D-amphetamine is a potent serotonin releaser [ 19 , 20 , 22 , 36 ] although usually seen as an agent for dopamine and noradrenaline release. In contrast to fenfluramine which was withdrawn from the market two decades ago [ 38 ], d-amphetamine is readily available for human research and is considered to be safe as an acute pharmacological challenge.
In multiple studies conducted in our centre, d-amphetamine demonstrated very good tolerability and low level of adverse events [ 30 , 31 , 33 ]. Overall, available data strongly supports the conclusion that the observed d-amphetamine-induced reduction of [ 11 C]CIMBI BP ND can be interpreted as a consequence of increased extracellular serotonin. Our subjects may have had some changes in arousal following amphetamine administration, potentially introducing a small additional contribution the signal change we observed.
Importantly, these studies not only focused on release of two transmitters known to be directly involved in reward processing for reviews, please see [ 44 ] and [ 45 ] for opioid and dopamine systems, respectively , but also reported specifically from the ventral striatum, a key region for rewarding effects of substances [ 46 ]. As the cerebellum serves as the reference region used in the calculation of the BP ND , changes in the cerebellar V T should be assessed carefully to estimate their impact on the study findings.
In our case, the magnitude of the reduction is small, and cannot explain a reduction in cortical BP ND , as it would lead to an increase rather than a decrease in the cortical BP ND , moderating any reductions due to serotonin release.
An analysis not requiring the use of an arterial plasma input function such as a simplified reference tissue model—SRTM would provide significant advantages with regard to study logistics, costs and subject comfort. The latter factor may be particularly relevant in a study using a highly vasoactive challenge such as d-amphetamine challenge, that may result in changes in vascular parameters that would be particularly notable in a region with very low binding, such as the cerebellum.
We have no robust explanation, but may speculate about the potential mechanisms underlying such an effect. If significant differences in synaptic 5-HT concentration are present across individuals, and the absolute magnitude of 5-HT released by a given dose of d-amphetamine were similar across individuals rather than being a function of the baseline 5-HT concentration —then a relationship between baseline [ 11 C]CIMBI BP ND and the magnitude of d-amphetamine induced change, similar to the one we observed, would be expected.
Similarly to the unsuccessful previous attempts to develop a neuroimaging method to assess acute serotonin release using 5-HT 2A radioligands [ 8 , 9 ], studies using 5-HT 1A selective radioligands such as [ 11 C]WAY and [ 11 C]CUMI have also produced mixed results. A paradoxical effect increases in radioligand binding following the administration of the selective serotonin reuptake inhibitor citalopram has been reported in two other studies using serotonin 5-HT 1A [ 13 ] and 5-HT 1B [ 14 ] antagonist radioligands.
The authors explained their results by hypothesizing a reduction in 5-HT release in the terminal fields, due to the activity of increased 5-HT on the inhibitory somatodendritic 5-HT 1A autoreceptors in the raphe nuclei, consistent with some microdialysis data in rodents [ 47 , 48 ]. Such an explanation would be consistent with a reduction in radioligand binding in the raphe region in these studies, but this has not been conclusively demonstrated.
The inconsistent results above may therefore reflect the deficiency of many of the pharmacological paradigms used to date, to elicit large magnitude release of 5-HT. Recent data also suggest that the pharmacological response in terms of serotonin release may be highly interindividually different [ 18 ].
The limited sensitivity of the antagonist radioligands used to date, to detect the binding of the agonist serotonin, is a contributory factor. Serotonin releasers such as fenfluramine and amphetamine are known to produce significantly higher change in extracellular serotonin levels compared with the challenges above.
Microdialysis evaluation in the pig brain found a fold increase in extracellular serotonin concentration following a 0. This fixed order raises the possibility of an order effect—due to either a systemic variation serotonin 2A receptor binding, or serotonin levels due to diurnal variability or a non-specific effects of the experimental procedures—such as a difference in anxiety levels between baseline- and post-d-amphetamine scans or due to a direct occupancy effect of the unlabelled CIMBI carried over from the baseline d-amphetamine scan.
We do not believe these considerations are relevant for the explanation of our data. In conclusion, we find that cerebral [ 11 C]CIMBI binding is sensitive to acute synaptic serotonin release in the human brain, and when combined with a d-amphetamine challenge the human brain serotonin system can be evaluated in neuropsychiatric disorders, such as major depression. There were no conflicts of interests to declare for this study.
Laruelle M. Imaging synaptic neurotransmission with in vivo binding competition techniques: a critical review. J Cereb Blood Flow Metab. Measuring endogenous 5-HT release by emission tomography: promises and pitfalls. Comparison of [ 18 F]altanserin and [ 18 F]deuteroaltanserin for PET imaging of serotonin 2A receptors in baboon brain: pharmacological studies.
Nucl Med Biol. Acute S-ketamine application does not alter cerebral [ 18 F]altanserin binding: a pilot PET study in humans. J Neural Transm Vienna. Med Res Rev. Application of cross-species PET imaging to assess neurotransmitter release in brain.
Influence of synaptic serotonin level on [ 18 F]altanserin binding to 5HT2 receptors in man. Behav Brain Res. Assessment of serotonin release capacity in the human brain using dexfenfluramine challenge and [ 18 F]altanserin positron emission tomography. Decreased [ 18 F]MPPF binding potential in the dorsal raphe nucleus after a single oral dose of fluoxetine: a positron-emission tomography study in healthy volunteers.
Biol Psychiatry. Mol Psychiatry. Effect of a single dose of escitalopram on serotonin concentration in the non-human and human primate brain. Int J Neuropsychopharmacol. Measuring endogenous changes in serotonergic neurotransmission with [ 11 C]Cimbi positron emission tomography in humans. Many of them said that SSRIs worsened their symptoms, while folic acid and vitamin B supplements helped.
Benzodiazepine medications may also help people with low-folate depression. Walsh said that a study of 50 school shootings over the past five decades showed that most shooters probably had this type of depression, as SSRIs can cause suicidal or homicidal ideation in these patients. This type of depression is caused by toxic-metal overload, usually lead poisoning.
Over the years, this type accounted for 5 percent of depressed patients, but removing lead from gasoline and paint has lowered the frequency of these cases. Last month, 66 doctors from Australia were trained in the approach, and training for U. Brendel added that depression likely has many causes and complex neurophysiological underpinnings.
Mona Shattell, PhD, RN, FAAN , professor and department chair of the Department of Community, Systems and Mental Health Nursing, College of Nursing at Rush University in Chicago, said that being able to diagnose depression with a blood test could potentially increase the number of people diagnosed and lead to more people being treated for the condition.
Its current publication date reflects an update, which includes a medical review by Timothy J. For those living with treatment resistant depression, finding an effective treatment can feel like an impossible task. But there are a number of…. Take this quiz to test your knowledge about depression symptoms, causes, treatments, and more. Masked depression is a term psychologists and doctors once used to describe depression with physical symptoms rather than mental or mood symptoms.
Watching a friend live with depression can be painful, but there are ways to help. Learn what to do, avoid, and how to recognize the signs of suicidal…. Although the concentration of monoamines in the brain is not high, multiple tissue micropunches made enough amount of monoamine and 5-HT to match the sensitivity of the assay.
Our results provided a possible role for catecholamines and indolamines in the altered feeding and reproductive behavior of the broiler chicken [ 6 ].
To finish my Ph. The role of monoaminergic neuromodulators in the reorganization of cortical topography following limited sensory deprivation in the adult cat was investigated in this study [ 8 ]. The total concentrations of dopamine, noradrenaline, 5-HT, and their major metabolites were measured in the visual cortex of both control and experimental animals using this microbore LC-ED method. The sensory deprivation cats were subjected to a binocular retinal lesion corresponding to the central 10 degrees of vision and sacrificed 2 weeks post-lesion.
The deprivation was confirmed in area 17 by measuring immediate-early gene if messenger RNA expression. The total concentration of 5-HT was significantly lower in the deprived cortex, and the metabolite of 5-HT, 5-hydroxyindoleacetic acid, was significantly higher in the nondeprived cortex than in deprived cortex and normal cortex.
The levels of noradrenaline and dopamine were significantly higher in the nondeprived cortex of retinal lesion cats than in the deprived cortex of retinal lesion cats and the cortex of normal animals.
This pattern follows the release of the excitatory neurotransmitter glutamate under the same conditions. These results suggest that the modulation of 5-HT, noradrenaline, and dopamine is regulated by visual afferent activity [ 8 ]. To switch my scientific career to the pharmaceutical industry, I joined the CNS drug discovery team for making a new generation dual function SSRI [ 9 ] for depression treatment. In vivo microdialysis has been extensively used to document the changes of extracellular level of 5-HT in the rat brain after administration of fluoxetine [ 11 ].
Animals were allowed at least 3 days to recover from surgery prior to experimentation. Samples were collected every 60 min. Microdialysates were analyzed by LC-ED. Separation was performed on a C18 column. All values for microdialysis studies were calculated as percentage change at each time point compared with the average of three baseline values.
Pharmacokinetic PK characterization and in vivo pharmacological properties of new chemical entities are important components during lead compound selection and optimization in the drug discovery process. When dealing with compounds targeting the central nervous system CNS , biophase PK may differ significantly from plasma PK, because blood-brain barrier BBB transport and brain distribution often do not occur instantaneously and to a full extent.
In vivo microdialysis technique can be used to collect not only the extracellular endogenous substances but also the extracellular free drug in the same local interstitial environment, which may reflect the amount of drug available at the pharmacological target. However, the application of this technique was highly limited by the lack of the proper sensitive analytical methods to determine the endogenous substance and exogenous drug.
The mass spectrometer has minimal baseline drift and can be equilibrated very rapidly. The World Health Organization WHO estimates that more than million individuals of all ages suffer from depression [ 14 ]. SSRIs have been the drugs for depression treatment. These drugs increase 5-HT levels in the synaptic cleft by inhibiting its reuptake into the presynaptic neuron through blockade of the SERT. Although many patients experience relief after treatment with one of the many marketed SSRIs, efficacy is noticeable only after weeks of treatment.
Many physicians are reported to co-prescribe stimulants with SSRI to provide subjective relief during the beginning weeks of antidepressant therapy [ 15 ]. Most of these stimulants are increased dopamine release and produced robust behavioral activation, which had the risk of allowing patients to act on their suicidal ideation.
It is very important to choose other classes of molecules that have been shown to produce wakefulness in animals without releasing dopamine or producing behavioral activation. Wake-promoting agents such as modafinil are used in the clinic as adjuncts to antidepressant therapy in order to alleviate lethargy. Histamine H 3 receptor antagonist has been demonstrated having the wake-promoting action in numerous animal studies and may therefore be a viable strategy for use as an antidepressant therapy in conjunction with SSRIs.
Carcinoid syndrome is a group of symptoms associated with carcinoid tumors. These are tumors of the small intestine, colon, appendix, and bronchial tubes in the lungs. People with carcinoid syndrome often have high levels of serotonin in the blood.
Note: Normal value ranges may vary slightly among different laboratories. Some labs use different measurements or test different samples. Talk to your health care provider about the meaning of your specific test results.
There is little risk in having your blood taken. Veins and arteries vary in size from one person to another, and from one side of the body to the other.
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