Potential for imaging the high-affinity state of the 5-HT1B receptor: a comparison of three PET radioligands with differing intrinsic activity

Abstract Background Over the last decade, a few radioligands have been developed for PET imaging of brain 5-HT1B receptors. The 5-HT1B receptor is a G-protein-coupled receptor (GPCR) that exists in two different agonist affinity states. An agonist ligand is expected to be more sensitive towards competition from another agonist, such as endogenous 5-HT, than an antagonist ligand. It is of interest to know whether the intrinsic activity of a PET radioligand for the 5-HT1B receptor impacts on its ability to detect changes in endogenous synaptic 5-HT density. Three high-affinity 11C-labeled 5-HT1B PET radioligands with differing intrinsic activity were applied to PET measurements in cynomolgus monkey to evaluate their sensitivity to be displaced within the brain by endogenous 5-HT. For these experiments, fenfluramine was pre-administered at two different doses (1.0 and 5.0 mg/kg, i.v.) to induce synaptic 5-HT release. Results A dose-dependent response to fenfluramine was detected for all three radioligands. At the highest dose of fenfluramine (5.0 mg/kg, i.v.), reductions in specific binding in the occipital cortex increased with radioligand agonist efficacy, reaching 61% for [11C]3. The most antagonistic radioligand showed the lowest reduction in specific binding. Conclusions Three 5-HT1B PET radioligands were identified with differing intrinsic activity that could be used in imaging high- and low-affinity states of 5-HT1B receptors using PET. From this limited study, radioligand sensitivity to endogenous 5-HT appears to depend on agonist efficacy. More extensive studies are required to substantiate this suggestion.

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Characterization of muscarinic cholinergic receptors in cat tracheal gland cells

Journal of Applied Physiology ◽

10.1152/jappl.1986.61.4.1375 ◽

1986 ◽

Vol 61 (4) ◽

pp. 1375-1382 ◽

Cited By ~ 6

Author(s):

D. J. Culp ◽

M. G. Marin

Keyword(s):

Muscarinic Receptors ◽

Specific Binding ◽

Isolated Cells ◽

High Affinity ◽

Gland Cells ◽

Beta Adrenergic Agonists ◽

Muscarinic Cholinergic ◽

Dose Dependent ◽

Nanomolar Range

Studies of airway glands indicate a muscarinic cholinergic regulation of secretion. Because of the cellular complexity of the airways, receptor characterization in whole tissue is unfeasible. Therefore, we utilized homogenates of disaggregated gland cells isolated from cat trachea and the muscarinic antagonist [1–3H]quinuclidinyl benzilate ([3H]QNB) to characterize glandular muscarinic receptors. Receptors of isolated cells were functionally intact as assessed by carbachol (10(-4) M) stimulation of O2 consumption 86 +/- 6% (+/- SE, n = 20). Stimulation was dose dependent (mean effective concentration = 3.5 microM), inhibited by atropine [dissociation constant (KD) = 4.2 nM] but not phentolamine nor propranolol. Specific binding of [3H]QNB to cell homogenates was saturable, of high affinity (KD = 36 pM) and to a single population of receptors. Maximum binding was 58 fmol/10(6) cells or about 35,000 receptors per cell. Estimated affinities for muscarinic agents were in the micromolar range for agonists and nanomolar range for antagonists. Histamine, alpha-adrenergic, and beta-adrenergic agonists and antagonists did not inhibit specific binding. These results suggest that muscarinic receptors on tracheal gland cells are of high affinity and density.

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The neurobiology and evolution of cannabinoid signalling

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2000.0787 ◽

2001 ◽

Vol 356 (1407) ◽

pp. 381-408 ◽

Cited By ~ 254

Author(s):

Maurice R. Elphick ◽

Michaelà Egertova

Keyword(s):

G Protein ◽

Cannabinoid Receptors ◽

Cannabis Sativa ◽

Specific Binding ◽

Acid Amide ◽

Presynaptic Terminals ◽

Smooth Muscle Contractility ◽

Signalling System ◽

G Protein Coupled ◽

The Brain

The plant Cannabis sativa has been used by humans for thousands of years because of its psychoactivity. The major psychoactive ingredient of cannabis is δ 9 –tetrahydrocannabinol, which exerts effects in the brain by binding to a G–protein–coupled receptor known as the CB 1 cannabinoid receptor. The discovery of this receptor indicated that endogenous cannabinoids may occur in the brain, which act as physiological ligands for CB 1 . Two putative endocannabinoid ligands, arachidonylethanolamide (‘anandamide’) and 2–arachidonylglycerol, have been identified, giving rise to the concept of a cannabinoid signalling system. Little is known about how or where these compounds are synthesized in the brain and how this relates to CB 1 expression. However, detailed neuroanatomical and electrophysiological analysis of mammalian nervous systems has revealed that the CB 1 receptor is targeted to the presynaptic terminals of neurons where it acts to inhibit release of ‘classical’ neurotransmitters. Moreover, an enzyme that inactivates endocannabinoids, fatty acid amide hydrolase, appears to be preferentially targeted to the somatodendritic compartment of neurons that are postsynaptic to CB 1 –expressing axon terminals. Based on these findings, we present here a model of cannabinoid signalling in which anandamide is synthesized by postsynaptic cells and acts as a retrograde messenger molecule to modulate neurotransmitter release from presynaptic terminals. Using this model as a framework, we discuss the role of cannabinoid signalling in different regions of the nervous system in relation to the characteristic physiological actions of cannabinoids in mammals, which include effects on movement, memory, pain and smooth muscle contractility. The discovery of the cannabinoid signalling system in mammals has prompted investigation of the occurrence of this pathway in non–mammalian animals. Here we review the evidence for the existence of cannabinoid receptors in non–mammalian vertebrates and invertebrates and discuss the evolution of the cannabinoid signalling system. Genes encoding orthologues of the mammalian CB 1 receptor have been identified in a fish, an amphibian and a bird, indicating that CB 1 receptors may occur throughout the vertebrates. Pharmacological actions of cannabinoids and specific binding sites for cannabinoids have been reported in several invertebrate species, but the molecular basis for these effects is not known. Importantly, however, the genomes of the protostomian invertebrates Drosophila melanogaster and Caenorhabditis elegans do not contain CB 1 orthologues, indicating that CB 1 –like cannabinoid receptors may have evolved after the divergence of deuterostomes (e.g. vertebrates and echinoderms) and protostomes. Phylogenetic analysis of the relationship of vertebrate CB 1 receptors with other G–protein–coupled receptors reveals that the paralogues that appear to share the most recent common evolutionary origin with CB 1 are lysophospholipid receptors, melanocortin receptors and adenosine receptors. Interestingly, as with CB 1 , each of these receptor types does not appear to have Drosophila orthologues , indicating that this group of receptors may not occur in protostomian invertebrates. We conclude that the cannabinoid signalling system may be quite restricted in its phylogenetic distribution, probably occurring only in the deuterostomian clade of the animal kingdom and possibly only in vertebrates.

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High-affinity choline uptake in regions of rat brain and the effect of antidepressants

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y79-091 ◽

1979 ◽

Vol 57 (6) ◽

pp. 595-599 ◽

Cited By ~ 5

Author(s):

P. D. Hrdina ◽

K. Elson

Keyword(s):

Rat Brain ◽

Tricyclic Antidepressants ◽

Brain Regions ◽

Choline Uptake ◽

Dependent Manner ◽

Choline Transport ◽

High Affinity ◽

Michaelis Constants ◽

Dose Dependent ◽

The Brain

The effect of tricyclic antidepressants, chlorpromazine, and some monoamine oxidase inhibitors on the accumulation of [14C]choline by crude synaptosomal (P2) fraction from different regions of rat brain (cortex, striatum, and hippocampus) was investigated. Analysis of choline uptake kinetics resulted in high- and low-affinity components with different Michaelis constants. All tricyclic antidepressants tested inhibited in a dose-dependent manner the high-affinity choline uptake in the three regions, amitriptyline being the most potent. The IC50 values correlated significantly with the relative potencies of imipramine congeners in binding to muscarinic receptors in the brain. Neither tranylcypromine nor pargyline in concentrations up to 0.1 mM had any effect on choline transport. Concentrations of tricyclic antidepressants effective in inhibiting the uptake of choline failed to influence significantly the activity of choline acetyltransferase in brain regions examined. The results suggest that the effect of imipramine congeners on high-affinity choline uptake may be reflected in the anticholinergic properties of these compounds.

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Evidence of increased brain amyloid in severe TBI survivors at 1, 12, and 24 months after injury: report of 2 cases

Journal of Neurosurgery ◽

10.3171/2015.6.jns15639 ◽

2016 ◽

Vol 124 (6) ◽

pp. 1646-1653 ◽

Cited By ~ 12

Author(s):

Joshua W. Gatson ◽

Cari Stebbins ◽

Dana Mathews ◽

Thomas S. Harris ◽

Christopher Madden ◽

...

Keyword(s):

Caudate Nucleus ◽

Pet Imaging ◽

Rating Scale ◽

Occipital Cortex ◽

Standard Uptake Value ◽

Severe Trauma ◽

Brain Regions ◽

Severe Tbi ◽

The Brain ◽

Time Point

Traumatic brain injury (TBI) is a major risk factor for Alzheimer’s disease. With respect to amyloid deposition, there are no published serial data regarding the deposition rate of amyloid throughout the brain after TBI. The authors conducted serial 18F-AV-45 (florbetapir F18) positron emission tomography (PET) imaging in 2 patients with severe TBI at 1, 12, and 24 months after injury. A total of 12 brain regions were surveyed for changes in amyloid levels. Case 1 involved a 50-year-old man who experienced a severe TBI. Compared with the 1-month time point, of the 12 brain regions that were surveyed, a decrease in amyloid (as indicated by standard uptake value ratios) was only observed in the hippocampus (−16%, left; −12%, right) and caudate nucleus (−18%, left; −18%, right), suggesting that initial amyloid accumulation in the brain was cleared between time points 1 and 12 months after injury. Compared to the scan at 1 year, a greater increase in amyloid (+15%) was observed in the right hippocampus at the 24-month time point. The patient in Case 2 was a 37-year-old man who suffered severe trauma to the head and a subsequent stroke; he had poor cognitive/functional outcomes and underwent 1.5 years of rehabilitation. Due to a large infarct area on the injured side of the brain (right side), the authors focused primarily on brain regions affected within the left hemisphere. Compared with the 1-month scan, they only found an increase in brain amyloid within the left anterior putamen (+11%) at 12 months after injury. In contrast, decreased amyloid burden was detected in the left caudate nucleus (−48%), occipital cortex (−21%), and precuneus (−19%) brain regions at the 12-month time point, which is indicative of early accumulation and subsequent clearance. In comparison with 12-month values, more clearance was observed, since a reduction in amyloid was found at 24 months after trauma within the left anterior putamen (−12%) and occipital cortex (−15%). Also, by 24 months, most of the amyloid had been cleared and the patient demonstrated improved results on the Rivermead symptom questionnaire, Glasgow Outcome Scale-Extended, and Disability Rating Scale. With respect to APOE status, the patient in Case 1 had two ε3 alleles and the patient in Case 2 had one ε2 and one ε3 allele. In comparison to the findings of the initial scan at 1 month after TBI, by 12 and 24 months after injury amyloid was cleared in some brain regions and increased in others. Serial imaging conducted here suggests that florbetapir F18 PET imaging may be useful in monitoring amyloid dynamics within specific brain regions following severe TBI and may be predictive of cognitive deficits.

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Confirmation of Fenfluramine Effect on 5-HT1B Receptor Binding of [11C]AZ10419369 using an Equilibrium Approach

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2011.172 ◽

2011 ◽

Vol 32 (4) ◽

pp. 685-695 ◽

Cited By ~ 27

Author(s):

Sjoerd J Finnema ◽

Andrea Varrone ◽

Tzung-Jeng Hwang ◽

Christer Halldin ◽

Lars Farde

Keyword(s):

Specific Binding ◽

Occipital Cortex ◽

Serotonin Release ◽

Binding Potential ◽

Bolus Administration ◽

Positron Emission ◽

Equilibrium Approach ◽

Induced Changes ◽

Dose Dependent

Assessment of serotonin release in the living brain with positron emission tomography (PET) may have been hampered by the lack of suitable radioligands. We previously reported that fenfluramine caused a dose-dependent reduction in specific binding in monkeys using a classical displacement paradigm with bolus administration of [11C]AZ10419369. The aim of this study was to confirm our previous findings using an equilibrium approach in monkey. A total of 24 PET measurements were conducted using a bolus infusion protocol of [11C]AZ10419369 in three cynomolgus monkeys. Initial PET measurements were performed to assess suitable Kbol values. The fenfluramine effect on [11C]AZ10419369 binding was evaluated in a displacement and pretreatment paradigm. The effect of fenfluramine on [11C]AZ10419369 binding potential ( BPND) was dose-dependent in the displacement paradigm and confirmed in the pretreatment paradigm. After pretreatment administration of fenfluramine (5.0 mg/kg), the mean BPND of the occipital cortex decreased by 39%, from 1.38 ± 0.04 to 0.84 ± 0.09. This study confirms that the new 5-HT1B receptor radioligand [11C]AZ10419369 is sensitive to fenfluramine-induced changes in endogenous serotonin levels in vivo. The more advanced methodology is suitable for exploring the sensitivity limit to serotonin release as measured using [11C]AZ10419369 and PET.

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Identification and characterization of receptors specific for human pancreatic secretory trypsin inhibitor.

Journal of Experimental Medicine ◽

10.1084/jem.172.4.1133 ◽

1990 ◽

Vol 172 (4) ◽

pp. 1133-1142 ◽

Cited By ~ 17

Author(s):

T Niinobu ◽

M Ogawa ◽

A Murata ◽

J Nishijima ◽

T Mori

Keyword(s):

Growth Factor ◽

Trypsin Inhibitor ◽

Thymidine Incorporation ◽

Specific Binding ◽

Membrane Receptors ◽

Scatchard Analysis ◽

Dependent Manner ◽

Pancreatic Secretory Trypsin Inhibitor ◽

High Affinity ◽

Dose Dependent

Specific binding sites for human pancreatic secretory trypsin inhibitor (PSTI) on 3T3 Swiss albino cells were studied using radioiodinated recombinant PSTI. Some ion species, pH, and temperature significantly influenced the binding of 125I-PSTI. Kinetic studies showed that the binding of 125I-PSTI to 3T3 Swiss albino cells reached the maximum level within 120 min at 4 degrees C, with a slow dissociation rate. The half-maximal inhibition (ID50) of 125I-PSTI binding by unlabeled PSTI occurred at 1.0 x 10(-10) M. On Scatchard analysis of the competitive binding data, linear plots indicated a single class of receptors with high affinity (Kd = 5.3 x 10(-10) M) on 3T3 Swiss albino cells, the number of receptors being 5,400 per cell. Treatment of surface-bound radiolabeled PSTI with a chemical crosslinker (disuccinimidyl suberate) led to the identification of a membrane polypeptide of Mr 140,000 to which PSTI was crosslinked. The formation was inhibited by an excess amount of unlabeled PSTI in a dose-dependent manner. The binding of 125I-PSTI to 3T3 Swiss albino cells was competitively inhibited by unlabeled PSTI but not by other peptide hormones, such as epidermal growth factor (EGF), bovine fibroblast growth factor, insulin-like growth factor, transforming growth factor alpha, platelet-derived growth factor, and tumor necrosis factor, indicating the presence of receptors specific for PSTI. Various protease inhibitors had no or only a little effect, and mercaptoethanol and dithiothreitol strongly decreased the binding of 125I-PSTI. Incubation at 37 degrees C resulted in rapid internalization of cell-bound 125I-PSTI, followed by the appearance of trichloroacetic acid-soluble 125I-radioactivity in the culture medium, due to degradation of internalized PSTI. In addition, PSTI stimulated [3H]thymidine incorporation into DNA on 3T3 Swiss albino cells in a dose-dependent manner. The combined addition of PSTI and EGF stimulated [3H]thymidine incorporation to an extent greater than that seen with either agent alone. These results indicated that the biological effect of PSTI was mediated by high affinity plasma membrane receptors, which were not a cell-surface proteinase(s). Specific binding of 125I-PSTI was noted with the following cells: WI-38, 3T3 Swiss albino, HUVE, BDC-1, and H4-II-E-C3.

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Hydroxychloroquine increased psychiatric-like behaviors and disrupted the expression of related genes in the mouse brain

10.1101/2020.09.27.316158 ◽

2020 ◽

Author(s):

H Xu ◽

XY Zhang ◽

WW Wang ◽

JS Wang

Keyword(s):

Mental Health ◽

Mrna Expression ◽

Drug Administration ◽

Psychiatric Symptoms ◽

Clinical Investigation ◽

Significant Risk ◽

Prophylactic Drug ◽

Dose Dependent ◽

The Brain ◽

Different Doses

AbstractHydroxychloroquine (HCQ), which has been proposed as a therapeutic or prophylactic drug for SARS-COV-2, has been administered to thousands of individuals with varying efficacy; however, our understanding of its adverse effects is insufficient. It was reported that HCQ induced psychiatric symptoms in a few patients with autoimmune diseases, but it is still uncertain whether HCQ poses a risk to mental health. Therefore, in this study, we treated healthy mice with two different doses of HCQ that are comparable to clinically administered doses for 7 days. Psychiatric-like behaviors and the expression of related molecules in the brain were evaluated at two time points, i.e., 24 h and 10 days after drug administration. We found that HCQ increased anxiety behavior at both 24 h and 10 days and enhanced depressive behavior at 24 h. Furthermore, HCQ decreased the mRNA expression of interleukin-1beta and corticotropin-releasing hormone (Crh) in the hippocampus and decreased the mRNA expression of brain-derived neurotrophic factor (Bdnf) in both the hippocampus and amygdala. Most of these behavioral and molecular changes were sustained beyond 10 days after drug administration, and some of them were dose-dependent. Although this animal study does not prove that HCQ has a similar effect in humans, it indicates that HCQ poses a significant risk to mental health and suggests that further clinical investigation is essential. According to our data, we recommend that HCQ be carefully used as a prophylactic drug in people who are susceptible to mental disorders.

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The effects of interleukin-10 and fibroblasts growth factor-2 in mice with toxic cuprizone model of demyelination

Cell and Organ Transplantology ◽

10.22494/cot.v7i1.93 ◽

2019 ◽

Vol 7 (1) ◽

Author(s):

I. Labunets ◽

A. Rodnichenko ◽

N. Utko ◽

T. Panteleimonova ◽

Ya. Pokholenko ◽

...

Keyword(s):

Nervous System ◽

Growth Factor ◽

Interleukin 10 ◽

Antioxidant Defence ◽

Positive Effects ◽

Test Parameters ◽

Human Proteins ◽

Dose Dependent ◽

The Brain ◽

Different Doses

Cytokines and growth factors exhibit neurotropic, anti-inflammatory and immunomodulatory properties, and therefore can affect the functioning of the nervous system at demyelinating disorders.Purpose. To identify changes in T-lymphocytes, macrophages, oxidative stress and antioxidant defence factors, endocrine thymus function in the brain and behaviour of mice receiving neurotoxin cuprizone and recombinant human proteins: interleukin-10 (rhIL-10) and fibroblast growth factor (rhFGF-2).Materials and methods. 4-6-month-old 129/Sv mice received cuprizone with food every day for 3 weeks. From the 7th day of cuprizone diet, they received different doses of rhIL-10 and rhFGF-2. The content of СD3+ Т-cells, macrophages, malondialdehyde, activity of antioxidant enzymes in the brain and the level of thymulin in the blood were determined. Behavioural reactions were assessed in the “open field” test.Results. In the brain of mice receiving cuprizone and rhIL-10, there was a decrease in the number of СD3+ Т-cells and the activity of macrophages, which significantly increased under the influence of the toxin. After cytokine injection, the activity of superoxide dismutase, catalase and glutathione peroxidase increased significantly in the brain, as well as the level of thymulin in the blood. Motor, emotional and exploratory activity of mice, significantly suppressed by the cuprizone, was increased after the introduction of rhIL-10. The effect of rhIL-10 on the test parameters is more pronounced at a dose of 5 μg/kg than 50 μg/kg. After injection of rhFGF-2 in the mice with cuprizone diet, there is a decrease in the activity of brain macrophages and an increase of the level of thymulin in the blood depending on the dose of this factor; the motor activity of these animals increased regardless of the rhFGF-2 dose.Conclusion. The injections of rhIL-10 and rhFGF-2 provide dose-dependent positive effects on the pathogenetic factors of experimental demyelinating pathology, as well as the functional state of the nervous system. Whereas, the injections of rhIL-10 have more pronounced effects.

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Trapping of Nicotinic Acetylcholine Receptor Ligands Assayed by in vitro Cellular Studies and in vivo PET Imaging

10.1101/2021.12.08.471775 ◽

2021 ◽

Author(s):

Hannah Zhang ◽

Chien-Min Kao ◽

Matthew Zammit ◽

Anitha P Govind ◽

Samuel Mitchell ◽

...

Keyword(s):

Residence Time ◽

Pet Imaging ◽

Nicotinic Receptors ◽

Receptor Ligands ◽

Ph Gradients ◽

High Affinity ◽

Acidic Vesicles ◽

The Brain

A question relevant to nicotine addiction is how nicotine and other nicotinic receptor membrane-permeant ligands, such as the anti-smoking drug varenicline (Chantix), distribute in the brain. Previously, we found that varenicline is trapped in intracellular acidic vesicles that contain α4β2-type nicotinic receptors (α4β2Rs). Nicotine is not trapped but concentrates there. Here, combining subcellular methods with in vivo PET imaging, we present evidence that the α4β2R PET ligand, 2-FA85380 (2-FA), is trapped within α4β2R-containing acidic vesicles, while the PET ligand, Nifene, is not trapped. Additional evidence, using a fluorescent-tagged α4β2R PET ligand, Nifrolidine, identified the trapping vesicles as Golgi satellites, an organelle regulated by nicotine in neurons where α4β2Rs are expressed and traffics and processes α4β2Rs in those neurons. Using PET imaging, 2-[18F]FA kinetics in high α4β2R-expressing regions were much slower than ligand unbinding rates consistent with 2-FA trapping in Golgi satellites extending ligand residence time and 2-[18F]FA imaging of the Golgi satellites. Chloroquine, which dissipates acidic organelle pH gradients, reduced 2-[18F]FA distribution in vivo consistent with ligand trapping. In contrast, [18F]Nifene kinetics were rapid, consistent with ligand residence time reflecting ligand unbinding rates, and [18F]Nifene imaging all α4β2R pools. Specific 2-[18F]FA and [18F]Nifene signals were eliminated in β2 subunit knockout mice or by acute nicotine injections demonstrating binding to high-affinity sites on β2-containing receptors. Altogether, we find that kinetic differences in α4β2R PET ligands are consistent with their distribution among different α4β2R pools in the brain, [18F]Nifene binding and imaging all ligand-binding α4β2Rs and 2-[18F]FA imaging α4β2Rs in Golgi satellites.

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Hydroxychloroquine Increased Anxiety-Like Behaviors and Disrupted the Expression of Some Related Genes in the Mouse Brain

Frontiers in Pharmacology ◽

10.3389/fphar.2021.633112 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hang Xu ◽

Xiang Yang Zhang ◽

Wei Wen Wang ◽

Jiesi Wang

Keyword(s):

Mental Health ◽

Mrna Expression ◽

Drug Administration ◽

Psychiatric Symptoms ◽

Clinical Investigation ◽

Significant Risk ◽

Prophylactic Drug ◽

Dose Dependent ◽

The Brain ◽

Different Doses

Hydroxychloroquine (HCQ), which has been proposed as a therapeutic or prophylactic drug for COVID-19, has been administered to thousands of individuals with varying efficacy; however, our understanding of its adverse effects is insufficient. It was reported that HCQ induced psychiatric symptoms in a few patients with autoimmune diseases, but it is still uncertain whether HCQ poses a risk to mental health. Therefore, in this study, we treated healthy mice with two different doses of HCQ that are comparable to clinically administered doses for 7 days. Psychiatric-like behaviors and the expression of related molecules in the brain were evaluated at two time points, i.e., 24 h and 10 days after drug administration. We found that HCQ increased anxiety behavior at both 24 h and 10 days. Furthermore, HCQ decreased the mRNA expression of interleukin-1beta, corticotropin-releasing hormone (Crh), a serotonin transporter (Slc6a4), and a microglia maker (Aif1) in the hippocampus and decreased the mRNA expression of brain-derived neurotrophic factor (Bdnf) in both the hippocampus and amygdala. Lots of these behavioral and molecular changes were sustained beyond 10 days after drug administration, and some of them were dose-dependent. Although this animal study does not prove that HCQ has a similar effect in humans, it indicates that HCQ poses a significant risk to mental health and suggests that further clinical investigation is essential. According to our data, we recommend that HCQ be carefully used as a prophylactic drug in people who are susceptible to mental disorders.

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