Modulation of cortical neuronal activity by a serotonergic agent: a PET study in humans

doi:10.1016/0006-8993(94)90091-4

Brain Research

Volume 646, Issue 2, 23 May 1994, Pages 292-294

https://doi.org/10.1016/0006-8993(94)90091-4 Get rights and content

Abstract

This study investigates the effect of a serotonergic agent, fenfluramine, on neuronal activity, as measured using [¹⁸F]fluorodeoxyglucose (FDG) uptake with positron emission tomography (PET) in humans. Eleven subjects each received oral fenfluramine and placebo, on two different occasions, followed by FDG PET scans. Our study shows that fenfluramine modulates ongoing neuronal activity in a regionally specific fashion with a relative increase in metabolism in the prefrontal cortex and a relative decrease in the occipital-temporal regions.

References (14)

FreoU. et al.
Parachloramphetamine selectively alters regional cerebral metabolic responses to serotonergic agonist methachlorophenyl-piperazine in rats
Brain Res.
(1991)
KellyP.A.T. et al.
Cerebral glucose utilization following striatal lesions: the effects of the GABA agonist, muscimol, and the dopaminergic agonist, apomorphine
Brain Res.
(1987)
LaferrereB. et al.
Effect ofd-fenfluramine on serotonin release in brains of anaesthetized rats
Brain Res.
(1989)
PapadopoulosG.C. et al.
Monoamine systems in the cerebral cortex: evidence for anatomical specificity
Prog. Neurobiol.
(1991)
StorlienL.H. et al.
d-Fenfluramine effects on hypothalamic monoamine activities and their hormonal correlates
Brain Res.
(1992)
Van PraagH.M. et al.
Hormonal probes of central serotonergic activity: do they really exist?
Biol. Psychiatry
(1987)
BaileyD.L. et al.
Physical validation of statistical parametric mapping
J. Cereb. Blood Flow Metab.
(1991)

There are more references available in the full text version of this article.

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"Domain gauges": A reference system for multivariate profiling of brain fMRI activation patterns induced by psychoactive drugs in rats
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Citation Excerpt :
Thalamic sites are richly innervated by serotonergic neurons from the raphe nuclei via different pathways (Parent, 1981; Lavoie and Parent, 1991; Gurevich and Joyce, 1996). In line with our results, several studies have reported decreased thalamic glucose metabolism and blood flow after (albeit acute) infusion of SSRIs and have linked this to effects of the drugs at serotonergic sites (Kapur etal., 1994; Meyer etal., 1998; Smith and Geday, 2001; Smith etal., 2002). By contrast, the weakly positive modulations of the amygdala and insula are not supported by perfusion imaging studies of depressive disorders, looking at the amygdala in particular because of its key role in processing emotional stimuli.
Pharmacological magnetic resonance imaging (phMRI) of the brain has become a widely used tool in both preclinical and clinical drug research. One of its challenges is to condense the observed complex drug-induced brain-activation patterns into semantically meaningful metrics that can then serve as a basis for informed decision making. To aid interpretation of spatially distributed activation patterns, we propose here a set of multivariate metrics termed “domain gauges”, which have been calibrated based on different classes of marketed or validated reference drugs. Each class represents a particular “domain” of interest, i.e., a specific therapeutic indication or mode of action. The drug class is empirically characterized by the unique activation pattern it evokes in the brain—the “domain profile”. A domain gauge provides, for any tested intervention, a “classifier” as a measure of response strength with respect to the domain in question, and a “differentiator” as a measure of deviation from the domain profile, both along with error ranges.
Capitalizing on our in-house database with an unprecedented wealth of standardized perfusion-based phMRI data obtained from rats subjected to various validated treatments, we exemplarily focused on 3 domains based on therapeutic indications: an antipsychotic, an antidepressant and an anxiolytic domain. The domain profiles identified as part of the gauge definition process, as well as the outputs of the gauges when applied to both reference and validation data, were evaluated for their reconcilability with prior biological knowledge and for their performance in drug characterization.
The domain profiles provided quantitative activation patterns with high biological plausibility. The antipsychotic profile, for instance, comprised key areas (e.g., cingulate cortex, nucleus accumbens, ventral tegmental area, substantia nigra) which are believed to be strongly involved in mediating an antipsychotic effect, and which are in line with network-level dysfunctions observed in schizophrenia. The domain gauges plausibly positioned the vast majority of the pharmacological and even non-pharmacological treatments. The results also suggest the segregation of sub-domains based on, e.g., the mode of action. Upon judicious selection of domains and careful calibration of the gauges, our approach represents a valuable analytical tool for biological interpretation and decision making in drug discovery.
Acute challenge with d-fenfluramine decreases regional cerebral glucose utilization in Sham, but not in OBX, rats: An autoradiographic study
2010, Brain Research
The olfactory bulbectomized (OBX) rat is an animal model of depression with neurochemical, neuroendocrinological and behavioral features resembling some human depression. d-Fenfluramine is a 5-HT releasing drug, frequently used in the study of the responsivity of the 5-HT system in subjects with psychiatric disorders, including depression. The aim of the study is to assess the influence of the serotonin-releaser, d-fenfluramine, in the OBX rat model of depression, as measured by the change in the regional cerebral glucose utilization rCGU) following d-fenfluramine injection. Male Sprague–Dawley rats (160–180 g) were used. The rats were divided into OBX and Sham groups. Two weeks following the olfactory bulbectomy or the sham surgery, six rats (randomly assigned) from each group received an i.p. injection of d-fenfluramine with a dose of 5 mg/kg or the same volume of saline. Twenty minutes later, the rCGU rates were measured using 2-[¹⁴C]deoxyglucose autoradiography. The general linear model statistical analysis has shown that the rCGU in the sham-operated rats treated with d-fenfluramine, compared to the sham-operated rats treated with saline, was lower in 14 (36%) out of 39 examined brain regions. There was no significant difference in the rCGU between the OBX rats treated with d-fenfluramine and OBX rats treated with saline. The results suggest the blunted capacity of the 5-HT system in OBX rats to respond to the challenge by the 5-HT releasing compound, d-fenfluramine. This resembles similar findings in clinical studies on depressed patients.
Modulation of behavior and cortical motor activity in healthy subjects by a chronic administration of a serotonin enhancer
2005, NeuroImage
SSRIs are postulated to modulate motor behavior. A single dose of selective serotoninergic reuptake inhibitors (SSRIs) like fluoxetine, paroxetine, or fluvoxamine, has been shown to improve motor performance and efficiency of information processing for simple sensorimotor tasks in healthy subjects. At a cortical level, a single dose of SSRI was shown to induce a hyperactivation of the primary sensorimotor cortex (S1M1) involved in the movement (Loubinoux, I., Boulanouar, K., Ranjeva, J. P., Carel, C., Berry, I., Rascol, O., Celsis, P., and Chollet, F., 1999. Cerebral functional magnetic resonance imaging activation modulated by a single dose of the monoamine neurotransmission enhancers fluoxetine and fenozolone during hand sensorimotor tasks. J. Cereb. Blood Flow Metab. 19 1365–1375, Loubinoux, I., Pariente, J., Boulanouar, K., Carel, C., Manelfe, C., Rascol, O., Celsis, P., and Chollet, F., 2002. A Single Dose of Serotonin Neurotransmission Agonist Paroxetine Enhances Motor Output. A double-blind, placebo-controlled, fMRI study in healthy subjects. NeuroImage 15 26–36). Since SSRIs are usually given for several weeks, we assessed the behavioral and cerebral effects of a one-month chronic administration of paroxetine on a larger group. In a double-blind, placebo controlled and crossover study, 19 subjects received daily 20 mg paroxetine or placebo, respectively, over a period of 30 days separated by a wash-out period of 3 months. After each period, the subjects underwent an fMRI (active or passive movement, dexterity task, sensory discrimination task) and a behavioral evaluation. Concurrently, a TMS (transcranial magnetic stimulation) study was conducted (Gerdelat-Mas, A., Loubinoux, I., Tombari, D., Rascol, O., Chollet, F., Simonetta-Moreau, M., 2005. Chronic administration of selective serotonin re-uptake inhibitor (SSRI) paroxetine modulates human motor cortex excitability in healthy subjects. NeuroImage 27 314–322). Results: On the one hand, paroxetine improved motor performances at the finger tapping test (P = 0.02) without affecting choice reaction time, strength and dexterity significantly. Subjects were also faster in processing the spatial incongruency between a stimulus and the motor response (P = 0.04). In order to differentiate behavioral components, a principal component analysis was performed on all motor tests, and several characteristics were differentiated: strength, speed, skill, attention, and motor response coding. Paroxetine would improve the efficiency of motor response coding (MANOVA on the factors; factor 3, P = 0.01). On the other hand, the chronic administration induced a significant hypoactivation of S1M1 whatever the task: motor or sensory, simple or complex (random effect analysis, P < 0.05). The hypoactivation correlated with the improvement of performances at the finger tapping test (P < 0.05) suggesting more efficiency in cerebral motor processing. Conclusions: Our results showed a clear modulation of sensory and motor cerebral activation after a chronic paroxetine administration. An improvement in both behavior and cerebral efficiency was suggested. It could be hypothesized that monoamines, by an unspecific effect, may tune the response of pyramidal neurons to optimize performances.
Gender differences in a fenfluramine-activated FDG PET study of borderline personality disorder
2005, Psychiatry Research - Neuroimaging
Neuroimaging studies of impulsive–aggressive subjects with borderline personality disorder (BPD) demonstrate hypometabolism in areas of prefrontal and frontal cortex, and a blunted cortical metabolic response to challenge with serotonergic agonists. Neuroendocrine responses to serotonergic challenge are known to vary greatly by gender, and may be related to sex differences in expression of impulsive aggression. We conducted single-blind, placebo-controlled fenfluramine-activated positron emission tomography (PET) studies in impulsive male and female subjects with BPD to look for gender differences in cortical response. The sample comprised 22 BPD (15 female, 7 male) and 24 control subjects (10 female, 14 male) who received placebo on Day 1 and d,l-fenfluramine on Day 2 before PET neuroimaging. In response to placebo, female, but not male, controls had areas of increased uptake of fluorodeoxyglucose-F18 in prefrontal cortex compared with BPD subjects, with greatest uptake in the medial orbital frontal cortex, bilaterally. Male, but not female, BPD subjects, showed areas of increased glucose utilization compared with controls in large areas of parietal and occipital cortex, bilaterally. In response to fenfluramine (relative to placebo), significant decreases in glucose uptake were found in male, but not female, BPD subjects, centered in the left temporal lobe. Female, but not male, control subjects showed significantly decreased uptake in areas of right frontal and temporal cortex. Covarying for impulsive-aggression rendered nonsignificant the gender differences in responses to placebo or fenfluramine. Gender differences in serotonergic function may mediate differences in behavioral expression of impulsive aggression in subjects with BPD.
Regional brain responses to serotonin in major depressive disorder
2004, Journal of Affective Disorders
Background: Positron Emission Tomography (PET) studies have reported altered resting regional brain glucose metabolism in mood disorders. This study examines the relationship of such changes to serotonin system abnormalities associated with depression. Methods: Thirteen male medication free subjects who were inpatients with a DSM-IIIR major depressive disorder and seven healthy male subjects underwent an [¹⁸F]-fluorodeoxyglucose (¹⁸FDG) PET scan on consecutive days. Three hours prior to ¹⁸FDG subjects received single blind placebo or fenfluramine. Comparisons of voxel level regional glucose metabolic rate responses (rCMRglu) between groups in the two states were performed with SPM99. Results: Unlike healthy male subjects who have significant increases in rCMRglu in prefrontal and parietal cortical regions after receiving fenfluramine, depressed male subjects have no significant increases in rCMRglu. Conclusions: Blunted increases in rCMRglu in response to fenfluramine in prefrontal and parietal cortex are consistent with our previous pilot study and the indoleamine hypothesis of depression. Differences in specific brain regions affected between this study and previous studies may be attributable to gender differences.
Low N-acetyl-aspartate and high choline in the anterior cingulum of recently abstinent methamphetamine-dependent subjects: A preliminary proton MRS study
2002, Psychiatry Research - Neuroimaging
Studies based on animal models report that methamphetamine (MA) abuse diminishes dopamine (DA) and serotonin innervation in frontal brain regions. In this in vivo human study, we used proton magnetic resonance spectroscopy (MRS), which yields measures of N-acetyl-aspartate (NAA), a marker of living neurons, to examine frontal brain regions possibly affected by methamphetamine dependence (MD). We tested the hypothesis that MD subjects would exhibit abnormally low levels of NAA, referenced to creatine (Cr), in anterior cingulate gray matter. We further hypothesized that the primary visual cortex, which receives relatively less DA innervation than the frontal brain regions, would show normal NAA/Cr ratios in MD subjects. Subjects included nine MD men (mean±standard deviation (S.D.)=32.5±6.4 years) and nine age-matched control men (mean±S.D.=32.7±6.8 years). The MD subjects were MA-free for 4–13 weeks. Proton MRS metabolites were expressed as ratios of creatine; the absolute values of which did not distinguish controls and MD subjects. With regard to metabolite ratios, the MD men had significantly lower NAA/Cr in the cingulum (mean±standard error (S.E.): control=1.46±0.03; MD=1.30±0.03; Mann–Whitney P=0.01) but not in the visual cortex (mean±S.E.: control=1.64±0.06; MD=1.69±11; Mann–Whitney P=0.52) relative to controls. These results provide evidence for NAA/Cr deficit that is selective to the anterior cingulum, at least with respect to visual cortex, in MD subjects. The neuronal compromise that these changes reflect may contribute to the attentional deficits and dampened reward system in MD.

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Modulation of cortical neuronal activity by a serotonergic agent: a PET study in humans

Abstract

Brain Res.

Brain Res.

Brain Res.

Prog. Neurobiol.

Brain Res.

Biol. Psychiatry

Physical validation of statistical parametric mapping

J. Cereb. Blood Flow Metab.