5-HT1A Receptor Binding Research Articles

Serotonergic underpinnings of obsessive-compulsive disorder: A systematic review and meta-analysis of neuroimaging findings.

Obsessive-compulsive disorder (OCD) is a frequent and disabling condition, with many patients being treatment-resistant. Improved understanding of its neurobiology is vital for better therapies. Evidence is still conflicting regarding specific serotonergic-related dysfunctions in OCD. We systematically reviewed the literature to provide a quantitative assessment of the role of serotonin (5-HT) in patients with untreated OCD through imaging. We searched for neuroimaging studies investigating central 5-HT tonus in unmedicated patients with OCD, excluding studies comprising treated patients to prevent bias from antidepressant-induced changes in serotonergic tonus. We also conducted a meta-analysis using a homogeneous group of positron emission tomography and single photon emission computed tomography articles that compared 5-HT transporter (SERT) and 5-HT2A receptor (HT2AR) binding potential in different brain regions of patients with untreated OCD and healthy controls. The systematic review encompassed 18 articles, with 13 included in the subsequent meta-analysis. Risk of bias was assessed by a revised form of the Newcastle-Ottawa Scale. We provided standardized mean difference (SMD) values for SERT and 5-HT2AR binding potential measures across 15 different brain regions. Patients with OCD showed lower SERT binding potential in the brainstem (SMD = -1.13,95% CI [-1.81 to -0.46]), midbrain (SMD = -0.54, 95% CI [-0.92 to -0.16]), and thalamus/hypothalamus regions (SMD = -0.58, 95% CI [-0.99 to -0.18]) with neglectable to moderate heterogeneity. By combining results from 2 decades of molecular imaging studies, we show that individuals with OCD exhibit lower SERT binding potential in specific brain regions, providing compelling evidence of a 5-HT system dysfunction. However, the exact mechanisms underlying this phenotype remain elusive. The limitations include heterogeneity across studies in populations, imaging techniques, and radiotracer usage.

Unveiling the power of optimism: Exploring behavioral and neuromolecular correlates of alcohol seeking and drinking in rats with biased judgement

Alcohol use disorder (AUD) is a common psychiatric condition with substantial global mortality. Despite extensive research into its pathophysiology, the cognitive predispositions driving alcohol dependence are less understood. This study explores whether biased cognition, specifically traits of optimism and pessimism, predicts susceptibility to alcohol-seeking behaviors using an animal model.Rats were initially tested for judgement bias through Ambiguous Cue Interpretation tests. Those identified as ‘optimistic' or ‘pessimistic' were further examined for their tendency to escalate alcohol intake using the intermittent access 2-bottle choice (2BC) paradigm. Additionally, we assessed how judgement bias influenced the development of compulsive alcohol-seeking behavior in a Seeking-Taking (ST) and Seeking-Taking Punishment tasks, alcohol-seeking motivation in the Progressive Ratio Schedule of Reinforcement paradigm, the speed of extinction, and reinstatement after abstinence. Neurochemical analyses were conducted to investigate trait-specific differences in neurotransmitter-related gene expression and receptor densities in the brain. We used TaqMan Gene Expression Array Cards to analyze expression levels of genes linked to serotonergic, dopaminergic, glutamatergic, and GABAergic pathways, and alcohol metabolism in various brain regions. Receptor densities for 5-HT1A, 5-HT2A, and D2 were measured using autoradiography analysis.Behaviorally, ‘optimistic' rats showed significantly lower alcohol consumption in the 2BC paradigm compared to ‘pessimistic' rats. This lowered intake correlated with decreased monoamine oxidase-A (Maoa) expression in the medial prefrontal cortex (mPFC) and increased metabotropic glutamate receptor 2 (Grm2) expression in the amygdala (Amy). Additionally, we observed significant interactions between judgement bias and alcohol intake in the expression of several genes in the mPFC, nucleus accumbens (Nacc), orbitofrontal cortex (OFC), and Amy, as well as in 5-HT2A receptor binding in the Nacc.Overall, these results suggest that optimism is linked to lower alcohol consumption and related neurochemical changes, indicating a potential cognitive mechanism in AUD risk.

Pharmacodynamic, pharmacokinetic and rat brain receptor occupancy profile of NLX-112, a highly selective 5-HT1A receptor biased agonist.

NLX-112 (i.e., F13640, befiradol) exhibits nanomolar affinity, exceptional selectivity and full agonist efficacy at serotonin 5-HT1A receptors. NLX-112 shows efficacy in rat, marmoset and macaque models of L-DOPA induced dyskinesia (LID) in Parkinson's disease and has shown clinical efficacy in a Phase 2a proof-of-concept study for this indication. Here we investigated, in rats, its pharmacodynamic, pharmacokinetic (PK) and brain 5-HT1A receptor occupancy profiles, and its PK properties in the absence and presence of L-DOPA. Total and free NLX-112 exposure in plasma, CSF and striatal ECF was dose-proportional over the range tested (0.04, 0.16 and 0.63mg/kg i.p.). NLX-112 exposure increased rapidly (Tmax 0.25-0.5h) and exhibited approximately threefold longer half-life in brain than in plasma (1.1 and 3.6h, respectively). At a pharmacologically relevant dose of 0.16 mg/kg i.p., previously shown to elicit anti-LID activity in parkinsonian rats, brain concentration of NLX-112 was 51-63 ng/g from 0.15 to 1h. In microPET imaging experiments, NLX-112 showed dose-dependent reduction of 18F-F13640 (i.e., 18F-NLX-112) brain 5-HT1A receptor labeling in cingulate cortex and striatum, regions associated with motor control and mood, with almost complete inhibition of labeling at the dose of 0.63 mg/kg i.p.. Co-administration of L-DOPA (6mg/kg s.c., a dose used to elicit LID in parkinsonian rats) together with NLX-112 (0.16mg/kg i.p.) did not modify PK parameters in rat plasma and brain of either NLX-112 or L-DOPA. Here, we demonstrate that NLX-112's profile is compatible with 'druggable' parameters for CNS indications, and the results provide measures of brain concentrations and 5-HT1A receptor binding parameters relevant to the anti-dyskinetic activity of the compound.

Neurochemical Anatomy of Cushing's Syndrome.

The neurochemical anatomy underlying Cushing's syndrome is examined for regional brain metabolism as well as neurotransmitter levels and receptor binding of biogenic amines and amino acids. Preliminary studies generally indicate that glucose uptake, blood flow, and activation on fMRI scans decreased in neocortical areas and increased in subcortical areas of patients with Cushing's syndrome or disease. Glucocorticoid-mediated increases in hippocampal metabolism occurred despite in vitro evidence of glucocorticoid-induced decreases in glucose uptake or consumption, indicating that in vivo increases are the result of indirect, compensatory, or preliminary responses. In animal studies, glucocorticoid administration decreased 5HT levels and 5HT1A receptor binding in several brain regions while adrenalectomy increased such binding. Region-specific effects were also obtained in regard to the dopaminergic system, with predominant actions of glucocorticoid-induced potentiation of reuptake blockers and releasing agents. More in-depth neuroanatomical analyses are warranted of these and amino acid-related neurotransmission.

Psilocybin restrains activity-based anorexia in female rats by enhancing cognitive flexibility: contributions from 5-HT1A and 5-HT2A receptor mechanisms

Psilocybin has shown promise for alleviating symptoms of depression and is currently in clinical trials for the treatment of anorexia nervosa (AN), a condition that is characterised by persistent cognitive inflexibility. Considering that enhanced cognitive flexibility after psilocybin treatment is reported to occur in individuals with depression, it is plausible that psilocybin could improve symptoms of AN by breaking down cognitive inflexibility. A mechanistic understanding of the actions of psilocybin is required to tailor the clinical application of psilocybin to individuals most likely to respond with positive outcomes. This can only be achieved using incisive neurobiological approaches in animal models. Here, we use the activity-based anorexia (ABA) rat model and comprehensively assess aspects of reinforcement learning to show that psilocybin (post-acutely) improves body weight maintenance in female rats and facilitates cognitive flexibility, specifically via improved adaptation to the initial reversal of reward contingencies. Further, we reveal the involvement of signalling through the serotonin (5-HT) 1 A and 5-HT2A receptor subtypes in specific aspects of learning, demonstrating that 5-HT1A antagonism negates the cognitive enhancing effects of psilocybin. Moreover, we show that psilocybin elicits a transient increase and decrease in cortical transcription of these receptors (Htr2a and Htr1a, respectively), and a further reduction in the abundance of Htr2a transcripts in rats exposed to the ABA model. Together, these findings support the hypothesis that psilocybin could ameliorate cognitive inflexibility in the context of AN and highlight a need to better understand the therapeutic mechanisms independent of 5-HT2A receptor binding.

Reduced Expression of the Htr2a, Grin1, and Bdnf Genes and Cognitive Inflexibility in a Model of High Compulsive Rats.

Compulsivity is a core symptom in different psychopathological disorders, characterized by excessive behaviors and behavioral inflexibility. The selection of high drinker (HD) versus low drinker (LD) rats by schedule-induced polydipsia (SIP) is a valid model for studying the compulsive phenotype. The compulsive HD rats showed cognitive inflexibility and reduced serotonin 2A (5-HT2A) receptor binding levels in the frontal cortex (FC). According to that, we hypothesize that compulsive HD rats might have an alteration in the cognitive control domain regarding inflexibility, assessed by spatial memory on the Morris Water Maze (MWM), working and reference memory by the Radial Arm Maze, and behavioral deficits in stimulus processing by the Novel Object Recognition test. The possible underlying mechanisms might be linked to the brain gene expression of 5HT2A, 5HT2C, glutamate NMDA receptors, and brain-derived neurotrophic factor (BDNF) in FC, hippocampus, and amygdala. HD rats confirmed a cognitive inflexibility profile on the reversal condition in the MWM compared to LD rats, while no differences were observed on stimulus processing, spatial, and working memory. Moreover, HD rats showed a reduced expression of the Htr2a, Grin1, and Bdnf genes in FC. Furthermore, there was a negative correlation between the relative expression of the Htr2a, Grin1, and Bdnf genes in FC and the level of compulsive water intake in HD rats on SIP. These data reveal that cognitive inflexibility may not be associated with a memory or stimulus processing deficit in compulsive individuals but may result by a region-specific alteration of the Htr2a, Grin1, and Bdnf gene expression in FC.

Brain serotonin 1A receptor binding: relationship to peripheral blood DNA methylation, recent life stress and childhood adversity in unmedicated major depression.

Childhood and lifetime adversity may reduce brain serotonergic (5-HT) neurotransmission by epigenetic mechanisms. We tested the relationships of childhood adversity and recent stress to serotonin 1A (5-HT1A) receptor genotype, DNA methylation of this gene in peripheral blood monocytes and in vivo 5-HT1A receptor binding potential (BPF) determined by positron emission tomography (PET) in 13 a priori brain regions, in participants with major depressive disorder (MDD) and healthy volunteers (controls). Medication-free participants with MDD (n = 192: 110 female, 81 male, 1 other) and controls (n = 88: 48 female, 40 male) were interviewed about childhood adversity and recent stressors and genotyped for rs6295. DNA methylation was assayed at three upstream promoter sites (-1019, -1007, -681) of the 5-HT1A receptor gene. A subgroup (n = 119) had regional brain 5-HT1A receptor BPF quantified by PET. Multi-predictor models were used to test associations between diagnosis, recent stress, childhood adversity, genotype, methylation and BPF. Recent stress correlated positively with blood monocyte methylation at the -681 CpG site, adjusted for diagnosis, and had positive and region-specific correlations with 5-HT1A BPF in participants with MDD, but not in controls. In participants with MDD, but not in controls, methylation at the -1007 CpG site had positive and region-specific correlations with binding potential. Childhood adversity was not associated with methylation or BPF in participants with MDD. These findings support a model in which recent stress increases 5-HT1A receptor binding, via methylation of promoter sites, thus affecting MDD psychopathology.

Elevated levels of serotonin 5-HT2A receptors in the orbitofrontal cortex of antisocial individuals.

Antisocial behavior (ASB) is characterized by frequent violations of the rights and properties of others, as well as aggressive conduct. While ample evidence points to a critical role of serotonin in the emotional modulation of social responses, the implication of this neurotransmitter in ASB is unclear. Here, we performed the first-ever postmortem analysis of serotonergic markers in the orbitofrontal cortex (OFC) of male subjects with ASB (n = 9). We focused on this brain region, given its well-recognized role in social response and ASB pathophysiology. Given that all individuals also had a substance use disorder (SUD) diagnosis, two age-matched control groups were used: SUD only and unaffected controls. Tissues were processed for immunoblotting analyses on eight key serotonergic targets: tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme of brain serotonin synthesis; serotonin transporter (SERT), the primary carrier for serotonin uptake; monoamine oxidase A (MAOA), the primary enzyme for serotonin catabolism; and five serotonin receptors previously shown to influence social behavior: 5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, and 5-HT4. Our analyses documented a significant increase in 5-HT2A receptor levels in the ASB + SUD group compared to SUD-only controls. Furthermore, TPH2 levels were significantly reduced in the SUD group (including SUD only and ASB + SUD) compared to unaffected controls. No difference was detected in the expression of any other serotonergic target. These results are in keeping with previous evidence showing high 5-HT2A receptor binding in the OFC of pathologically aggressive individuals and point to this molecule as a potential target for ASB treatment.

St. John's wort extract STW3-VI affects the binding behaviour, signal transduction and lateral mobility of 5-HT2A receptors observed by single molecule detection and the use of a novel fluorescence-labeled ligand

Background5-HT2A receptors play an important role in the development and therapy of depression. St. John's wort (SJW) extracts are used in the treatment of depression. The effects of pre-treatment with SJW extract on the behaviour of 5-HT2A receptors in the plasma membrane have not been well described at the molecular level. MethodsIn this work, the influence of the SJW extract STW3-VI on 5-HT2A receptor internalization and calcium response under stimulating conditions are determined using different reporter cell lines. Influences on 5-HT2A receptor binding as well as on the lateral diffusion behaviour of receptor-ligand complexes (RLC) in the plasma membrane are investigated by fluorescence correlation spectroscopy (FCS) and single particle tracking (SPT) in real time on living cells. Therefore, a selective fluorescently labeled ligand was first developed. ResultsSTW3-VI pre-treatment inhibited both the 5-HT2A receptor internalization and the calcium response after agonistic stimulation with (±)-TCB-2, which suggests an inhibitory effect. Receptor binding studies using FCS surprisingly showed a dose-dependent increase in 5-HT2A receptor binding under STW3-VI. However, it is noticeable that there was a clear redistribution towards faster diffusing RLC, who possibly contribute less to signal transduction. The diffusive states of 5-HT2A receptors identified by SPT changed also under STW3-VI. Remarkably, there was a redistribution from faster diffusing to immobile RLC, while at the same time the transition probabilities for a receptor to change the diffusive state decreased clearly compared to control cells. This particular lateral diffusion behaviour likely characterizes 5-HT2A receptors with impaired signal transduction. ConclusionThe present data indicate a correlation between receptor status and lateral mobility, with STW3-VI apparently having an inhibitory effect on 5-HT2A receptor-mediated signaling in the cell models used here. Single-molecule techniques such as FCS and SPT provide important data that contribute to a better understanding of therapeutically relevant drug-target interactions and downstream regulatory processes.

Brain 5-HT2A receptor binding and its neural network related to behavioral inhibition system

The tendency to avoid punishment, called behavioral inhibition system, is an essential aspect of motivational behavior. Behavioral inhibition system is related to negative affect, such as anxiety, depression and pain, but its neural basis has not yet been clarified. To clarify the association between individual variations in behavioral inhibition system and brain 5-HT2A receptor availability and specify which brain networks were involved in healthy male subjects, using [18F]altanserin positron emission tomography and resting-state functional magnetic resonance imaging. Behavioral inhibition system score negatively correlated with 5-HT2A receptor availability in anterior cingulate cortex. A statistical model indicated that the behavioral inhibition system score was associated with 5-HT2A receptor availability, which was mediated by the functional connectivity between anterior cingulate cortex and left middle frontal gyrus, both of which involved in the cognitive control of negative information processing. Individuals with high behavioral inhibition system displays low 5-HT2A receptor availability in anterior cingulate cortex and this cognitive control network links with prefrontal-cingulate integrity. These findings have implications for underlying the serotonergic basis of physiologies in aversion.

Brain 5-HT1A Receptor PET Binding, Cortisol Responses to Stress, and the Familial Transmission of Suicidal Behavior.

BackgroundThe serotonin 1A (5-HT1A) receptor has been implicated in depression and suicidal behavior. Lower resting cortisol levels are associated with higher 5-HT1A receptor binding, and both differentiate suicide attempters with depression. However, it is not clear whether 5-HT1A receptor binding and cortisol responses to stress are related to familial risk and resilience for suicidal behavior.Methods[11C]CUMI-101 positron emission tomography imaging to quantify regional brain 5-HT1A receptor binding was conducted in individuals considered to be at high risk for mood disorder or suicidal behavior on the basis of having a first- or second-degree relative(s) with an early onset mood disorder and history of suicidal behavior. These high-risk individuals were subdivided into the following groups: high risk resilient having no mood disorder or suicidal behavior (n = 29); high risk with mood disorder and no suicidal behavior history (n = 31); and high risk with mood disorder and suicidal behavior (n = 25). Groups were compared with healthy volunteers without a family history of mood disorder or suicidal behavior (n = 34). Participants underwent the Trier Social Stress Task (TSST). All participants were free from psychotropic medications at the time of the TSST and PET scanning.ResultsWe observed no group differences in 5-HT1A receptor binding considering all regions simultaneously, nor did we observe heterogeneity of the effect of group across regions. These results were similar across outcome measures (BPND for all participants and BPp in a subset of the sample) and definitions of regions of interest (ROIs; standard or serotonin system-specific ROIs). We also found no group differences on TSST outcomes. Within the high risk with mood disorder and suicidal behavior group, lower BPp binding (β = −0.084, SE = 0.038, P = .048) and higher cortisol reactivity to stress (β = 9.25, 95% CI [3.27,15.23], P = .004) were associated with higher lethality attempts. There were no significant relationships between 5-HT1A binding and cortisol outcomes.Conclusions5-HT1A receptor binding in ROIs was not linked to familial risk or resilience protecting against suicidal behavior or mood disorder although it may be related to lethality of suicide attempt. Future studies are needed to better understand the biological mechanisms implicated in familial risk for suicidal behavior and how hypothalamic-pituitary-adrenal axis function influences such risk.

Long-term effects of young-adult methamphetamine on dorsal raphe serotonin systems in mice: Role of brain-derived neurotrophic factor

To assess the long-term effects of chronic adolescent methamphetamine (METH) treatment on the serotonin system in the brain, we used serotonin-1A receptor (5-HT1A) and serotonin transporter (SERT) autoradiography, and quantitative tryptophan-hydroxylase 2 (TPH2) immunohistochemistry in the raphe nuclei of mice. Because of the modulatory role of brain-derived neurotrophic factor (BDNF) on the serotonin system and the effects of METH, we included both BDNF heterozygous (HET) mice and wildtype (WT) controls. Male and female mice of both genotypes were treated with an escalating METH dose regimen from the age of 6–9 weeks. At least two weeks later, acute locomotor hyperactivity induced by a 5 mg/kg D-amphetamine challenge was significantly enhanced in METH-pretreated mice, showing long-term sensitisation. METH pretreatment caused a small, but significant decrease of 5-HT1A receptor binding in the dorsal raphe nucleus (DRN) of males independent of genotype, but there were no changes in the median raphe nucleus (MRN) or in SERT binding density. METH treatment reduced the number of TPH2 positive cells in ventral subregions of the rostral and medial DRN independent of genotype. METH treatment selectively reduced DRN cell counts in BDNF HET mice compared to wildtype mice in medial and caudal ventrolateral subregions previously associated with panic-like behaviour. The data increase our understanding of the long-term and selective effects of METH on brain serotonin systems. These findings could be relevant for some of the psychosis-like symptoms associated with long-term METH use.

Alterations in dopamine system and in its connectivity with serotonin in a rat model of Alzheimer's disease.

Dopamine pathways alterations are reported in Alzheimer’s disease. However, it is difficult in humans to establish when these deficits appear and their impact in the course of Alzheimer’s disease. In the TgF344-Alzheimer’s disease rat model at the age of 6 months, we showed a reduction in in vivo release of striatal dopamine due to serotonin 5HT2A-receptor blockade, in the absence of alterations in 5HT2A-receptor binding, suggesting a reduction in 5HT2A-receptor-dopamine system connectivity. In addition, a functional hypersensitivity of postsynaptic dopamine D2-receptors and D2-autoreceptors was also reported without any change in D2-receptor density and in the absence of amyloid plaques or overexpression of the 18 kDa translocator protein (an inflammatory marker) in areas of the dopamine system. Citalopram, a selective serotonin reuptake inhibitor, induced functional 5HT2A-receptor−D2-receptor connectivity changes but had no effect on D2-autoreceptor hypersensitivity. In older rats, dopamine cell bodies overexpressed translocator protein and dopamine projection sites accumulated amyloid. Interestingly, the 5HT2A-receptor density is decreased in the accumbens subdivisions and the substantia nigra pars compacta. This reduction in the striatum is related to the astrocytic expression of 5HT2A-receptor. Our results indicate that both serotonin/dopamine connectivity and dopamine signalling pathways are dysregulated and potentially represent novel early diagnostic and therapeutic avenues.

Region- and receptor-specific effects of chronic social stress on the central serotonergic system in mice.

Serotonin (5-HT), via its receptors expressed in discrete brain regions, modulates aversion and reward processing and is implicated in various psychiatric disorders including depression. Stressful experiences affect central serotonergic activity and act as a risk factor for depression; this can be modelled preclinically. In adult male C57BL/6J mice, 15-day chronic social stress (CSS) leads to depression-relevant behavioural states, including increased aversion and reduced reward sensitivity. Based on this evidence, here we investigated CSS effects on 5-HT1A, 5-HT2A, and 5-HT2C receptor binding in discrete brain regions using in vitro quantitative autoradiography with selective radioligands. In addition, mRNA expression of Htr1a, 2a, 2c and Slc6a4 (5-HT transporter) was measured by quantitative PCR. Relative to controls, the following effects were observed in CSS mice: 5-HT1A receptor binding was markedly increased in the dorsal raphe nucleus (136%); Htr1a mRNA expression was increased in raphe nuclei (19%), medial prefrontal cortex (35%), and hypothalamic para- and periventricular nuclei (21%) and ventral medial nucleus (38%). 5-HT2A receptor binding was decreased in the amygdala (48%) and ventral tegmental area (60%); Htr2a mRNA expression was increased in the baso-lateral amygdala (116%). 5-HT2C receptor binding was decreased in the dorsal raphe nucleus (42%). Slc6a4 mRNA expression was increased in the raphe (59%). The present findings add to the translational evidence that chronic social stress impacts on the central serotonergic system in a region- and receptor-specific manner, and that this altered state of the serotonergic system contributes to stress-induced dysfunctions in emotional processing.

Discovery and SAR studies of 2-alkyl-3-phenyl-2,4,5,6,7,8-hexahydropyrazolo[3,4-d]azepines as 5-HT7/2 inhibitors leading to the identification of a clinical candidate

We report here the synthesis and characterization of a dual 5-HT7 / 5-HT2 receptor antagonist 3-(4-Fluoro-phenyl)-2-isopropyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (4j). 4j is a high affinity 5-HT7 and 5-HT2A receptor ligand having a pKi = 8.1 at both receptors. It behaves as an antagonist in an in vitro functional assay for 5-HT2A and as an inverse agonist in an in vitro functional assay for 5-HT7. In a validated in vivo model for central 5-HT7 activity in rats, blockade of 5-carboxamidotryptamine (5-CT) induced hypothermia, 4j shows efficacy at low doses (ED50 = 0.05 mg/kg, p.o., 1 h) and maximal efficacy was observed at 0.3 mg/kg p.o. with a corresponding plasma concentration of ~27 ng/ml. In a validated in vivo model for central 5-HT2A activity, blockade of 2,5-dimethoxy-4-iodoamphetamine (DOI) induced head-twitches in mice, 4j shows efficacy at low doses with an ED50 = 0.3 mg/kg p.o. Ex vivo receptor binding studies demonstrate that 4j occupied 5-HT2A receptor binding sites in the frontal cortex of the rat brain with an ED50 in good agreement with the ED50 value for central functional effect mediated by 5-HT2A receptor (ED50 = 0.8 mg/kg, p.o., 1 h).

Sex-dependent effects of social status on the regulation of arginine-vasopressin (AVP) V1a, oxytocin (OT), and serotonin (5-HT) 1A receptor binding and aggression in Syrian hamsters (Mesocricetus auratus)

Dominance status in hamsters is driven by interactions between arginine-vasopressin V1a, oxytocin (OT), and serotonin 1A (5-HT1A) receptors. Activation of V1a and OT receptors in the anterior hypothalamus (AH) increases aggression in males, while decreasing aggression in females. In contrast, activation of 5-HT1A receptors in the AH decreases aggression in males and increases aggression in females. The mechanism underlying these differences is not known. The purpose of this study was to determine if dominance status and sex interact to regulate V1a, OT, and 5-HT1A receptor binding. Same-sex hamsters (N = 47) were paired 12 times across six days in five min sessions. Brains from paired and unpaired (non-social control) hamsters were collected immediately after the last interaction and processed for receptor binding using autoradiography. Differences in V1a, OT, and 5-HT1A receptor binding densities were observed in several brain regions as a function of social status and sex. For example, in the AH, there was an interaction between sex and social status, such that V1a binding in subordinate males was lower than in subordinate females and V1a receptor density in dominant males was higher than in dominant females. There was also an interaction in 5-HT1A receptor binding, such that social pairing increased 5-HT1A binding in the AH of males but decreased 5-HT1A binding in females compared with unpaired controls. These results indicate that dominance status and sex play important roles in shaping the binding profiles of key receptor subtypes across the neural circuitry that regulates social behavior.

Selective serotonin reuptake inhibitor use is associated with worse sleep-related breathing disturbances in individuals with depressive disorders and sleep complaints: a retrospective study.

The effects of serotonergic agents on respiration neuromodulation may vary according to differences in the serotonin system, such as those linked to depression. This study investigated how sleep-related respiratory disturbances relate to depression and the use of medications commonly prescribed for depression. Retrospective polysomnography was collated for all 363 individuals who met selection criteria out of 2,528 consecutive individuals referred to a specialized sleep clinic (Ottawa, Canada) between 2006 and 2016. The apnea-hypopnea index (AHI), oxygen saturation nadir, and oxygen desaturation index during REM and NREM sleep were analyzed using mixed analyses of covariance comparing 3 main groups: (1) medicated individuals with depressive disorders (antidepressant group; subdivided into the selective serotonin reuptake inhibitor and norepinephrine-dopamine reuptake inhibitor subgroups), (2) non-medicated individuals with depressive disorders (non-medicated group), and (3) mentally healthy control patients (control group). Individuals with depressive disorders (on antidepressants or not) had significantly higher AHIs compared to control patients (both P ≤ .007). The antidepressant group had a lower NREM sleep oxygen saturation nadir and a higher NREM sleep oxygen desaturation index than the control and non-medicated groups (all P ≤ .009). Within individuals with depressive disorders, independent of depression severity, the selective serotonin reuptake inhibitor group had a lower oxygen saturation nadir and a higher oxygen desaturation index during NREM sleep than the norepinephrine-dopamine reuptake inhibitor (both P ≤ .045) and non-medicated groups (both P < .001) and a higher NREM sleep AHI than the non-medicated group (P = .014). These findings suggest that the use of selective serotonin reuptake inhibitors may be associated with impaired breathing and worse nocturnal oxygen saturation in individuals with depressive disorders and sleep complaints, but this needs to be confirmed by prospective studies.

Mood-related behavioral and neurochemical alterations in mice exposed to low chlorpyrifos levels during the brain growth spurt.

Organophosphates are among the most used pesticides. Particularly, chlorpyrifos (CPF) is responsible for a number of deleterious effects on brain development, which may program behavioral changes later in life. Here, we investigated whether a regimen of early low level CPF exposure that did not result in a significant inhibition of acetylcholinesterase (AChE) had deleterious effects on mood-related behaviors, as well as on cholinergic and serotonergic biomarkers in the mice brain. From the 3rd to 9th postnatal day (PN), male and female Swiss mice were subcutaneously injected with CPF. Mice were submitted to a battery of behavioral tests from PN60 to PN63: open field, elevated plus maze and forced swimming tests. The cholinergic and serotonergic biomarkers were assessed at PN10 and PN63. Our data indicated that early CPF exposure increased anxiety-like behavior in females and altered decision-making behavior in both sexes. Most biochemical alterations were sex-dependent and restricted to females. At PN10, CPF female mice showed increased serotonin and choline transporter binding in cerebral cortex. Distinctively, in adult females, the effects indicated a hypoactive state: CPF exposure reduced 5-HT1a receptor binding in cerebral cortex, as well as serotonin transporter binding and choline acetyltransferase activity in brainstem. Our results indicate that CPF exposure during the brain growth spurt deregulates serotonergic and cholinergic biomarkers. The effects are consistent with impaired synaptic function, may be related to long-term mood disorders and point out to higher female susceptibility.

Increased amygdala and decreased hippocampus volume after schedule-induced polydipsia in high drinker compulsive rats

Fronto-limbic structures and serotonin 2A receptors (5-HT2A) have been implicated in the pathophysiology and treatment of compulsive spectrum disorders. Schedule-Induced Polydipsia (SIP), characterized by the development of excessive drinking under intermittent food reinforcement schedules, is a valid preclinical model for studying the compulsive phenotype. In the present study, we explored the individual differences and effect of SIP in brain volume and 5-HT2A receptor binding in fronto-limbic structures in rats selected according to their compulsive drinking behavior. Rats were divided into high (HD) and low drinkers (LD) by SIP (20 sessions); later, we analyzed the brains of HD and LD selected rats, in two different conditions: non-re-exposure (NRE) or re-exposure to SIP (RE), with four groups: LD-NRE, LD-RE, HD-NRE and HD-RE. Histological analyses were carried out for volumetric (stereology) and receptor binding (autoradiography) in the prelimbic and infralimbic cortex, dorsal hippocampus and basolateral amygdala. After SIP re-exposure, HD-RE showed an increased basolateral amygdala and a reduced hippocampus volume compared to HD-NRE rats, and also compared to LD-RE rats. No differences were found between HD and LD in NRE condition. Moreover, HD rats exhibit a lower 5-HT2A receptor binding in the basolateral amygdala, independently of SIP re-exposure, compared to LD rats. However, LD-RE showed a decreased 5-HT2A receptor binding in basolateral amygdala compared to LD-NRE. No differences were found in the remaining structures. These findings suggest that SIP might be differentially impacting HD and LD brains, pointing towards a possible explanation of how the latent vulnerability to compulsivity is triggered.

Blast‐induced Traumatic Brain Injury Elicits Sociability Deficits and Aggressive Behaviors Coinciding with Transient Variations in CNS 5‐HT Levels and 5‐HT2A Hypersensitivity

Traumatic brain injury (TBI) is a leading cause of mortality and morbidity. In the United States alone, TBI accounts for 2.8 million emergency department visits and an economic cost of nearly $80 billion annually. The lack of any FDA‐approved therapies for treatment of acute or chronic symptoms of TBI necessitates the identification and characterization of novel drug targets. TBI often results in the generation of neuropsychiatric disorders including major depressive disorder (MDD), anxiety, aggression, and social withdrawal within the first 12 months following injury, disorders linked to altered serotonin (5‐HT) signaling. Currently, the effects of TBI on physiologic function of the 5‐HT signaling system within the CNS are poorly understood. We hypothesize that TBI drives the formation of aberrant behavioral states linked to neuropsychiatric disorders through alterations of normal, physiologic 5‐HT signaling. To test this hypothesis, adult, wild type C57Bl/6J mice were subjected to a single, blast‐induced TBI or sham treatment, followed by behavioral and/or molecular analyses 0–30 days post‐injury (dpi). High performance liquid chromatography (HPLC) revealed a time‐dependent increase and subsequent decrease in total 5‐HT and 5HIAA levels within the dorsal raphe nucleus (DRN) 10 and 30 dpi, respectively. No effect of TBI on 5‐HT levels was found in prefrontal cortex (PFC) or somatosensory cortex (SSC), areas of high 5‐HT innervation. Using the tube test for social dominance, time‐dependent alterations in DRN 5‐HT levels were found to correlate with altered social dominance behavior. TBI resulted in decreased social dominance/aversion 10 dpi, but an increase in dominance behavior 30 dpi. Using the Crawley Three Chamber Sociability Assay, TBI‐induced decreases in sociability were observed 10 dpi, an effect not present at 30 dpi. To investigate alterations in 5‐HT receptor pharmacology associated with TBI, 5‐HT2A receptor sensitivity was determined using DOI‐induced head twitch response (HTR) assays. TBI rapidly increased 5‐HT2A receptor sensitivity, effects persisting for 10 dpi. TBI‐elicited increases in DOI‐induced HTR were attenuated by administration of the 5‐HT2A antagonist M100907, indicating a dependence on intact 5‐HT2A receptor signaling. [3H]Ketanserin receptor binding studies revealed an increase in cortical 5‐HT2A receptor binding at 3 and 10 dpi. Collectively, these data provide evidence that TBI elicits time‐dependent alterations in the 5‐HT architecture of the CNS, effects that coincide with altered social function. A more thorough understanding of specifically how neurotrauma alters 5‐HT signaling will allow for the informed clinical utilization of available 5‐HT‐oriented pharmacotherapies and may provide drug discovery targets for TBI‐elicited neuropsychiatric sequelae.Support or Funding InformationStudies were supported by the Brain &amp; Behavior Research Foundation, PhRMA Foundation, and the University of Cincinnati