5-HT1A Receptors In Hippocampus Research Articles

Neonatal nociceptive stimulation results in pain sensitization, reduction of hippocampal 5-HT1A receptor, and p-CREB expression in adult female rats

Painful invasive procedures are often performed on newborns admitted to intensive care units (ICU). The acute and long-term effects caused by these stimuli can be investigated in animal models, such as newborn rats. Previous studies have shown that animals subjected to nociceptive stimuli in the neonatal period show sex-specific behavioral changes such as signs of anxiety or depression. Under the same conditions, neonatal stimuli also provoke an increase in the rate of neurogenesis and cell activation in the hippocampal dentate gyrus. So, this study aims to identify the possible roles of central monoamines, receptor expression (5-HT1A), and signaling factors (p-CREB) underlying the long-term effects of neonatal nociceptive stimulation. For this, noxious stimulation was induced by intra-plantar injection of Complete Freund´s adjuvant (CFA) on the postnatal day 1 (P1) or 8 (P8). Control animals were not stimulated. On P75 the behavioral tests were conducted (hotplate and elevated plus maze), followed by sacrifice and molecular studies. Our results showed that neonatal nociceptive stimulation alters pain sensitization specially in females, while stimulation on P1 increases pain threshold, P8-stimulated animals respond with reduced pain threshold (P < 0.001). Hippocampal expression of 5-HT1A receptor and p-CREB were reduced in P8 F group (P < 0.001) in opposition to the increased utilization rate of dopamine and serotonin in this group (P < 0.05). This study shows sex- and age-specific responses of signaling pathways within the hippocampus accompanied by altered behavioral repertoire, at long-term after neonatal painful stimulation.

Cross state-dependent memory retrieval between cannabinoid CB1 and serotonergic 5-HT1A receptor agonists in the mouse dorsal hippocampus

Understanding the neurobiological mechanisms of drug-related learning and memory formation may help the treatment of cognitive disorders. Dysfunction of the cannabinoid and serotonergic systems has been demonstrated in learning and memory disorders.The present paper investigates the phenomenon called state-dependent memory (SDM) induced by ACPA (a selective cannabinoid CB1 receptor agonist) and 8-OH-DPAT (a nonselective 5-HT1A receptor agonist) with special focus on the role of the 5-HT1A receptor in the effects of both ACPA and 8-OH-DPAT SDM and cross state-dependent memory retrieval between ACPA and 8-OH-DPAT in a step-down inhibitory avoidance task.The dorsal hippocampal CA1 regions of adult male NMRI mice were bilaterally cannulated, and all drugs were microinjected into the intended injection sites. A single-trial step-down inhibitory avoidance task was used to assess memory retrieval and state-dependence.Post-training and/or pre-test microinjections of ACPA (1 and 2 ng/mouse) and 8-OH-DPAT (0.5 and 1 μg/mouse) dose-dependently induced amnesia. Pre-test administration of the same doses of ACPA and 8-OH-DPAT reversed the post-training ACPA- and 8-OH-DPAT-induced amnesia, respectively. This phenomenon has been named SDM. 8-OH-DPAT (1 μg/mouse) reversed the amnesia induced by ACPA (0.5, 1, and 2 ng/mouse) and induced ACPA SDM. ACPA (2 ng/mouse) reversed the amnesia induced by 8-OH-DPAT (0.25, 0.5, and 1 μg/mouse) and induced 8-OH-DPAT SDM. Pre-test administration of a 5-HT1A receptor antagonist, (S)-WAY 100,135 (0.25 and 0.5 μg/mouse), 5 min before ACPA and 8-OH-DPAT dose-dependently inhibited ACPA- and 8-OH-DPAT-induced SDM, respectively.The present study results demonstrated ACPA- and 8-OH-DPAT- induced SDM. Overall, the data revealed that dorsal hippocampal 5-HT1A receptor mechanisms play a pivotal role in modulating cross state-dependent memory retrieval between ACPA and 8-OH-DPAT.

Biased 5-HT1A receptor agonists F13714 and NLX-101 differentially affect pattern separation and neuronal plasticity in rats after acute and chronic treatment

Pattern separation is a hippocampal process in which highly similar stimuli are recognized as separate representations, and deficits could lead to memory impairments in neuropsychiatric disorders such as schizophrenia. The 5-HT1A receptor (5-HT1AR) is believed to be involved in these hippocampal pattern separation processes. However, in the dorsal raphe nucleus (DRN), the 5-HT1AR is expressed as a somatodendritic autoreceptor, negatively regulates serotonergic signaling, and could thereby counteract the effects of hippocampal postsynaptic 5-HT1A receptors. Therefore, this study aims to identify how pre- and post-synaptic 5-HT1AR activity affects pattern separation. Object pattern separation (OPS) performance was measured in male Wistar rats after both acute and chronic treatment (i.p.) with 5-HT1AR biased agonists F13714 (0.0025 mg/kg acutely, 0.02 mg/kg/day chronically) or NLX-101 (0.08 mg/kg acutely, 0.32 mg/kg/day chronically), which preferentially activate autoreceptors or postsynaptic receptors respectively, for 14 days. Body temperature - a functional correlate of hypothalamic 5-HT1AR stimulation - was measured daily. Additionally, 5-HT1AR density (DRN) and plasticity markers (hippocampus) were assessed. Acute treatment with F13714 impaired OPS performance, whereas chronic treatment normalized this, and a drop in body temperature was found from day 4 onwards. NLX-101 enhanced OPS performance acutely and chronically, and caused an acute drop in body temperature. Chronic NLX-101 treatment increased doublecortin positive neurons in the dorsal hippocampus, while chronic treatment with F13714 resulted in a downregulation of 5-HT1A autoreceptors, which likely reversed the acute impairment in OPS performance. Chronic treatment with NLX-101 appears to have therapeutic potential to improve brain plasticity and OPS performance.

Alteration of the α5 GABA receptor and 5HTT lead to cognitive deficits associated with major depressive-like behaviors in a 14-day combined stress rat model

Introduction: Current models used to study the pathophysiology of major depressive disorder (MDD) are laborious and time consuming. This study examined the effect of a 14-day combined stress model (CS; corticosterone injection and restraint stress) in male Sprague-Dawley rats and also compare the effect of CS versus 28-day corticosterone treatment on depressive-like behaviour and cognitive deficits. Materiel and methods: Depressive-like behaviours and cognitive deficits were assessed in the forced swim test (FST), sucrose preference (SPT), Morris water maze (MWM) and novel object recognition (NORT) tests. Real-time PCR and ELISA were respectively used to detect expression of the serotonin transporter (5-HTT), serotonin 1 A receptor (5-HT1A), α5 GABAA receptor, and the concentrations of corticosterone (plasma), GABA and acetylcholinesterase (AChE) in the hippocampus and Prefrontal cortex (PFC). Results CS group showed increased immobility time in the FST, time to reach the MWM platform, higher corticosterone level, and increased expressions of hippocampal and PFC 5-HT1A and α5 GABAA receptors, and AChE compared to their control groups. In contrast, reductions in SPT ratio, discrimination index in NORT, time in target quadrant, and hippocampal 5-HTT expression was noted relative to their control group. Compared to the 28-day corticosterone only group, PFC 5-HT1A, Hippocampal 5-HTT were reduced, while PFC 5-HTT, Hippocampal α5 GABAA receptors, and AChE concentrations were higher in the CS group. Conclusion: Our CS model induced depressive-like behaviour with early cognitive deficits in rats affecting both hippocampus and PFC. The CS model may be useful in investigating new and comprehensive treatment strategies for MDD.

Hippocampal and Septal 5-HT1A Receptor Expression in Two Rat Models of Temporal Lobe Epilepsy

Experimental and clinical data suggest an impact of serotonergic signaling on seizure susceptibility and epilepsy-associated psychiatric comorbidities. Previous µPET studies revealed increased binding of the 5-HT1A receptor ligand [18F]MPPF in two rat models with spontaneous recurrent seizures. These findings raised the question whether these alterations are due to altered 5-HT1A receptor expression or a modification of extracellular serotonin concentrations. 5-HT1A receptor expression rates were quantitatively analyzed in rat brain tissue from an electrical and a chemical post-status epilepticus model. Based on the µPET findings, stereological analysis was focused on hippocampal subregions and the septum. Evaluation of 5-HT1A receptor expression in the electrical post-status epilepticus model revealed a decreased optical density in hippocampal CA3 region. In all other brain regions of interest, the analysis demonstrated comparable 5-HT1A receptor expression rates among all experimental groups in the brain regions evaluated. Moreover, 5-HT1A total receptor volume did not differ between groups. A model-specific correlation was demonstrated between 5-HT1A receptor expression and selected seizure and behavioral parameters. In conclusion, analysis in post-status epilepticus models in rats argued against widespread and pronounced alterations in 5-HT1A receptor expression. In view of previous µPET findings, the present data indicate that alterations in in-vivo receptor binding are due to a reduction in extracellular serotonin concentrations rather than changes in receptor density. Correlation analysis points to a possible link between 5-HT1A receptor expression and ictogenesis, seizure termination and behavioral patterns. However, as these findings proved to be model specific, the relevance needs to be further assessed in future studies focusing on other models and species.

Electroacupuncture improves synaptic plasticity by regulating the 5-HT1A receptor in hippocampus of rats with chronic unpredictable mild stress.

ObjectivesTo investigate the antidepressant effects of electroacupuncture (EA) on chronic unpredictable mild stress (CUMS) in rats, as well as the effects of EA on hippocampal neurons, synaptic morphology, and 5-hydroxytryptamine (HT) receptor expression.MethodsForty adult male Wistar rats were randomly divided into normal control, CUMS, EA, and paroxetine groups. CUMS modeling was performed for 21 days, followed by 14 days of intervention: rats in the EA group underwent stimulation of GV20 and GV29 acupuncture points for 30 minutes daily; rats in the paroxetine group were administered paroxetine daily. Behavioral tests, transmission electron microscopy, western blotting, and real-time quantitative polymerase chain reaction were used to evaluate the effects of the intervention.ResultsEA treatment reversed the behavioral changes observed in rats due to CUMS modeling; it also improved the pathological changes in organelles and synaptic structures of hippocampal neurons, and upregulated the protein and mRNA expression levels of 5-HT1A receptor. There were no significant differences in 5-HT1B receptor protein and mRNA expression levels among the groups.ConclusionsEA treatment can alleviate depression-like symptoms in CUMS rats. The underlying mechanism may include promoting the expression of 5-HT1A receptor mRNA and protein, thereby improving synaptic plasticity in the hippocampus.

Antidepressive Effects of Kamishoyosan through 5-HT1AReceptor and PKA-CREB-BDNF Signaling in the Hippocampus in Postmenopausal Depression-Model Mice.

Females are well known to suffer disproportionately more than males from stress-related neuropsychiatric disorders, especially during perimenopausal and postmenopausal periods. In addition to a decline in serum estradiol levels, environmental stress and social stress likely contribute to the development of neuropsychiatric symptoms in perimenopausal and postmenopausal women. Kamishoyosan (KSS) is a traditional Japanese Kampo medicine, composed of a specified mixture of 10 crude compounds derived from plant sources, widely used for various neuropsychiatric symptoms in perimenopausal and postmenopausal women. However, the molecular mechanisms underlying KSS-mediated attenuation of neuropsychological symptoms and stress-response behaviors in perimenopausal and postmenopausal women remain unknown. In the present study, we first established a mouse model for postmenopausal depression-like signs using chronic water-immersion and restraint-stressed ovariectomized (OVX) mice to investigate the underlying molecular mechanism of KSS. We found that continuous administration of KSS to these mice normalized the activation of the hypothalamic-pituitary-adrenal (HPA) axis, ameliorated stress-induced depressive behavior, and prevented a decrease of neurogenesis in the hippocampus. As previous studies have implicated dysfunction of the hippocampal 5-HT1A receptor (5-HT1AR) in depressive disorders, we also evaluated the effect of KSS on 5-HT1AR expression and the protein kinase A- (PKA-) cAMP response element-binding- (CREB-) brain-derived neurotrophic factor (BDNF) signaling pathway in the hippocampus in this model. The level of 5-HT1AR in the hippocampus decreased in chronic stress-exposed OVX mice, while KSS treatment normalized the stress-induced decrease in 5-HT1AR expression in the hippocampus of chronic stress-exposed OVX mice. Furthermore, we found that KSS treatment upregulated the expression levels of phosphorylated PKA (p-PKA), phosphorylated CREB (p-CREB), and BDNF in the hippocampus in chronic stress-exposed OVX mice. These results suggest that KSS improves neuropsychiatric symptoms through 5-HT1AR and PKA-CREB-BDNF signaling in the hippocampus in postmenopausal women.

Electroacupuncture ameliorates learning and memory deficits via hippocampal 5-HT1A receptors and the PKA signaling pathway in rats with ischemic stroke.

Hippocampal 5-HT1A receptors and the PKA signaling pathway have been implicated in learning and memory. This study aimed to investigate whether PKA signaling mediated by 5-HT1A receptors was involved in the electroacupuncture (EA)-mediated learning and memory in a rat model of middle cerebral artery occlusion-induced cognitive deficit (MICD). Compared to no treatment or non-acupoint EA treatment, EA at DU20 and DU24 acupoints improved the neurological deficit of scores, shortened escape latency and increased the frequency of crossing the platform in the Morris water maze test. T2-weighted imaging demonstrated that the MICD rat brain lesions were mainly located in the cortex and hippocampus, and injured volumes were reduced after EA. Furthermore, we found that these behavioral changes were concomitant with the deficit of the 5HT1A and PKA signaling pathways in the hippocampus, as the activation of the 5-HT1A receptor, the reduction of PKA kinase activity, and AMPA and NMDA receptor phosphorylation occurred in the injured hippocampus at Day 14 after MICD. Additionally, EA dramatically elevated the activation of PKA. Moreover, EA significantly increased intracellular calcium concentrations regulated by the activation of NMDA receptors. Therefore, PKA kinase and NMDA receptors mediated by 5-HT1A receptors in the hippocampus might contribute to improving learning and memory during the recovery process following ischemic stroke with an EA intervention.

Role of hippocampal 5-HT1A receptors in the antidepressant-like phenotype of mice expressing RGS-insensitive Gαi2 protein

A single base mutation in the Gαi2 protein (G184S) renders this Gα subunit insensitive to the negative modulatory effects of Regulator of G-protein Signaling (RGS) proteins. Mice expressing this RGS insensitive (RGSi) variant of Gαi2 (RGSi Gαi2) display a spontaneous antidepressant-like phenotype that is reversible by treatment with the 5-HT1A receptor (5-HT1AR) antagonist WAY100635. Here we test the hypothesis that increased activity of 5-HT1ARs in the hippocampus of RGSi Gαi2 knock-in mice is responsible for the expression of the observed antidepressant-like behavior. We administered the 5-HT1AR antagonist WAY100635 or the agonist 8-OH-DPAT via bilateral intra-hippocampal infusion cannulae and evaluated antidepressant-like behavior using the tail suspension test (TST). WAY100635 reversed the antidepressant-like phenotype of the RGSi Gαi2 knock-in mice and 8-OH-DPAT produced an antidepressant-like response in wild type mice that was blocked by systemic WAY100635. Furthermore, intra-hippocampal infusion of the RGS19/4 inhibitor CCG-203769 produced an antidepressant-like effect in female mice. Ex-vivo slice recording confirmed the 5-HT1AR-mediated decrease in hippocampal CA1 pyramidal neuron excitability was enhanced in the RGSi Gαi2 knock-in mice. There was no change in hippocampal 5-HT1AR expression as measured by ligand binding but there was a compensatory reduction in Gαi proteins. The findings demonstrate that RGS protein control of hippocampal 5-HT1AR signaling is necessary and sufficient to account for the antidepressant-like phenotype in the RGSi Gαi2 knock-in mice and that RGS proteins highly expressed in the hippocampus should be investigated as targets for novel antidepressant therapies.

The long-term effect of maternal dietary protein restriction on 5-HT1A receptor function and behavioral responses to stress in adulthood

Maternal nutrition impacts fetal development, and may play a role in determining resilience to stress and vulnerability to stress-precipitated psychiatric disorders, such as anxiety and depression. In this study, we examined the effect of a reduction in maternal dietary protein during pregnancy on the brain neurochemistry and behavior of offspring. We focused specifically on the serotonin system, the 5-HT1A receptor and the responsivity of offspring as adults to stress. Dams were fed either a low protein diet (10% protein by weight) or isocaloric control diet (20% protein by weight). The low protein diet did not alter maternal food intake and body weight, or litter size and the average birth weight of male or female littermates. 5-HT1A receptor function, as measured by quantitative autoradiography of 8-OH-DPAT (1 μM)-stimulated [35S]GTPγS binding, was markedly reduced in hippocampus of weanling female, but not male offspring (postnatal day, PND 21) of dams fed the low protein diet. The number of serotonergic cell bodies in the rostral raphe, and 5-HT metabolism in the limbic system of weanling offspring was not altered by maternal low protein diet. The deficit in hippocampal 5-HT1A receptor function observed in weanling female offspring persisted into adulthood (PND 112), and was accompanied by an increased sensitivity to stress, specifically increased immobility during a 15-minute forced swim challenge and increased anorexia following 30-minute restraint (PND 97-100). The present work begins to uncover important future directions for understanding the early developmental origins of resilience to stress, and factors that may put individuals at greater risk for stress-related psychiatric disorders.

Role of the hippocampal 5-HT1A receptor-mediated cAMP/PKA signalling pathway in sevoflurane-induced cognitivedysfunction in aged rats.

ObjectiveThis study aimed to evaluate the role of the hippocampal 5-hydroxytryptamine-1A (5-HT1A)-mediated cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) signalling pathway in sevoflurane-induced cognitive dysfunction in aged rats.MethodsSixty 18-month-old Sprague–Dawley rats were divided into the control (n = 30) and experimental (Sev, n = 30) groups. The experimental group inhaled 50% air/oxygen mixture (2 L/min) and 2% sevoflurane for 4 hours. The control group inhaled 50% air/oxygen mixture (2 L/min) for 4 hours. The Morris water maze test was performed The mRNA expression of 5-HT1A receptor, and cAMP PKA, cAMP response element-binding protein (CREB), and phosphorylated CREB (p-CREB) protein expression were determined.ResultsThe escape latency and swimming distance were greater, and the number of crossings of the platform location and time spent in the platform quadrant were less in the Sev group compared with the control group. cAMP, PKA, CREB, and p-CREB protein expression was downregulated in the Sev group 1 day after anaesthesia compared with the control group. Hippocampal 5-HT1A receptor mRNA expression was higher 7 days after anaesthesia compared with the control group.ConclusionSevoflurane-induced cognitive dysfunction in aged rats may be related to inhibited expression of the hippocampal 5-HT1A receptor-mediated cAMP/PKA signalling pathway.

F17464 a new antipsychotic with preferential D3 antagonist, 5-HT1A partial agonist properties. Neurochemical studies

F17464 is a new dopamine receptor antagonist that recently demonstrated antipsychotic activity in a proof of concept study in schizophrenic patients under acute exacerbation. The compound has a unique profile with high affinity for hD3 receptors (Ki = 0.17 nM) and lower affinity for hD2L (Ki = 12.1 nM) and hD2S (Ki = 6.5 nM). F17464 exhibits also high affinity for h5-HT1A receptors (Ki = 0.16 nM). F17464 is a hD3 antagonist (pKB = 9.13), hD2S very week partial agonist (pKB = 7.87, emax 8% of DA stimulated in ERK assay) and a 5-HT1A partial agonist (pEC50 = 7.99). F17464 exhibits consistent affinities for rat striatal D2 (Ki = 4.8 nM) and for rat hippocampal 5-HT1A receptors (Ki = 1.14 nM). Neurochemical studies show that F17464 ip (1 h post-dose) produces a significant dose–dependent increase in the levels of DOPAC and HVA in the frontal cortex, caudate-putamen and limbic forebrain and an increase in 3-MT levels in the latter two regions with no changes in total DA content. The effect is significant at the doses of 0.63–2.5 mg/kg ip (PK/PD data will be provided). This pattern of DA metabolite changes is similar to that described for several antipsychotic drugs in rodents and it is indicative of a cortical effect of F17464. F17464 has a very low cataleptogenic activity in rats and mice and does not induce serotoninergic signs typical of 5-HT1A. F17464 is therefore a novel a D3 preferential antipsychotic with a unique mechanism of action and receptor affinity profile and a consistent effect in neurochemistry studies in rodents.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Editorial: Serotonin and Memory.

Several neurotransmission systems have been involved in function and dysfunctional memory (e.g., Myhrer, 2003; Decker and McGaugh, 2004; Reis et al., 2009; Cassel, 2010; Rodriguez et al., 2012; Komal and Nashmi, 2015), including serotonin (5-hydroxytryptamine, 5-HT), which accounts with multiple neural markers (receptors, transporter; e.g., Hannon and Hoyer, 2008; Saulin et al., 2012; Seyedabadi et al., 2014; McCorvy and Roth, 2015). Indeed, the 5-HT system can be manipulated in multiple ways with pharmacological tools and possesses well characterized downstream signaling in mammals' species (e.g., Marin et al., 2012; McCorvy and Roth, 2015). Emergent evidence indicates that this monoamine system might be a therapeutic target and neural marker regarding function and dysfunctional memory. This issue presents recent advances including the role of 5-HT2A and 5-HT1A receptors in the medial prefrontal cortex during recognition memory (Morici et al.). Hippocampal 5-HT1A receptors and spatial and memory is revised by Glikmann-Johnston et al. Ochoa et al. report that post-training serotonergic depletions of the basolateral amygdala did not disrupt discrimination, retention or reversal learning; suggesting that this serotonergic activity is not required for formation and flexible adjustment of new stimulus-reward associations when the strategy to efficiently solve the task has already been learned. Hernandez-Perez et al. report that serotonin reduction in the supramammillary nucleus alters place learning and concomitant hippocampal, septal, and supramammillar theta activity in spatial memory. Zhang and Stackman review progress in the 5-HT2A receptor distribution, signaling, polymerization, and allosteric modulation; as well as functions in learning and memory, hallucination and spatial cognition, and mental disorders. Pereira et al. show us that 5-HT6 receptor agonism facilitates emotional learning and involves prefrontal cortex and hippocampal signaling. Serotonergic transporter function is reported by Sivamaruthi et al. demonstrating that cronobacter sakazakii infection alters serotonin transporter and improved fear memory retention. Stiedl et al. discuss the role of the serotonin receptor subtypes 5-HT1A and 5-HT7 and their interaction in emotional learning and memory; including the role of these receptors and their interplay at the molecular, neurochemical, and behavioral level. The potential involvement of serotonergic neural markers with respect to memory is reviewed by Meneses. Special mention and thanks to the expert work of the referees, who made professional and careful reviews that improved the papers in this topic.

Hippocampal 5-HT1A Receptor and Spatial Learning and Memory.

Spatial cognition is fundamental for survival in the topographically complex environments inhabited by humans and other animals. The hippocampus, which has a central role in spatial cognition, is characterized by high concentration of serotonin (5-hydroxytryptamine; 5-HT) receptor binding sites, particularly of the 1A receptor (5-HT1A) subtype. This review highlights converging evidence for the role of hippocampal 5-HT1A receptors in spatial learning and memory. We consider studies showing that activation or blockade of the 5-HT1A receptors using agonists or antagonists, respectively, lead to changes in spatial learning and memory. For example, pharmacological manipulation to induce 5-HT release, or to block 5-HT uptake, have indicated that increased extracellular 5-HT concentrations maintain or improve memory performance. In contrast, reduced levels of 5-HT have been shown to impair spatial memory. Furthermore, the lack of 5-HT1A receptor subtype in single gene knockout mice is specifically associated with spatial memory impairments. These findings, along with evidence from recent cognitive imaging studies using positron emission tomography (PET) with 5-HT1A receptor ligands, and studies of individual genetic variance in 5-HT1A receptor availability, strongly suggests that 5-HT, mediated by the 5-HT1A receptor subtype, plays a key role in spatial learning and memory.

Effects of acute and sustained administration of vortioxetine on the serotonin system in the hippocampus: electrophysiological studies in the rat brain.

RationaleVortioxetine is a novel multimodal antidepressant that is a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist, an inhibitor of the serotonin (5-HT) transporter, and a 5-HT1D, 5-HT3, and 5-HT7 receptor antagonist in vitro. In vivo studies have shown that vortioxetine enhances levels of 5-HT and desensitizes 5-HT1A autoreceptors.ObjectivesThe aim of the present study was to investigate the effects of acute and long-term administration of vortioxetine on the terminal 5-HT1B receptor and the tonic activation of 5-HT1A receptor in the rat hippocampus.MethodsThese receptors were assessed following vortioxetine administration acutely or subcutaneously using minipumps for 14 days. These studies were carried out using in vivo electrophysiological recording, microiontophoresis, and stimulation of the ascending 5-HT fibers.ResultsVortioxetine enhanced the inhibitory effect of the stimulation of the 5-HT bundle at a high, but not low frequency and reversed the inhibitory effect of the 5-HT1B receptor agonist CP 94253. These results indicate that this compound acted as a 5-HT1B receptor partial agonist. Vortioxetine inhibited 5-HT reuptake but did not dampen the sensitivity of postsynaptic 5-HT1A receptors on pyramidal neurons. Long-term administration of vortioxetine and escitalopram (both at 5 mg/kg/day) induced an increase of tonic activation of the 5-HT1A receptors in CA3 pyramidal neurons, resulting in an increase in 5-HT transmission. In addition, vortioxetine decreased the function of terminal 5-HT1B autoreceptor following its sustained administration.ConclusionsDesensitization of 5-HT1B autoreceptor and an increase of tonic activation of 5-HT1A receptors in the hippocampus may contribute to the antidepressant effect of vortioxetine.

Expression of the 5-HT1A serotonin receptor in the hippocampus is required for social stress resilience and the antidepressant-like effects induced by the nicotinic partial agonist cytisine.

Nicotinic acetylcholine receptor (nAChR) blockers potentiate the effects of selective serotonin reuptake inhibitors (SSRIs) in some treatment-resistant patients; however, it is not known whether these effects are independent, or whether the two neurotransmitter systems act synergistically. We first determined that the SSRI fluoxetine and the nicotinic partial agonist cytisine have synergistic effects in a mouse model of antidepressant efficacy, whereas serotonin depletion blocked the effects of cytisine. Using a pharmacological approach, we found that the 5-HT1A agonist 8-OH-DPAT also potentiated the antidepressant-like effects of cytisine, suggesting that this subtype might mediate the interaction between the serotonergic and cholinergic systems. The 5-HT1A receptors are located both presynaptically and postsynaptically. We therefore knocked down 5-HT1A receptors in either the dorsal raphe (presynaptic autoreceptors) or the hippocampus (a brain area with high expression of 5-HT1A heteroreceptors sensitive to cholinergic effects on affective behaviors). Knockdown of 5-HT1A receptors in hippocampus, but not dorsal raphe, significantly decreased the antidepressant-like effect of cytisine. This study suggests that serotonin signaling through postsynaptic 5-HT1A receptors in the hippocampus is critical for the antidepressant-like effects of a cholinergic drug and begins to elucidate the molecular mechanisms underlying interactions between the serotonergic and cholinergic systems related to mood disorders.

The Antidepressant-Like Effect of Fish Oil: Possible Role of Ventral Hippocampal 5-HT1A Post-synaptic Receptor.

The pathophysiology of depression is not completely understood; nonetheless, numerous studies point to serotonergic dysfunction as a possible cause. Supplementation with fish oil rich docosahexaenoic (DHA) and eicosapentaenoic acids (EPA) during critical periods of development produces antidepressant effects by increasing serotonergic neurotransmission, particularly in the hippocampus. In a previous study, the involvement of 5-HT1A receptors was demonstrated and we hypothesized that fish oil supplementation (from conception to weaning) alters the function of post-synaptic hippocampal 5-HT1A receptors. To test this hypothesis, female rats were supplemented with fish oil during habituation, mating, gestation, and lactation. The adult male offspring was maintained without supplementation until 3 months of age, when they were subjected to the modified forced swimming test (MFST) after infusion of vehicle or the selective 5-HT1A antagonist, WAY100635, and frequency of swimming, immobility, and climbing was recorded for 5 min. After the behavioral test, the hippocampi were obtained for quantification of serotonin (5-HT) and its metabolite, 5-hydroxyindoleacetic acid (5-HIAA) and for 5-HT1A receptor expression by Western blotting analysis. Fish oil-supplemented offspring displayed less depressive-like behaviors in the MFST reflected by decreased immobility and increased swimming and higher 5-HT hippocampal levels. Although there was no difference in the expression of hippocampal 5-HT1A receptors, intra-hippocampal infusion of a sub-effective dose of 8-OH-DPAT enhanced the antidepressant effect of fish oil in supplemented animals. In summary, the present findings suggest that the antidepressant-like effects of fish oil supplementation are likely related to increased hippocampal serotonergic neurotransmission and sensitization of hippocampal 5-HT1A receptors.

Hippocampal 5-HT1A receptor binding is related to object-location memory in humans.

Animal studies suggest that serotonin, mediated by the 5-HT1A receptor, plays a key role in spatial learning and memory. The role of serotonin in spatial memory in humans has, however, been less well studied. This study examined the relationship between serotonin receptor density in the human brain and spatial learning and memory using the 5-HT1A receptor ligand (18)F-4-(2'-methoxyphenyl)-1-[2'-(N-2-pyridinyl)-p-fluorobenzamido]-ethyl-piperazine ([(18)F] MPPF) and positron emission tomography (PET). Ten neurologically healthy individuals underwent two [(18)F] MPPF PET scans, one while performing a task which involves processing of high-level spatial information ('house scan'), and one while performing a task which involves processing of low-level spatial information ('tunnel scan'). Navigation, recall of arbitrary associations between objects and their spatial location, and ability to draw a plan of the environment were tested following the house scan. 5-HT1A receptor binding did not differ significantly between processing high and low levels of spatial information. Hippocampal asymmetry in [(18)F] MPPF binding, however, was associated with memory for object-location associations; lower right than left hippocampal binding potential (BPND) was related to better memory performance. We conclude that hippocampal serotonergic function plays a role in a fundamental component of human spatial memory, the ability to recall the location of encountered objects.

The effects of chronic ethanol self-administration on hippocampal 5-HT1A receptors in monkeys

BackgroundChronic alcohol consumption reduces brain serotonin and alters the synaptic mechanisms involved in memory formation. Hippocampal 5-HT1A receptors modulate these mechanisms, but the neuroadaptive response of 5HT1A receptors to chronic alcohol self-administration is not well understood. MethodsHippocampal tissue from monkeys that voluntarily self-administered ethanol for 12 months (n=9) and accompanying controls (n=8) were prepared for in vitro receptor autoradiography and laser capture microdissection. The 5-HT1A receptor antagonist, [3H]MPPF, and the agonist, [3H]8-OH-DPAT, were used to measure total and G-protein coupled 5-HT1A receptors respectively. The expression of the genes encoding the 5-HT1A receptor and its trafficking protein Yif1B was measured in microdissected dentate gyrus (DG) granule cells and CA1 pyramidal neurons. ResultsAn increase in G-protein coupled, but not total, receptors was observed in the posterior pyramidal cell layer of CA1 in ethanol drinkers compared to controls. Chronic ethanol self-administration was also associated with an up-regulation of total and G-protein coupled 5-HT1A receptors in the posterior DG polymorphic layer. Changes in receptor binding were not associated with concomitant changes in 5-HT1A receptor mRNA expression. Chronic ethanol self-administration was associated with a significant increase in Yif1B gene expression in posterior CA1 pyramidal neurons. ConclusionsChronic, ethanol self-administration up-regulates hippocampal 5-HT1A receptor density in a region-specific manner that does not appear to be due to alterations at the level of transcription but instead may be due to increased receptor trafficking. Further exploration of the mechanisms mediating chronic ethanol-induced 5-HT1A receptor up-regulation and how hippocampal neurotransmission is altered is warranted.

Brain-derived neurotrophic factor genotype status impacts on hippocampal serotonin 5-HT1A receptor binding

Brain-derived neurotrophic factor genotype status impacts on hippocampal serotonin 5-HT1A receptor binding