRL rats. The FSL rats showed lower densities of mGluR5 in many brain regions compared to either the SPD and/or FRL rats. In addition, the densities in the FRL rats were larger than in the SPD rats, suggesting possible problems in using FRL rats as controls. The presented data suggest that mGluR5 is lower in animal models of depression which could be related to the cognitive and emotional dysfunctions in the FSL rat model of depression and could be relevant to a better understanding of depression in humans.

Imaging in Vivo Glutamate Fluctuations with [11C]ABP688: A GLT-1 Challenge with Ceftriaxone

Molecular imaging offers unprecedented opportunities for investigating dynamic changes underlying neuropsychiatric conditions. Here, we evaluated whether [11C]ABP688, a positron emission tomography (PET) ligand that binds to the allosteric site of the metabotropic glutamate receptor type 5 (mGluR5), is sensitive to glutamate fluctuations after a pharmacological challenge. For this, we used ceftriaxone (CEF) administration in rats, an activator of the GLT-1 transporter (EAAT2), which is known to decrease extracellular levels of glutamate. MicroPET [11C]ABP688 dynamic acquisitions were conducted in rats after a venous injection of either saline (baseline) or CEF 200 mg/kg (challenge). Binding potentials (BPND) were obtained using the simplified reference tissue method. Between-condition statistical parametric maps indicating brain regions showing the highest CEF effects guided placement of microdialysis probes for subsequent assessment of extracellular levels of glutamate. The CEF administration increased [11C]ABP688 BPND in the thalamic ventral anterior (VA) nucleus bilaterally. Subsequent microdialysis assessment revealed declines in extracellular glutamate concentrations in the VA. The present results support the concept that availability of mGluR5 allosteric binding sites is sensitive to extracellular concentrations of glutamate. This interesting property of mGluR5 allosteric binding sites has potential applications for assessing the role of glutamate in the pathogenesis of neuropsychiatric conditions.

Chronic buspirone treatment decreases 5-HT1B receptor densities and the serotonin transporter but increases the density of 5-HT2A receptors in the bulbectomized rat model of depression: an autoradiographic study

The olfactory bulbectomized (OBX) rat model is an animal model of depression. The deregulation of the serotonergic (5-HT) system is implicated in the pathophysiology of depression. Buspirone is a partial agonist of 5-HT(1A) receptors and is used in the treatment of depression and anxiety. The aim of this study was to assess, in OBX rats and sham operated controls, the effect of chronic buspirone treatment on the densities of 5-HT(2A) and 5-HT(1B) receptors, as well as the 5-HT transporter (5-HTT), which are all important mediators of 5-HT transmission. Male Sprague-Dawley rats (180-240 g) were used. Two weeks following the surgeries, the rats were assigned into the saline or treatment groups, receiving either saline, or 10 or 20 mg/kg day of buspirone, for 2 weeks by subcutaneous mini pump. Following the treatment, the rats were sacrificed. The autoradiographic experiments were performed ex vivo using [(3)H]5-HT for the 5-HT(1B) receptors, [(3)H]-ketanserin for the 5-HT(2A) receptors, and [(3)H]-paroxetine for the 5-HTT binding. The receptors and 5-HTT densities were quantified in 38 brain regions as well as the pineal body. Chronic treatment with buspirone produced the following: 1) a decrease in the 5-HT(1B) densities, which was more pronounced in the Sham rats; 2) an increase in the 5-HT(2A) receptor densities, which was more pronounced in the Sham rats; and 3) an decrease in 5-HTT densities in both groups. The results indicate differential effects of chronic antidepressant treatment on the 5-HT system regulation in the OBX model of depression and normal rats.

Shift in the brain network of emotional regulation in midlife women: is the menopausal transition the turning point?

Objective:The menopausal transition is marked by hormonal changes and is quite often accompanied by cognitive and emotional complaints. Recent data also suggest a heightened risk for depression. Little is known about the changes in emotional regulation that might contribute to the increased risk of depression in this population. The aim of this study was to examine the brain correlates of emotional regulation in healthy, nondepressed midlife women. Methods:Functional magnetic resonance imaging was obtained in response to a standardized emotional regulation task. Levels of congruency were set and brain activation was measured during high- and low-conflict-resolution trials. Results:Fourteen women aged 40 to 60 years were enrolled into the study, and 11 were included in the final analyses. Activity associated with resolution of emotional conflict was observed in the dorsolateral prefrontal cortex (P < 0.05). No regions were engaged in the generation/monitoring of emotional conflict. Moreover, there was a significant deactivation of the amygdala in response to fearful faces (P < 0.05). Conclusions:Unlike similar studies in younger populations, these results suggest a more significant engagement of the dorsolateral prefrontal cortex and less amygdala activation in emotional regulation in midlife women. These findings are, however, consistent with previous studies in older populations. We hypothesize that a shift in emotional regulation circuitry might therefore occur in women during the menopausal transition and possibly contribute to the occurrence of mood and anxiety symptoms in women during/after this period in life.

Flesinoxan challenge suggests that chronic treatment with paroxetine in rats does not desensitize receptors controlling 5-HT synthesis

It has been proposed that the desensitization of 5-HT(1A) (5-hydroxytryptamine; serotonin) receptors following chronic therapy with selective serotonin reuptake inhibitors (SSRIs) is necessary for their therapeutic efficacy. Stimulation of the 5-HT(1A) receptors decreases serotonin (5-HT) synthesis and release, but it is not clear if the receptors are fully desensitized following chronic SSRI treatment. The main objective of this study was evaluation of ability of 5-HT(1A) receptors to modulate 5-HT synthesis after 14-day paroxetine treatment. 5-HT(1A) receptor sensitivity following chronic administration of the SSRI paroxetine was assessed by the ability of an acute challenge with the 5-HT(1A) agonist, flesinoxan, to modulate 5-HT synthesis in the rat brain. The rates of 5-HT synthesis were measured using the alpha-[(14)C]methyl-l-tryptophan autoradiographic method. The rats were treated for 2 weeks with paroxetine (10mg/(kgday), s.c., delivered by osmotic minipump). After this treatment, the rats received an acute challenge with flesinoxan (5mg/kg, i.p.), while the control rats were injected with the vehicle. Forty minutes following the flesinoxan injection, the tracer, alpha-[(14)C]methyl-l-tryptophan, was injected over 2min. 5-HT synthesis rates were calculated from autoradiographically measured tissue tracer concentrations and plasma time-activity curves. The results demonstrated that the acute flesinoxan challenge produced a significant decrease in 5-HT synthesis rates throughout the rat brain. The greatest decrease was observed in the ventral hippocampus, somatosensory cortex and the ascending serotonergic cell bodies. In comparison with data reported on an acute challenge with flesinoxan in naïve rats (rats without any other treatment), the results presented here suggest a greater effect of flesinoxan on synthesis reduction in rats chronically treated with paroxetine. The results also suggest that the 5-HT receptors were not fully desensitized by paroxetine treatment, and that the stimulation of 5-HT(1A) receptors with an agonist is still capable of reducing 5-HT synthesis.

Both acute and subchronic treatments with pindolol, a 5-HT1A and β1 and β2 adrenoceptor antagonist, elevate regional serotonin synthesis in the rat brain: An autoradiographic study

Antidepressant treatments, including those that increase serotonin (5-HT) neurotransmission, require several weeks or months until the onset of the therapeutic effect in depressed patients. The negative feedback on 5-HT transmission exhibited by the 5-HT(1A) and 5-HT(1B) autoreceptors has been postulated as a possible delaying factor. The aim of the present study was to assess the effect of the acute and subchronic treatment with pindolol, a 5-HT(1A/1B,) β₁ and β₂ adrenoceptor antagonist, on 5-HT synthesis, one of the key parameters of 5-HT neurotransmission. Male Sprague-Dawley (SPD) rats (180-220 g) were treated with pindolol or an adequate volume of saline, administered either acutely (15 mg/kg i.p.; SPD-AC-SAL, SPD-AC-TR) or subchronically (15 mg/kg day i.p. for 7 days; SPD-SUBCHR-SAL, SPD-SUBCHR-TR). Thirty minutes following the single i.p. injection (acute experiment) or at the 8th day following the commencement of the subchronic treatment (subchronic experiment), 5-HT synthesis was measured using α-[¹⁴C]methyl-L-tryptophan autoradiography. The analysis of variance (ANOVA), followed by the Benjamini-Hochberg correction for multiple comparisons, revealed: (1) a significant increase of 5-HT synthesis in the SPD-AC-TR rats, relative to the SPD-AC-SAL rats in all brain regions examined except the substantia nigra--pars reticularis, dorsal subiculum, inferior olive, raphe magnus and raphe obscurus and (2) a significant increase of 5-HT synthesis in the SPD-SUBCHR-TR rats, relative to the SPD-SUBCHR-SAL rats in all brain regions except the median raphe, hypothalamus and raphe pontine. On the basis of these results, we hypothesized that the antagonism of the 5-HT(1A/1B) receptors prevents the negative feedback mediated by these receptors on 5-HT synthesis, resulting in a persistent increase of 5-HT synthesis. The results accord with clinical reports on the utility of pindolol in the augmentation of antidepressant treatment.

P01-293 Gender differences in brain serotonin synthesis in individuals with major depressive disorder: A A-[11C]MT pet imaging study

Objective Women are at higher risk than men to develop major depressive disorder (MDD), but the mechanisms underlying the higher risk for MDD in women are unknown. There is a wealth of data showing gender differences in brain morphology and function. In addition, preclinical studies have demonstrated reciprocal relationships between ovarian hormones and serotonin neurotransmission. Thus, gender differences in brain serotonin neurotransmission are potential underlying mechanisms. In the present study, we compared normalized α-[11C]methyl-L-tryptophan brain trapping constant (α-[11C]MTrp K*; ml/g/min), an index of serotonin synthesis, between men and women with MDD. Method α-[11C]MTrp K* was measured in 25 medication-free individuals with MDD (13 females and 12 males) using positron emission tomography. Comparisons of normalized α-[11C]MTrp K* values between men and women were conducted at the voxel level using Statistical Parametric Mapping 2 (SPM2) analysis. Results Women with MDD displayed significantly higher (p Conclusions This finding suggests that depressive women have higher serotonin synthesis in multiple regions of the prefrontal cortex and limbic system involved with mood regulation. Gender differences in brain serotonin synthesis may be associated with higher risk for MDD in women because extra levels of tissue 5-HT could create non-physiological connections influencing changes in mood.