Search

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-HT 1A receptor (5-HT 1A R) is believed to be involved in these hippocampal pattern separation processes. However, in the dorsal raphe nucleus (DRN), the 5-HT 1A R is expressed as a somatodendritic autoreceptor, negatively regulates serotonergic signaling, and could thereby counteract the effects of hippocampal postsynaptic 5-HT 1A receptors. Therefore, this study aims to identify how pre- and post-synaptic 5-HT 1A R 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-HT 1A R 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-HT 1A R stimulation - was measured daily. Additionally, 5-HT 1A R 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-HT 1A 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., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Although serotonin 1A (5-HT1A) receptor agonists are widely used as the additive compound to reduce l-dopa-induced dyskinesia in Parkinson's disease (PD), few studies focused on the effect and mechanism of 5-HT1A receptor agonist on the motor symptoms of PD. Unilateral 6-hydroxydopamine (6-OHDA)-lesioned rats were used and implantation of electrodes was performed in the motor cortex of these rats. So the effect of 5-HT1A receptor agonist 8-OH-DPAT on motor behaviors and oscillatory activities were evaluated. In addition, 8-OH-DPAT combined with D2 receptor antagonist raclopride, NMDA receptor antagonist MK-801, or its agonist d-cycloserine (DCS) were co-administrated. 8-OH-DPAT administration significantly improved spontaneous locomotor activity and asymmetric forepaw function in 6-OHDA-lesioned rats. Meanwhile, 8-OH-DPAT identified selective modulation of the abnormal high beta oscillations (25-40 Hz) in the motor cortex of 6-OHDA-lesioned rats, without inducing pathological finely tuned gamma around 80 Hz. Different from 8-OH-DPAT, l-dopa treatment produced a prolonged improvement on motor performances and differential regulation of high beta and gamma oscillations. However, dopamine D2 receptor antagonist had no influence on the 8-OH-DPAT-mediated-motor behaviors and beta oscillations in 6-OHDA-lesioned rats. In contrast, subthreshold NMDA receptor antagonist MK-801 obviously elevated the 8-OH-DPAT-mediated-motor behaviors, while NMDA receptor agonist DCS partially impaired the 8-OH-DPAT-mediated symptoms in 6-OHDA-lesioned rats. This study suggests that 5-HT1A receptor agonist 8-OH-DPAT improves motor activity and modulates the oscillations in the motor cortex of parkinsonian rats. Different from l-dopa, 8-OH-DPAT administration ameliorates motor symptoms of PD through glutamatergic rather than the dopaminergic pathway., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Systemic 8-OH-DPAT (a 5-HT 1A receptor agonist) challenge evokes hyperventilation independent of peripheral 5-HT 1A receptors. Though the pre-Botzinger Complex (PBC) is critical in generating respiratory rhythm and activation of local 5-HT 1A receptors induces tachypnea via disinhibition of local GABA A neurons, its role in the respiratory response to systemic 8-OH-DPAT challenge is still unclear. In anesthetized rats, 8-OH-DPAT (100 μg/kg, iv) was injected twice to confirm the reproducibility of the evoked responses. The same challenges were performed after bilateral microinjections of (S)-WAY-100135 (a 5-HT 1A receptor antagonist) or gabazine (a GABA A receptor antagonist) into the PBC. Our results showed that: 1) 8-OH-DPAT caused reproducible hyperventilation associated with hypotension and bradycardia; 2) microinjections of (S)-WAY-100135 into the PBC attenuated the hyperventilation by ˜60 % without effect on the evoked hypotension and bradycardia; and 3) the same hyperventilatory attenuation was also observed after microinjections of gabazine into the PBC. Our data suggest that PBC 5-HT 1A receptors play a key role in the respiratory response to systemic 8-OH-DPAT challenge likely via disinhibiting local GABAergic neurons., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Neuromodulatory systems may provide information on social context to auditory brain regions, but relatively few studies have assessed the effects of neuromodulation on auditory responses to acoustic social signals. To address this issue, we measured the influence of the serotonergic system on the responses of neurons in a mouse auditory midbrain nucleus, the inferior colliculus (IC), to vocal signals. Broadband vocalizations (BBVs) are human-audible signals produced by mice in distress as well as by female mice in opposite-sex interactions. The production of BBVs is context-dependent in that they are produced both at early stages of interactions as females physically reject males and at later stages as males mount females. Serotonin in the IC of males corresponds to these events, and is elevated more in males that experience less female rejection. We measured the responses of single IC neurons to five recorded examples of BBVs in anesthetized mice. We then locally activated the 5-HT1A receptor through iontophoretic application of 8-OH-DPAT. IC neurons showed little selectivity for different BBVs, but spike trains were characterized by local regions of high spike probability, which we called "response features." Response features varied across neurons and also across calls for individual neurons, ranging from 1 to 7 response features for responses of single neurons to single calls. 8-OH-DPAT suppressed spikes and also reduced the numbers of response features. The weakest response features were the most likely to disappear, suggestive of an "iceberg"-like effect in which activation of the 5-HT1A receptor suppressed weakly suprathreshold response features below the spiking threshold. Because serotonin in the IC is more likely to be elevated for mounting-associated BBVs than for rejection-associated BBVs, these effects of the 5-HT1A receptor could contribute to the differential auditory processing of BBVs in different behavioral subcontexts., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gentile Polese, Nigam and Hurley.)

Rationale: The prevalence of depression is ever-increasing throughout the population. However, available treatments are ineffective in around one-third of patients and there is a need for more effective and safer drugs., Objectives: The antidepressant-like and procognitive effects of the "biased agonists" F15599 (also known as NLX-101) which preferentially targets postsynaptic 5-HT 1A receptors and F13714, which targets 5-HT 1A autoreceptors, were investigated in mice., Methods: Antidepressant-like properties of the compounds and their effect on cognitive functions were assessed using the forced swim test (FST) and the novel object recognition (NOR), respectively. Next, we induced a depressive-like state by an unpredictable chronic mild stress (UCMS) procedure to test the compounds' activity in the depression model, followed by measures of sucrose preference, FST, and locomotor activity. Levels of phosphorylated cyclic AMP response element-binding protein (p-CREB) and phosphorylated extracellular signal-regulated kinase (p-ERK1/2) were also determined., Results: F15599 reduced immobility time in the FST over a wider dose-range (2 to 16 mg/kg po) than F13714 (2 and 4 mg/kg po), suggesting accentuated antidepressant-like properties in mice. F15599 did not disrupt long-term memory consolidation in the NOR at any dose tested, while F13714 impaired memory formation, notably at higher doses (4-16 mg/kg). In UCMS mice, a single administration of F15599 and F13714 was sufficient to robustly normalize depressive-like behavior in the FST but did not rescue disrupted sucrose preference. Both F15599 and F13714 rescued cortical and hippocampal deficits in p-ERK1/2 levels of UCMS mice but did not influence the p-CREB levels., Conclusions: Our studies showed that 5-HT 1A receptor biased agonists such as F13714 and especially F15599, due to its less pronounced side effects, might have potential as fast-acting antidepressants., (© 2021. The Author(s).)

Changes in 5-HT 1A receptor (5-HT 1A R)-mediated neurotransmission in the hippocampus have been associated with anxiety, depression and in the mode of action of antidepressant drugs. It has been commonly accepted that whereas the dorsal pole of the hippocampus (DH) is involved in cognitive processing, the ventral pole (VH) is associated with emotional regulation. However, to date, only a few studies have directly addressed the role played by VH 5-HT 1A Rs in anxiety and panic processing, and their results are conflicting. Here we report that intra-VH administration of the 5-HT 1A receptor agonist 8-OH-DPAT, the endogenous agonist serotonin (5-HT), or the standard anxiolytic benzodiazepine midazolam impaired the acquisition of inhibitory avoidance in the elevated T-maze (ETM) of male Wistar rats, indicating an anxiolytic effect. Conversely, local injection of the 5-HT 1A R antagonist WAY-100635 caused the opposite effect. These results were equally found in the Vogel conflict test. None of these drugs interfered with locomotor activity in the open-field test, nor did they alter the expression of the escape response in the ETM, a defensive behavior associated with panic. Pre-injection of a sub-effective dose of WAY-100635 in the VH blocked the anxiolytic effect of 5-HT or 8-OH-DPAT in the Vogel test, confirming the involvement of 5-HT 1A R for this behavioral effect. The effect in this test was anxiety-selective as none of the drugs affected water consumption or nociception. In conclusion, our results suggest that 5-HT 1A Rs in the VH play a tonic inhibitory role in anxiety processing. These receptors, however, are not involved in the regulation of panic-related escape behavior., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Antidepressant drugs are first-line treatment for panic disorder. Facilitation of 5-HT 1A receptor-mediated neurotransmission in the dorsal periaqueductal gray (dPAG), a key panic-associated area, has been implicated in the panicolytic effect of the selective serotonin reuptake inhibitor fluoxetine. However, it is still unknown whether this mechanism accounts for the antipanic effect of other classes of antidepressants drugs (ADs) and whether the 5-HT interaction with 5-HT 2C receptors in this midbrain area (which increases anxiety) is implicated in the anxiogenic effect caused by short-term treatment with ADs. The results showed that previous injection of the 5-HT 1A receptor antagonist WAY-100635 in the dPAG blocked the panicolytic-like effect caused by chronic systemic administration of the tricyclic AD imipramine in male Wistar rats tested in the elevated T-maze. Neither chronic treatment with imipramine nor fluoxetine changed the expression of 5-HT 1A receptors in the dPAG. Treatment with these ADs also failed to significantly change ERK1/2 (extracellular-signal regulated kinase) phosphorylation level in this midbrain area. Blockade of 5-HT 2C receptors in the dPAG with the 5-HT 2C receptor antagonist SB-242084 did not change the anxiogenic effect caused by a single acute injection of fluoxetine or imipramine in the Vogel conflict test. These results reinforce the view that the facilitation of 5-HT 1A receptor-mediated neurotransmission in the dPAG is a common mechanism involved in the panicolytic effect caused by chronic administration of ADs. On the other hand, the anxiogenic effect observed after short-term treatment with these drugs does not depend on 5-HT 2C receptors located in the dPAG., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Serotonin (5-HT) neurotransmission has been associated with reward-related behaviour. Moreover, the serotonergic system modulates the basolateral amygdala (BLA), a structure involved in reward encoding, and reward prediction error. However, the role played by 5-HT on BLA during a reward-driven task has not been fully elucidated. In this paper, we investigated whether serotonergic modulation of the BLA is involved in reward-driven learning. To this end, we trained Long Evans rats in an operant conditioning task, and examined the effects of fluoxetine treatment (a selective serotonin reuptake inhibitor, 10 mg/kg) in combination with BLA lesions with NMDA (20 mg/mL) on extinction learning. We also investigated whether intra-BLA injection of the serotonergic 5-HT 1A receptor agonist 8-OH DPAT, or antagonist WAY-100635, alters extinction performance. We found that fluoxetine treatment strongly accelerated extinction learning, while BLA lesions partially reverted this effect and slightly impaired consolidation of extinction. Stimulation and inhibition of 5-HT 1A receptors in BLA induced opposite effects to those of fluoxetine, impairing or accelerating extinction performance, respectively. Our findings suggest that 5-HT modulates reward-driven learning, and 5-HT 1A receptors located in the BLA are relevant for extinction., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Rats show mutual-reward preferences, i.e., they prefer options that result in a reward for both themselves and a conspecific partner to options that result in a reward for themselves, but not for the partner. In a previous study, we have shown that lesions of the basolateral amygdala (BLA) reduced choices for mutual rewards. Here, we aimed to explore the role of 5-HT 1A receptors within the BLA in mutual-reward choices. Rats received daily injections of either 50 or 25 ng of the 5-HT 1A receptor agonist 8-OH-DPAT or a vehicle solution into the BLA and mutual-reward choices were measured in a rodent prosocial choice task. Compared to vehicle injections, 8-OH-DPAT significantly increased mutual-reward choices when a conspecific was present. By contrast, mutual-reward choices were significantly reduced by 8-OH-DPAT injections in the presence of a toy rat. The effect of 8-OH-DPAT injections was statistically significant during the expression, but not during learning of mutual-reward behavior, although an influence of 8-OH-DPAT injections on learning could not be excluded. There were no differences between 8-OH-DPAT-treated and vehicle-treated rats in general reward learning, behavioral flexibility, locomotion or anxiety. In this study, we have shown that repeated injections of the 5-HT 1A receptor agonist 8-OH-DPAT have the potential to increase mutual-reward choices in a social setting without affecting other behavioral parameters.

The majority of the fibroblast growth factor receptor 1-serotonin 1 A receptor (FGFR1-5-HT1AR) heterocomplexes in the hippocampus appeared to be located mainly in the neuronal networks and a relevant target for antidepressant drugs. Through a neurochemical and electrophysiological analysis it was therefore tested in the current study if astrocytic FGFR1-5-HT1AR heterocomplexes also exist in hippocampus. They may modulate the structure and function of astroglia in the hippocampus leading to possible changes in the gamma oscillations. Localization of hippocampal FGFR1-5-HT1AR heterocomplexes in astrocytes was found using in situ proximity ligation assay combined with immunohistochemistry using glial fibrillary acidic protein (GFAP) immunoreactivity as a marker for astroglia. Acute i.c.v. treatment with 8-OH-DPAT alone or together with basic fibroblast growth factor (FGF2) significantly increased FGFR1-5-HT1AR heterocomplexes in the GFAP positive cells, especially in the polymorphic layer of the dentate gyrus (PoDG) but also in the CA3 area upon combined treatment. No other hippocampal regions were studied. Also, structural plasticity changes were observed in the astrocytes, especially in the PoDG region, upon these pharmacological treatments. They may also be of relevance for enhancing the astroglial volume transmission with increased modulation of the neuronal networks in the regions studied. The effects of combined FGF2 and 5-HT agonist treatments on gamma oscillations point to a significant antagonistic interaction in astroglial FGFR1-5-HT1AR heterocomplexes that may contribute to counteraction of the 5-HT1AR-mediated decrease of gamma oscillations. This article is part of the special issue entitled 'Serotonin Research: Crossing Scales and Boundaries'., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Forming effective responses to threatening stimuli requires the adequate and coordinated emergence of stress-related internal states. Such ability depends on early-life experiences and, in connection, the adequate formation of neuromodulatory systems, particularly serotonergic signaling. Here, we assess the serotonergic background of experience-dependent behavioral responsiveness using male and female zebrafish ( Danio rerio ). For the first time, we have characterized a period during behavioral metamorphosis in which zebrafish are highly reactive to their environment. Absence of social stimuli during this phase established by isolated rearing fundamentally altered the behavioral phenotype of postmetamorphic zebrafish in a challenge-specific manner, partially due to reduced responsiveness and an inability to develop stress-associated arousal state. In line with this, isolation differentially affected whole-brain serotonergic signaling in resting and stress-induced conditions, an effect that was localized in the dorsal pallium and was negatively associated with responsiveness. Administration of the serotonin receptor 1A partial agonist buspirone prevented the isolation-induced serotonin response to novelty in the level of the whole brain and the forebrain as well, without affecting catecholamine levels, and rescued stress-induced arousal along with challenge-induced behaviors, which together indicates functional connection between these changes. In summary, there is a consistent negative association between behavioral responsiveness and serotonergic signaling in zebrafish, which is well recognizable through the modifying effects of developmental perturbation and pharmacological manipulations as well. Our results imply a conserved serotonergic mechanism that context-dependently modulates environmental reactivity and is highly sensitive to experiences acquired during a specific early-life time window, a phenomenon that was previously only suggested in mammals. SIGNIFICANCE STATEMENT The ability to respond to challenges is a fundamental factor in survival. We show that zebrafish that lack appropriate social stimuli in a sensitive developmental period show exacerbated alertness in nonstressful conditions while failing to react adequately to stressors. This shift is reflected inversely by central serotonergic signaling, a system that is implicated in numerous mental disorders in humans. Serotonergic changes in brain regions modulating responsivity and behavioral impairment were both prevented by the pharmacological blockade of serotonergic function. These results imply a serotonergic mechanism in zebrafish that transmits early-life experiences to the later phenotype by shaping stress-dependent behavioral reactivity, a phenomenon that was previously only suggested in mammals. Zebrafish provide new insights into early-life-dependent neuromodulation of behavioral stress-responses., (Copyright © 2020 the authors.)

To facilitate smoking genetics research we determined whether a screen of mutagenized zebrafish for nicotine preference could predict loci affecting smoking behaviour. From 30 screened F 3 sibling groups, where each was derived from an individual ethyl-nitrosurea mutagenized F 0 fish, two showed increased or decreased nicotine preference. Out of 25 inactivating mutations carried by the F 3 fish, one in the slit3 gene segregated with increased nicotine preference in heterozygous individuals. Focussed SNP analysis of the human SLIT3 locus in cohorts from UK (n=863) and Finland (n=1715) identified two variants associated with cigarette consumption and likelihood of cessation. Characterisation of slit3 mutant larvae and adult fish revealed decreased sensitivity to the dopaminergic and serotonergic antagonist amisulpride, known to affect startle reflex that is correlated with addiction in humans, and increased htr1aa mRNA expression in mutant larvae. No effect on neuronal pathfinding was detected. These findings reveal a role for SLIT3 in development of pathways affecting responses to nicotine in zebrafish and smoking in humans., Competing Interests: JG, AB, MP, RR, DJ, AS, MT, EB, DS, AM, JK, TP, VK, RW, CB No competing interests declared, (© 2020, García-González et al.)

Ethnopharmacological Relevance: Salvia divinorum Epling & Játiva is a Mexican plant used not only in rituals but also in traditional medicine for pain relief. One of the most known bioactive compounds is salvinorin A, which acts centrally in kappa-type opioid receptors., Aim of the Study: Despite its traditional use as a medicinal plant, there is not enough scientific investigation to reinforce its potential as analgesic. In this study, Salvia divinorum antinociceptive activity was evaluated in experimental models of nociceptive pain; the writhing test and formalin-induced licking behavior in mice., Material and Methods: Different Salvia divinorum extracts were prepared by maceration at room temperature in increased polarity (hexane, ethyl acetate and methanol). The ethyl acetate extract (EAEx) was chosen in order to be fractioned and to obtain a mixture of salvinorins. The antinociceptive effect of EAEx (3, 10, 30, and 100 mg/kg, i.p.) was compared with that of tramadol (a partial opioid agonist analgesic drug, 30 mg/kg, i.p.) and the mixture of salvinorins (30 mg/kg, i.p.). In addition, a participation of opioids (naloxone, NX 1 and/or 3 mg/kg, i.p.) and serotonin 5-HT 1A receptors (WAY100635, 0.32 mg/kg, i.p.) was investigated as possible inhibitory neurotransmission involved., Results: As a result, the EAEx produced significant and dose-dependent antinociceptive effect concerning salvinorins constituents. This effect was blocked in the presence of NX and WAY100635 in the abdominal test, but only by NX in the formalin-induced licking behavior. Whereas, the effect of salvinorins mixture involved opioids and serotonin 5-HT 1A receptors., Conclusion: Data provide evidence of the potential of this species, where salvinorin A is in part responsible bioactive constituent involving participation of the opioids and/or 5-HT 1A serotonin receptors depending on the kind of pain model explored., (Copyright © 2019. Published by Elsevier B.V.)

Although the dorsal hippocampus (dHPC) and serotonin 1A (5-HT 1A ) receptor are involved in cognition, their roles in cognitive impairments in Parkinson' disease (PD) are still unclear. In the present study, the effects of the 5-HT 1A receptor agonist 8-OH-DPAT and antagonist WAY100635 administrated into the dHPC of rats were assessed in T-maze rewarded alternation test for working memory and in hole-board test for long-term habituation. Unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle in rats impaired working memory and long-term habituation, decreased dopamine (DA) levels in the medial prefrontal cortex (mPFC), dHPC and ventral hippocampus (vHPC), and decreased the mean density of 5-HT 1A receptors and co-localization of 5-HT 1A receptor and excitatory amino acid carrier 1-immunoreactive (EAAC1-ir) neurons in the dHPC compared to sham-operated rats. Activation of dHPC 5-HT 1A receptors by local infusion of 8-OH-DPAT impaired working memory and long-term habituation in both sham-operated and the 6-OHDA-lesioned rats. Furthermore, blockade of dHPC 5-HT 1A receptors by WAY100635 improved the memories in the 6-OHDA-lesioned rats, but had no effects in sham-operated rats. Additionally, dHPC injection of 8-OH-DPAT decreased noradrenaline (NA) levels, increased 5-HT levels in the mPFC, dHPC and vHPC in sham-operated and lesioned rats, while WAY100635 increased DA and NA levels only in lesioned rats. The results of the present study suggest that dHPC 5-HT 1A receptors regulate cognitive impairments in PD by changes of monoamines in the related brain regions., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common childhood behavioural disorders, the frontline treatments for which are drugs with abuse potential. As a consequence, there is an urgent need to develop non addictive drug treatments with equivalent efficacy. Preclinical evidence suggests that selective serotonin uptake inhibitors (SSRIs) are likely to be effective in ADHD, however clinical reports suggest that SSRIs are of limited therapeutic value for the treatment of ADHD. We propose that this disconnect can be explained by the pattern of drug administration in existing clinical trials (administration for short periods of time, or intermittently) leading to inadequate control of the autoregulatory processes which control 5-HT release, most notably at the level of inhibitory 5-HT 1A somatodendritic autoreceptors. These autoreceptors reduce the firing rate of 5-HT neurons (limiting release) unless they are desensitised by a long term, frequent pattern of drug administration. As such, we argue that the participants in earlier trials were not administered SSRIs in a manner which realises any potential benefits of targeting 5-HT in the pharmacotherapy of ADHD. In light of this, we hypothesise that there may be under-researched potential to exploit 5-HT transmission therapeutically in ADHD, either through changing the administration regime, or by pharmacological means. Recent pharmacological research has successfully potentiated the effects of SSRIs in acute animal preparations by antagonising inhibitory 5-HT 1A autoreceptors prior to the administration of the SSRI fluoxetine. We suggest that combination therapies linking SSRIs and 5-HT 1A antagonists are a potential way forward in the development of efficacious non-addictive pharmacotherapies for ADHD., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Long-term single housing increases aggressive behavior in mice, a condition named isolation-induced aggression or territorial aggression, which can be attenuated by anxiolytic, antidepressant, and antipsychotic drugs. Preclinical and clinical findings indicate that cannabidiol (CBD), a non-psychotomimetic compound from Cannabis sativa, has anxiolytic, antidepressant, and antipsychotic properties. Few studies, however, have investigated the effects of CBD on aggressive behaviors. Here, we investigated whether CBD (5, 15, 30, and 60 mg/kg; i.p.) could attenuate social isolation-induced aggressive behavior in the resident-intruder test. Male Swiss mice (7-8 weeks) were single-housed for 10 days (resident mice) to induce aggressive behaviors, while conspecific mice of same sex and age (intruder mice) were group-housed. During the test, the intruder was placed into the resident's home-cage and aggressive behaviors initiated by the resident, including the latency for the first attack, number of attacks, and total duration of aggressive encounters, were recorded. The involvement of 5-HT1A and CB1 receptors (CB1R) in the effects of CBD was also investigated. All tested CBD doses induced anti-aggressive effects, indicated by a decrease in the number of attacks. CBD, at intermediary doses (15 and 30 mg/kg), also increased latency to attack the intruder and decreased the duration of aggressive encounters. No CBD dose interfered with locomotor behavior. CBD anti-aggressive effects were attenuated by the 5-HT1A receptor antagonist WAY100635 (0.3 mg/kg) and the CB1 antagonist AM251 (1 mg/kg), suggesting that CBD decreases social isolation-induced aggressive behaviors through a mechanism associated with the activation of 5-HT1A and CB1 receptors. Also, CBD decreased c-Fos protein expression, a neuronal activity marker, in the lateral periaqueductal gray (lPAG) in social-isolated mice exposed to the resident-intruder test, indicating a potential involvement of this brain region in the drug effects. Taken together, our findings suggest that CBD may be therapeutically useful to treat aggressive behaviors that are usually associated with psychiatric disorders., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The aim of the present study was to determine the involvement of the VTA 5-HT 1A receptors in analgesia induced by the co-administration of morphine and dextromethorphan (DM). Male Wistar rats were bilaterally cannulated in the VTA by the stereotaxic instrument. The tail-flick and formalin tests were performed to assess nociception in the acute and tonic pain conditions respectively. The present data indicated that intraperitoneal (i.p.) administration of morphine increased the tail-flick latency (1-4 mg/kg) and decreased the pain score of formalin test (2-8 mg/kg), showing an analgesic effect. Co-administration of ineffective doses of morphine (1 or 2 mg/kg) with DM (30 mg/kg, i.p.) induced analgesia in both animal models. Interestingly, intra-VTA microinjection of 5HT 1A receptors antagonist, S-WAY100-135 (0.5 and 1 µg/kg), inhibited the analgesic effect of morphine plus DM in both acute and tonic pain models. It should be considered that the same doses of DM or S-WAY100-135 by itself had no effects on antinociception in the animal models. Overall, these results indicated that systemic blockade of NMDA receptors via DM administration potentiated the response of a low dose of morphine to induce analgesic effect. Additionally, it seems that the VTA serotonergic system via 5HT 1A receptors mediates the potentiative effect of DM on morphine-induced analgesia., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Rationale: Pre-clinical and clinical studies have suggested that the antidepressant efficacy of escitalopram (ESC) can be augmented by co-administration of aripiprazole (ARI)., Objective: To establish if the effects of ESC + ARI can be altered by modulating the 5-HT 1a receptor., Methods: Sprague-Dawley male rats received ESC + ARI (10 and 2 mg/kg/day, respectively, via osmotic or by cumulative injections), as well as the 5-HT 1a antagonist WAY-100635 (WAY; 0.01-1 mg/kg) and the 5-HT 1a agonist 8-OH-DPAT (DPAT; 0.3-1 mg/kg) prior to testing in locomotion chambers and in the forced swim test (FST). Expression of the 5-HT 1a receptor mRNA in the dorsal raphe nucleus, hippocampus, septum, and entorhinal cortex was also assessed., Results: WAY generally synergized, while DPAT antagonized, the effect of ESC + ARI on motor activity. All groups showed significantly lower 5-HT 1a mRNA in the dorsal raphe nucleus. In the hippocampus, ESC + ARI and WAY + ESC + ARI groups displayed equivalent elevations of 5-HT 1a mRNA, but this was not observed in groups that received DPAT + ESC + ARI. Finally, the addition of ARI to ESC augmented the effect that ESC alone had on reducing immobility in the FST. Importantly, WAY antagonized this effect, while DPAT had no consequences., Conclusions: Taken together, these results in rats indicate that the 5-HT 1a receptor is involved in the behavioral and brain region-specific mRNA effects of ESC + ARI.

Therapy of depression is difficult and still insufficient despite the presence of many antidepressants on the market. Therefore, there is a constant need to search for new, safer, and more effective drugs that could be used in the treatment of depression. Among many methods, chemical modification is an important strategy for new drug development. This study evaluates antidepressant-like effects and possible mechanism of action of two new arylpiperazine derivatives with isonicotinic and picolinic nuclei, compounds 4pN-(3-(4-(piperonyl)piperazin-1-yl)propyl) isonicotinamide and 3oN-(2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl) picolinamide. The forced swim test (FST) and tail suspension test (TST), as two predictive tests for antidepressant effect in mice, were used. The possible involvement of serotonergic system in the effects of the new compounds in the FST through pharmacological antagonists/modulators of serotonergic transmission was also investigated. Compounds 4p and 3o were shown to possess antidepressant activity in both tests, FST and TST. The antidepressant-like effects of the new compounds in the FST were prevented by pretreatment of mice with pCPA (serotonin depletor), (-)pindolol (mixed 5-HT 1A/1B and β-adrenergic antagonist), and WAY 100635 (selective 5-HT 1A antagonist). Additionally, in drug interaction studies, the 5-HT 2A/2C antagonist, ketanserin, and the classic antidepressant, imipramine, potentiated antidepressant-like effect of both new compounds. The obtained results demonstrate that the new compounds 4p and 3o produce an antidepressant-like effect in mice which seems to be mediated by interaction with the serotonin 5-HT 1A receptors and in the case of 4p, also with the 5-HT 2C receptors.

Serotonin is involved in the regulation of many physiological and behavioral processes in vertebrates and invertebrates. The effects of serotonin are mediated through interactions of several 5-HT receptor types. The expression and pharmacological properties of 5-HT1 have received more attention than other serotonin receptors, but its functions at the individual level are little studied in arthropods. Silkworm, a Lepidoptera model, almost has no reports about serotonin receptors. To analyze the function of Bm5-HT1A receptor in vitro, the ORF of Bm5-HT1A was cloned into the pcDNA3.1 vector and expressed in HEK 293 cells. Serotonin activation of Bm5-HT1A-expressing cells decreased forskolin-stimulated cAMP synthesis and had the most potent effect compared to other biogenic amines. Serotonin reduced cAMP synthesis in a dose-dependent manner, and half-maximal activation (EC50) occurred at a concentration of 1.17 × 10 -7  M (117 nM). The pharmacological analysis demonstrated that the rank potency of agonists was pimozide >8-OH-DPAT >5-MeOT ~ αm-5-HT, and antagonists was WAY-100635 > prazosin > SB-269970 > methiothepin at the Bm5-HT1A receptor. Injecting the antagonist of Bm5-HT1A receptor into larvae caused slow or weak motility, and adults lowered courtship vitality or moving speed. Injecting dsRNA of Bm5-HT1A into adults also dropped locomotivity in courtship. These results show that the Bm5-HT1A receptor is related to locomotor activity. This study provides the first information of serotonin receptor on pharmacological in silkworm and on individual functions in arthropods., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Ethnopharmacological Relevance: Piper auritum Kunth is employed as an aphrodisiac in the traditional medicine, but corroborative evidence for such effect is scarce., Aim of the Study: The pro-sexual effect of an aqueous extract of P. auritum and its possible mechanisms were analyzed in two paradigms of male sexual function., Material and Methods: Effects of an aqueous extract of P. auritum (PA, single administration) were investigated in the fictive ejaculation, and copulatory behavior paradigms in sexually sluggish male rats. WAY 100635 (antagonist of 5-HT 1A receptors), atosiban (antagonist of oxytocinergic receptors), L-NAME (inhibitor of the nitric oxide synthase) and baclofen (antagonist of GABA B receptors) were used as pre-treatments in order to investigate the role of different neurotransmitter systems in PA actions. Chemical profile of PA was determined by Gases Chromatography and Ultra Performance Chromatography-Electrospray Ionization-Masses Spectrometry (UPLC-ESI-MS)., Results: In males with retarded ejaculation, PA stimulated ejaculatory behavior and recovered electromyographic activity of pelvic musculature participating in seminal emission and ejaculation. All pre-treatments blocked stimulating effects of PA on the fictive ejaculation; additionally WAY 100635 interfered with PA actions on ejaculatory behavior. Safrol, apigenin dimethylether, myristicin, vaccihein A, sakuranin and sakuranetin flavonoids, were main constituents of PA, with possible participation in its pro-sexual effects., Conclusions: Pro-sexual effects of P. auritum elicited at level of ejaculation were mediated by several neurotransmitter systems, among which serotonin and its 5-HT 1A receptors play an important role. Present findings support P. auritum reputation as an aphrodisiac, with potential use in delayed ejaculation disorder., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Serotonin (5-hydroxytryptamine, 5-HT) receptor agonists are neuroprotective in CNS injury models. However, the neuroprotective functional implications and synaptic mechanism of 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH-DPAT), a serotonin receptor (5-HT1A) agonist, in an adult male Wistar rat model of chronic glaucoma model remain unknown. We found that ocular hypertension decreased 5-HT1A receptor expression in rat retinas because the number of retinal ganglion cells (RGCs) was significantly reduced in rats with induced ocular hypertension relative to that in control retinas and 8-OH-DPAT enhanced the RGC viability. The protective effects of 8-OH-DPAT were blocked by intravitreal administration of the selective 5-HT1A antagonist WAY-100635 or the selective GABA A receptor antagonist SR95531. Using patch-clamp techniques, spontaneous and miniature GABAergic IPSCs (sIPSCs and mIPSCs, respectively) of RGCs in rat retinal slices were recorded. 8-OH-DPAT significantly increased the frequency and amplitude of GABAergic sIPSCs and mIPSCs in ON- and OFF-type RGCs. Among the signaling cascades mediated by the 5-HT1A receptor, the role of cAMP-protein kinase A (PKA) signaling was investigated. The 8-OH-DPAT-induced changes at the synaptic level were enhanced by PKA inhibition by H-89 and blocked by PKA activation with bucladesine. Furthermore, the density of phosphorylated PKA (p-PKA)/PKA was significantly increased in glaucomatous retinas and 8-OH-DPAT significantly decreased p-PKA/PKA expression, which led to the inhibition of PKA phosphorylation upon relieving neurotransmitter GABA release. These results showed that the activation of 5-HT1A receptors in retinas facilitated presynaptic GABA release functions by suppressing cAMP-PKA signaling and decreasing PKA phosphorylation, which could lead to the de-excitation of RGC circuits and suppress excitotoxic processes in glaucoma. SIGNIFICANCE STATEMENT We found that serotonin (5-HT) receptors in the retina (5-HT1A receptors) were downregulated after intraocular pressure elevation. Patch-clamp recordings demonstrated differences in the frequencies of miniature GABAergic IPSCs (mIPSCs) in ON- and OFF-type retinal ganglion cells (RGCs) and RGCs in normal and glaucomatous retinal slices. Therefore, phosphorylated protein kinase A (PKA) inhibition upon release of the neurotransmitter GABA was eliminated by 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH-DPAT), which led to increased levels of GABAergic mIPSCs in ON- and OFF-type RGCs, thus enhancing RGC viability and function. These protective effects were blocked by the GABA A receptor antagonist SR95531 or the 5-HT1A antagonist WAY-100635. This study identified a novel mechanism by which activation of 5-HT1A receptors protects damaged RGCs via the cAMP-PKA signaling pathway that modulates GABAergic presynaptic activity., (Copyright © 2019 the authors 0270-6474/19/391485-21$15.00/0.)

Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are first-line antidepressants but require several weeks to elicit their actions. Chronic SSRI treatment induces desensitization of 5-HT1A autoreceptors to enhance 5-HT neurotransmission. Mice (both sexes) with gene deletion of 5-HT1A autoreceptors in adult 5-HT neurons ( 1AcKO ) were tested for response to SSRIs. Tamoxifen-induced recombination in adult 1AcKO mice specifically reduced 5-HT1A autoreceptor levels. The 1AcKO mice showed a loss of 5-HT1A autoreceptor-mediated hypothermia and electrophysiological responses, but no changes in anxiety- or depression-like behavior. Subchronic fluoxetine (FLX) treatment induced an unexpected anxiogenic effect in 1AcKO mice in the novelty suppressed feeding and elevated plus maze tests, as did escitalopram in the novelty suppressed feeding test. No effect was seen in wild-type ( WT ) mice. Subchronic FLX increased 5-HT metabolism in prefrontal cortex, hippocampus, and raphe of 1AcKO but not WT mice, suggesting hyperactivation of 5-HT release. To detect chronic cellular activation, FosB + cells were quantified. FosB + cells were reduced in entorhinal cortex and hippocampus (CA2/3) and increased in dorsal raphe 5-HT cells of 1AcKO mice, suggesting increased raphe activation. In WT but not 1AcKO mice, FLX reduced FosB + cells in the median raphe, hippocampus, entorhinal cortex, and median septum, which receive rich 5-HT projections. Thus, in the absence of 5-HT1A autoreceptors, SSRIs induce a paradoxical anxiogenic response. This may involve imbalance in activation of dorsal and median raphe to regulate septohippocampal or fimbria-fornix pathways. These results suggest that markedly reduced 5-HT1A autoreceptors may provide a marker for aberrant response to SSRI treatment. SIGNIFICANCE STATEMENT Serotonin-selective reuptake inhibitors (SSRIs) are effective in treating anxiety and depression in humans and mouse models. However, in some cases, SSRIs can increase anxiety, but the mechanisms involved are unclear. Here we show that, rather than enhancing SSRI benefits, adulthood knockout (KO) of the 5-HT1A autoreceptor, a critical negative regulator of 5-HT activity, results in an SSRI-induced anxiety effect that appears to involve a hyperactivation of the 5-HT system in certain brain areas. Thus, subjects with very low levels of 5-HT1A autoreceptors, such as during childhood or adolescence, may be at risk for an SSRI-induced anxiety response., (Copyright © 2019 the authors 0270-6474/19/391334-13$15.00/0.)

As G-protein-coupled receptors (GPCRs), 5-hydroxytryptamine 1A receptor (5-HT1AR) and orexin receptor 2 (OX2R) regulate the levels of the cellular downstream molecules. The heterodimers of different GPCRs play important roles in various of neurological diseases. Moreover, 5-HT1AR and OX2R are involved in the pathogenesis of neurological diseases such as depression with deficiency of hippocampus plasticity. However, the direct interaction of the two receptors remains elusive. In the present study, we firstly demonstrated the heterodimer formation of 5-HT1AR and OX2R. Exchange protein directly activated by cAMP (Epac) cAMP bioluminescence resonance energy transfer (BRET) biosensor analysis revealed that the expression levels of cellular cAMP significantly increased in HEK293T cells transfected with the two receptors compared with the 5-HT1AR group. Additionally, the cellular level of calcium was upregulated robustly in HEK293T cells co-transfected with 5-HT1AR and OX2R group after agonist treatment. Furthermore, western blotting data showed that 5-HT1AR and OX2R heterodimer decreased the levels of phosphorylation of extracellular signal-regulated kinase (ERK) and cAMP-response element-binding protein (CREB). These results not only unraveled the formation of 5-HT1AR and OX2R heterodimer but also suggested that the heterodimer affected the downstream signaling pathway, which will provide new insights into the function of the two receptors in the brain., (Copyright © 2018. Published by Elsevier Inc.)

We show that in an animal model of anxiety the overall excitation, particularly in the infralimbic region of the medial prefrontal cortex (IL), is increased and that the activity ratio between excitatory pyramidal neurons and inhibitory interneurons (AR PN/IN) is shifted towards excitation. The same change in AR PN/IN is evident for wildtype mice, which have been exposed to an anxiety stimulus. We hypothesize, that an elevated activity and the imbalance of excitation (PN) and inhibition (IN) within the neuronal microcircuitry of the prefrontal cortex is responsible for anxiety behaviour and employed optogenetic methods in freely moving mice to verify our findings. Consistent with our hypothesis elevation of pyramidal neuron activity in the infralimbic region of the prefrontal cortex significantly enhanced anxiety levels in several behavioural tasks by shifting the AR PN/IN to excitation, without affecting motor behaviour, thus revealing a novel mechanism by which anxiety is facilitated., Competing Interests: The authors have declared that no competing interests exist.

Various types of adaptive behavior during the prepubertal period were analyzed in the offspring of rats receiving chronic injections of serotonin (5-HT) reuptake inhibitor fluoxetine, 5-HT 1A receptor agonist buspirone, or their combination starting from gestation day 9 and subjected to immobilization stress from the 15th day of pregnancy until delivery. Prenatal stress increased pain sensitivity, prolonged inflammatory pain response, and increased the levels of anxiety and depression. Chronic administration of drugs acting through 5-HT 1A receptors to pregnant rats improved the studied behavioral parameters in their offspring. Differences in the pain sensitivity were found between the effect of drug combination and each of them separately, and in the level of depression between combined administration and fluoxetine alone.

The present study was conducted to investigate the sedative and hypnotic activities of Vaccinium bracteatum Thunb. fruit (VBFW) in an animal model and to identify the underlying mechanisms of its action. VBFW exhibited sedative effects through a reduction in the locomotor activity in the open field test (OFT). In addition, VBFW significantly reduced the sleep latency and increased total sleep duration in pentobarbital-induced sleeping behaviors in mice. The effects of 4-Chloro-DL-phenylalanine methyl ester hydrochloride (PCPA) were studied in normal and serotonin-depleted mice. Additionally, the changes in the related serum corticosterone (CORT) and neurotransmitter levels were evaluated. Pretreatment with VBFW (50, and 100 mg/kg) produced a significant decrease in the immobility time in the forced swim test (FST), while VBFW 100 plus PCPA treatment attenuated the change in immobility time observed following administration of VBFW alone. However, VBFW plus PCPA treatments did not significantly influence the changes in the locomotor activity that were induced by VBFW alone. The results suggest that VBFW leads to a decrease in the levels of serum CORT and norepinephrine in the hippocampus (HC) region (P < 0.01). Furthermore, PCPA treatment alone decreased serotonin (5-HT) levels in the HC (P < 0.05) and the prefrontal cortex (PFC; P < 0.05), while VBFW plus PCPA significantly increased the 5-HT levels in both the HC and the PFC (P < 0.05). In addition, we also found that VBFW showed a strong agonistic effect at the 5-HT 1A receptor by activating 5-HT 1A receptor-mediated intracellular Ca 2+ and ERK1/2 phosphorylation. Similarly, VBFW (30 and 100 μg/mL) significantly increased the intracellular Cl - influx through its effects on the γ-aminobutyric acid type A receptor (GABA A receptor) subunits (α 5 , β 1 , and β 2 ) in primary rat cerebellar granule cells. Moreover, the glutamate decarboxylase (GAD) 65/67 protein was upregulated following VBFW treatment (30 and 100 μg/mL). The results of our study indicate that VBFW induces sedative and hypnotic effects by regulating the serotonergic and GABA A -ergic systems, which is possibly associated with 5-HT 1A receptor agonistic activity. Additionally, this data suggests that VBFW up-regulates intracellular Cl - and GABA A receptor subunits as well as GAD 65/67 protein levels., (Copyright © 2018. Published by Elsevier Masson SAS.)

A single base mutation in the Gα i2 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 Gα i2 (RGSi Gα i2 ) 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 Gα i2 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 Gα i2 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 Gα i2 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 Gα i2 knock-in mice and that RGS proteins highly expressed in the hippocampus should be investigated as targets for novel antidepressant therapies., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Serotonin (5-HT) neurons are strongly implicated in mood disorders such as depression and are importantly regulated by feedback inhibition mediated by 5-HT 1A receptors. These receptors may play a role, albeit a poorly understood one, in the generation of mood disorders, treatment response to antidepressants and delayed therapeutic efficacy. Here we sought to gain insight into the role of 5-HT 1A receptor-mediated feedback inhibition in these processes by studying Fos protein expression within serotonin neurons in a rat model of stress-related mood disorder, early life maternal separation (MS), combined with two-week treatment with the antidepressant fluoxetine (FLX) in adulthood. We gauged 5-HT 1A receptor-mediated feedback inhibition by the ability of the antagonist, WAY-100635 (WAY), to disinhibit Fos expression in 5-HT neurons. We found that two-week FLX treatment dramatically inhibited Fos expression in serotonin neurons and that this effect was reversed by blocking 5-HT 1A receptors with WAY. Together these observations reveal that after prolonged exposure to SSRIs, endogenous 5-HT 1A receptors continue to exert feedback inhibition of serotonin neurons. Furthermore we found unique effects of pharmacological treatments after MS in that the WAY effect was greatest in MS rats treated with FLX, a phenomenon selective to the rostral 2/3 of the dorsal raphe nucleus (B7). These results indicate that the balance between activation and feedback inhibition of serotonin neurons in B7 is altered and uniquely sensitive to FLX after early-life stress., (Copyright © 2018. Published by Elsevier Ltd.)

The confinement of rodents to the open arm of the elevated-plus maze provokes antinociception (OAA). As a type of defensive reaction, the OAA has been investigated through systemic and intramesencephalic (e.g., dorsal portion of the periaqueductal gray - dPAG) injections of anxiolytic-like drugs [e.g., serotonergic (5-HT) receptor agonists or antagonists]. Here we investigated the effects of (i) intra-dPAG injections of a 5HT 2C receptor agonist (MK-212; 0.21 or 0.63 nmol) and antagonist (SB 242084; 0.01, 0.1 or 1.0 nmol); (ii) combined injections of SB 242084 and MK-212 into the dPAG; (iii) combined injections of SB 242084 with 8-OHDPAT (10 nmol) into the dPAG on the OAA in male Swiss mice. Nociception was assessed with the writhing test induced by acetic acid injection. Results showed that (i) intra-dPAG injection of MK-212 (0.63 nmol) increased the OAA; (ii) intra-dPAG SB 242084 (1.0 nmol) prevented the OAA; (iii) SB 242084 (0.1 nmol, a dose devoid of intrinsic effect on nociception) blocked the OAA enhancement provoked by MK-212 and enabled 8-OH-DPAT to prevent the OAA. These results suggest that OAA is mediated by 5-HT 2C receptors within the dPAG. Intra-dPAG SB242084 administration provoked similar results on the effects produced by MK-212 and 8-OH-DPAT on OAA. In addition, the dPAG 5-HT 1A and 5-HT 2C receptors interact each other in the modulation of OAA., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Neuromodulatory transmitters, such as serotonin (5-HT), selectively regulate the excitability of subpopulations of cortical projection neurons to gate cortical output to specific target regions. For instance, in the mouse prelimbic cortex, 5-HT selectively excites commissurally projecting (COM) intratelencephalic neurons via activation of 5-HT 2A (2A) receptors, while simultaneously inhibiting, via 5-HT 1A (1A) receptors, corticofugally projecting pyramidal neurons targeting the pons. Here we characterize the physiology, morphology, and serotonergic regulation of corticoamygdalar (CAm) projection neurons in the mouse prelimbic cortex. Layer 5 CAm neurons shared a number of physiological and morphological characteristics with COM neurons, including higher input resistances, smaller HCN-channel mediated responses, and sparser dendritic arbors than corticopontine neurons. Across cortical lamina, CAm neurons also resembled COM neurons in their serotonergic modulation; focally applied 5-HT (100 μM; 1 s) generated 2A-receptor-mediated excitation, or 1A- and 2A-dependent biphasic responses, in ipsilaterally and contralaterally projecting CAm neurons. Serotonergic excitation depended on extrinsic excitatory drive, as 5-HT failed to depolarize CAm neurons from rest, but could enhance the number of action potentials generated by simulated barrages of synaptic input. Finally, using dual tracer injections, we identified double-labeled CAm/COM neurons that displayed primarily excitatory or biphasic responses to 5-HT. Overall, our findings reveal that prelimbic CAm neurons in layer 5 overlap, at least partially, with COM neurons, and that neurons projecting to either, or both targets, exhibit 2A-dependent serotonergic excitation. These results suggest that 5-HT, acting at 2A receptors, may promote cortical output to the amygdala.

The present study investigated the effects of estradiol (E2) on ingestive behavior after activation of 5-HT1A receptors in the lateral hypothalamus (LH) of female rats habituated to eat a wet mash diet. Ovariectomized rats treated with corn oil (OVX) or estradiol cypionate (OVX+E) received local injections into the LH of vehicle or an agonist of 5-HT1A receptors, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT; at a dose of 6 nmol). To determine the involvement of these receptors in food intake, some animals were pretreated with N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane carboxamide maleate (WAY-100635, a 5-HT1A receptor full antagonist, at a dose of 0.37 nmol), followed by the injection of the agonist 8-OH-DPAT or its vehicle. The results showed that the injection of 8-OH-DPAT into the LH of OVX rats significantly increased food intake, and the duration and frequency of this behavior. The pretreatment with E2 suppressed the hyperphagic response induced by 8-OH-DPAT in OVX animals. The inhibition of 5-HT1A receptors after pretreatment with WAY-100635 blocked the hyperphagic effects evoked by 8-OH-DPAT in OVX. These results indicate that the activity of LH 5-HT1A receptors could be affected by blood E2 levels.

Adaptations within the nucleus accumbens (NAc) and caudate nucleus (CN) dopamine neurotransmission are involved in behavioral sensitization and enhanced incentive motivation towards drug paired stimuli which lead to drug addiction. Serotonin (5-hydroxytryptamine; 5-HT) can modulate dopamine neurotransmission to reduce rewarding effects of drugs of abuse. A recent study from our laboratory shows that rewarding effects of morphine are inhibited in rats co-treated with buspirone. To understand the neurochemical mechanism involved in morphine addiction and its inhibition with buspirone, present study determines the effects of buspirone, morphine and their co-administration on the metabolism of serotonin and dopamine in the NAc and CN. We find that rewarding effects of morphine are associated with an enhancement and attenuation of dopamine metabolism, respectively in the CN and NAc. Serotonin metabolism is enhanced in both regions. Co-administration of buspirone not only prevents rewarding effects of morphine, but its effects on the metabolism of dopamine and serotonin in the NAc and CN are also reversed. Results suggest that 5-HT1A receptor dependent modulation of dopamine neurotransmission in the CN and NAc is involved in the modulation of the rewarding effects of morphine in buspirone co-treated animals. The findings documenting an important role of 5-HT1A receptors in drug addiction suggest that synthetic opioid drugs with agonist activity of 5-HT1A receptors may prove non addictive analgesics., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The piperazine derivatives correspond to an extensive chemical class of compounds with numerous neuropharmacological activities, including antidepressant (e.g., nefazodone, trazodone) and anxiolytic (e.g., buspirone) properties. Therefore, aiming to identify a new antidepressant and antianxiety lead-compound, our group designed, synthesized, and investigated the effects of a new piperazine compound, namely, LQFM104, on the behavior of mice. Male albino Swiss mice were treated with LQFM104 prior to predictive behavioral tests as open field (OFT), elevated plus maze (EPM), forced swimming (FST), and tail suspension tests (TST). The participation of the serotonergic system was evaluated by pretreatment with a 5-HT1A antagonist receptor (WAY100635) and serotonin (5-HT) synthesis inhibitor (p-chlorphenylalanine, pCPA) before oral administration of LQFM104 and behavioral tests. The treatment with LQFM104 did not interfere with locomotor activity but revealed suggestive data of anxiolytic-like effects by the increase in the time spent in the center of the OFT. This activity was confirmed by the results obtained in the EPM, and it was abolished after pretreatment with WAY100635 and pCPA. The immobility time decreased in both the FST and TST. The antidepressant-like activity was completely abolished after WAY100635 pretreatment. Altogether, these data revealed that LQFM104 possesses anxiolytic and antidepressant-like properties in behavioral tests on mice, and these activities are possibly mediated, directly and/or indirectly, by serotonergic pathways., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Previous work suggests that 5-HT 1A receptors play a special role in rodent maternal aggression, but not in other aspects of maternal care (e.g. pup retrieval and nest building). The present study re-assessed the basic effects of 5-HT 1A activation or blockade on various maternal responses in postpartum female rats. We also examined the possible behavioral mechanisms underlying the maternal effects of 5-HT 1A . Sprague-Dawley mother rats were injected with a 5-HT 1A agonist 8-OH-DPAT (0.1, 0.5 or 1.0 mg/kg, sc), a 5-HT 1A antagonist WAY-101405 (0.1, 0.5 or 1.0 mg/kg, sc) or 0.9% saline solution on postpartum days 3, 5, and 7. Maternal behavior was tested 30 min before, 30 min, 120 min, and 240 min after the injection. Acute and repeated 8-OH-DPAT treatment significantly disrupted pup retrieval, pup licking, nursing, and nest building in a dose-dependent fashion, whereas WAY-101405 had no effect at the tested doses. The 5-HT 1A receptor specificity of 8-OH-DPAT's action was confirmed as its maternal disruption effect was reversed by pretreatment of WAY-100635 (a highly selective 5-HT 1A receptor antagonist). Subsequent pup preference test found that 8-OH-DPAT did not decrease the pup preference over a novel object, thus no inhibition on maternal motivation or maternal affect. The pup separation test and pup retrieval on an elevated plus maze test also failed to find any motivational and motor impairment effect with 8-OH-DPAT. However, 8-OH-DPAT at the maternal disruptive dose did disrupt the prepulse inhibition (a measure of attentional function) of acoustic startle response and enhanced the basal startle response. These findings suggest that stimulation of 5-HT 1A receptors by 8-OH-DPAT impairs maternal care by partially interfering with the attentional processing or basal anxiety. More work is needed to further delineate the psychological and neuronal mechanisms underlying the maternal disruptive effect of 5-HT 1A receptor activation., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background and Purpose: The aim of this study was to compare the abilities of cannabidiolic acid methyl ester (HU-580) and cannabidiolic acid (CBDA) to enhance 5-HT 1A receptor activation in vitro and produce 5-HT 1A -mediated reductions in nausea and anxiety in vivo., Experimental Approach: We investigated the effects of HU-580 and CBDA on (i) activation by 8-hydroxy-2-(di-n-propylamino)tetralin of human 5-HT 1A receptors in CHO cell membranes, using [ 35 S]-GTPγS binding assays, (ii) gaping by rats in acute and anticipatory nausea models, and (iii) stress-induced anxiety-like behaviour, as indicated by exit time from the light compartment of a light-dark box of rats subjected 24 h earlier to six tone-paired foot shocks., Key Results: HU-580 and CBDA increased the E max of 8-hydroxy-2-(di-n-propylamino) tetralin in vitro at 0.01-10 and 0.1-10 nM, respectively, and reduced signs of (i) acute nausea at 0.1 and 1 μg·kg -1 i.p. and at 1 μg·kg -1 i.p., respectively, and (ii) anticipatory nausea at 0.01 and 0.1 μg·kg -1 , and at 0.1 μg·kg -1 i.p. respectively. At 0.01 μg·kg -1 , HU-580, but not CBDA, increased the time foot-shocked rats spent in the light compartment of a light-dark box. The anti-nausea and anti-anxiety effects of 0.01 or 0.1 μg·kg -1 HU-580 were opposed by the 5-HT 1A antagonist, WAY100635 (0.1 mg·kg -1 i.p.)., Conclusions and Implications: HU-580 is more potent than CBDA at enhancing 5-HT 1A receptor activation, and inhibiting signs of acute and anticipatory nausea, and anxiety. Consequently, HU-580 is a potential medicine for treating some nausea and anxiety disorders and possibly other disorders ameliorated by enhancement of 5-HT 1A receptor activation., (© 2017 The British Pharmacological Society.)

Postsynaptic 5-HT 1A receptors (5-HT 1A R) play an important role in anxiety and stress, although their contribution is still controversial. Previous studies report that mice overexpressing postsynaptic 5-HT 1A Rs show no changes in basal anxiety, though the influence of stress conditions has not been addressed yet. In this study, we used this animal model to evaluate the role of 5-HT 1A Rs in anxiety response after pre-exposure to an acute stressor. Under basal conditions, 5-HT 1A R overexpressing animals presented high corticosterone levels and a lower mineralocorticoid/glucocorticoid receptor ratio. After pre-exposure to a single stressor, they showed a high anxiety-like response, associated with a blunted increase in corticosterone levels and higher c-Fos activation in the prefrontal cortex. Moreover, these mice also presented a lack of downregulation of hippocampal long-term potentiation after stress exposure. Therefore, higher postsynaptic 5-HT 1A R activation might predispose to a high anxious phenotype and an impaired stress coping behavior.

Bisabolol (α-(-)-bisabolol) is a sesquiterpene which is a part of the essential oil of a variety of plants, but its common source is German chamomile. Several bioactivities including anti-inflammatory, anti-nociceptive, and anti-tumor effects were attributed to bisabolol. However, the neuropharmacological properties of bisabolol have not yet been reported. The present study evaluated behavioral effects of bisabolol using elevated plus maze (EPM), open field test (OFT), and rotarod test. Moreover, this study also examined whether the 5-HT 1A and GABA A -benzodiazepine receptor systems are involved in the anxiolytic-like effects of bisabolol. After acute intraperitoneal treatment with bisabolol at the doses of 0.5, 1, 2, 5, and 10 mg/kg, OFT, EPM, and rotarod were utilized for investigating behavioral effects. Flumazenil, a benzodiazepine receptor antagonist, and WAY-100635, a 5-HT 1A receptor antagonist, were used to determine the action mechanism in the EPM. Bisabolol especially at the dose of 1 mg/kg was effective in increasing the total number of entries and time spent in the open arms of EPM while number of rearing and grooming in OFT was decreased in comparison to the control. In the rotarod, permanence time was decreased in the mice treated with the high doses of bisabolol. Pretreatment with flumazenil, but not WAY-100635, was able to reverse the effect of bisabolol 1 mg/kg in the EPM, indicating that the anxiolytic-like activity of bisabolol occurs via the GABAergic but not serotonergic transmission. The present study supports the idea that bisabolol may mediate its anxiolytic-like and sedative mechanisms involving GABA A receptors.

Cannabidiol (CBD) is a phytocannabinoid that has demonstrated anticonvulsant efficacy in several animal models of seizure. The current experiment validated CBD's anticonvulsant effect using the acute pentylenetetrazol (PTZ) model. Furthermore, it tested whether CBD reduces seizure activity by interacting with either the serotonergic 5HT1A or 5HT2A receptor. 120 male adolescent Wistar-Kyoto rats were randomly assigned to 8 treatment groups in two consecutive experiments. In both experiments, subjects received either CBD (100mg/kg) or vehicle 60min prior to seizure testing. In Experiment 1, subjects received either WAY-100635 (1mg/kg), a 5HT1A antagonist, or saline vehicle injection 80min prior to seizure testing. In Experiment 2, subjects received either MDL-100907 (0.3mg/kg), a specific 5HT2A antagonist, or 40% DMSO vehicle 80min prior to seizure testing. 85mg/kg of PTZ was administered to induce seizure, and behavior was recorded for 30min. Seizure behaviors were subsequently coded using a 5-point scale of severity. Across both experiments, subjects in the vehicle control groups exhibited high levels of seizure activity and mortality. In both experiments, CBD treatment significantly attenuated seizure activity. Pre-treatment with either WAY-100635 or MDL-100907 did not block CBD's anticonvulsant effect. WAY-100635 administration, by itself, also led to a significant attenuation of seizure activity. These results do not support the hypothesis that CBD attenuates seizure activity through activation of the 5HT1A or 5HT2A receptor. While this work further confirms the anticonvulsant efficacy of CBD and supports its application in the treatment of human seizure disorders, additional research on CBD's mechanism of action must be conducted., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Serotonin (5-HT) and the 5-HT 1A receptor during development are known to modulate anxiety and depression in later life. However, the brain mechanisms linking the postnatal 5-HT system and adult behavior remain unknown. Here, we examined the effects of pharmacological 5-HT 1A receptor activation during the postnatal period on anxiety and depression-like behavior in adult BALB/c male mice. To elucidate the underlying mechanisms, we measured mRNA expression of the 5-HT 1A receptor, brain-derived neurotrophic factor (BDNF), GABA A receptor subunits, and AMPA receptor subunits in the medial prefrontal cortex (mPFC), amygdala, and hippocampus. Treatment with the selective 5-HT reuptake inhibitor (fluoxetine) and 5-HT 1A receptor agonist (8-OH-DPAT) during the postnatal period decreased anxiety-like behavior in adulthood, whereas only 8-OH-DPAT treatment increased depression-like behavior. Concomitantly with the behavioral effects, postnatal treatment with fluoxetine and 8-OH-DPAT decreased the mRNA expression of the GABA A receptor α3 subunit in the mPFC and ventral hippocampus in adulthood, while 8-OH-DPAT, but not fluoxetine, decreased the mRNA expression of the 5-HT 1A receptor and BDNF in the mPFC and the GABA A receptor α2 subunit in the mPFC and ventral hippocampus. On the basis of the correlative changes between behavior and mRNA expression, these results suggest that the GABA A receptor α3 subunit in the mPFC and ventral hippocampus may regulate anxiety-like behavior. In contrast, depression-like behavior may be regulated by the 5-HT 1A receptor and BDNF in the mPFC and by the GABA A receptor α2 subunit in the mPFC and ventral hippocampus. In summary, activation of the 5-HT 1A receptor during the postnatal period may reduce anxiety levels, but increase depression levels during adulthood via different multiple molecules in the mPFC and ventral hippocampus., (Copyright © 2017 Elsevier Inc. All rights reserved.)

LSP4-2022 is a novel, orthosteric agonist of mGlu 4 receptor that induces antipsychotic-like activity in animal studies. In the present study, the involvement of 5-HT 1A receptors in LSP4-2022-induced antipsychotic actions and the neurochemical background of that interaction were investigated. In several behavioral tests the actions of effective doses of the compound (0.5-2 mg/kg) were antagonized via the administration of the 5-HT 1A antagonist WAY100635 (0.1 mg/kg). The co-administration of sub-effective dose of the 5-HT 1A agonist (R)-(S)-8-OH-DPAT (0.01 mg/kg) intensified the activity of ineffective doses of LSP4-2022, having no influence on the efficacy of the active doses. The co-administration of effective doses of both compounds did not intensify each other's action. In the microdialysis in vivo tests, MK-801 (0.6 mg/kg) induced an enhancement of the release of dopamine, serotonin, glutamate and GABA in the prefrontal cortex. Administration of LSP4-2022 (2 mg/kg) abolished this MK-801-induced effect on neurotransmitter release. Co-administration with WAY100635 (0.1 mg/kg), a 5-HT 1A antagonist, completely (dopamine, serotonin) or partially (glutamate, GABA) counteracted this LSP4-2022-induced effect. Subsequently, the patch-clamp recordings of spontaneous EPSCs were performed. sEPSCs were evoked in slices from the mouse prefrontal cortex by DOI (10 μM). LSP4-2022 (2.5; 5 and 10 μm) reversed DOI-induced changes in both the frequency and amplitude of the sEPSCs, but the more robust effect on the frequency was observed. The administration of WAY100635 had no effect on the LSP4-2022-induced effects on sEPSCs, indicating that the mGlu 4 -5-HT 1A interaction does not occur via single-neuron signaling but involves neuronal circuits that regulate neurotransmitter release. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Key Points: In the adult turtle spinal cord, action potential generation in motoneurones is inhibited by spillover of serotonin to extrasynaptic serotonin 1A (5-HT 1A ) receptors at the axon initial segment. We explored whether ingestion of the 5-HT 1A receptor partial agonist, buspirone, decreases motoneurone excitability in humans. Following ingestion of buspirone, two tests of motoneurone excitability showed decreases. F-wave areas and persistence in an intrinsic muscle of the hand were reduced, as was the area of cervicomedullary motor evoked potentials in biceps brachii. Our findings suggest that activation of 5-HT 1A receptors depresses human motoneurone excitability. Such a depression could contribute to decreased motoneurone output during fatiguing exercise if there is high serotonergic drive to the motoneurones., Abstract: Intense serotonergic drive in the turtle spinal cord results in serotonin spillover to the axon initial segment of the motoneurones where it activates serotonin 1A (5-HT 1A ) receptors and inhibits generation of action potentials. We examined whether activation of 5-HT 1A receptors decreases motoneurone excitability in humans by determining the effects of a 5-HT 1A receptor partial agonist, buspirone, on F waves and cervicomedullary motor evoked potentials (CMEPs). In a placebo-controlled double-blind study, 10 participants were tested on two occasions where either placebo or 20 mg of buspirone was administered orally. The ulnar nerve was stimulated supramaximally to evoke F waves in abductor digiti minimi (ADM). CMEPs and the maximal M wave were elicited in biceps brachii by cervicomedullary stimulation and brachial plexus stimulation, respectively. Following buspirone intake, F-wave area and persistence, as well as CMEP area, were significantly decreased. The mean post-pill difference in normalized F-wave areas and persistence between buspirone and placebo days was -27% (-42, -12; 95% confidence interval) and -9% (-16, -2), respectively. The mean post-pill difference in normalized CMEP area between buspirone and placebo days showed greater variation and was -31% (-60, -2). In conclusion, buspirone reduces motoneurone excitability in humans probably via activation of 5-HT 1A receptors at the axon initial segment. This has implications for motor output during high drive to the motoneurones when serotonin may spill over to these inhibitory receptors and consequently inhibit motoneurone output. Such a mechanism could potentially contribute to fatigue with exercise., (© 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.)

Psychiatric disorders are associated with excitation-inhibition (E-I) balance impairment in the prefrontal cortex. However, how the E-I balance is regulated is poorly known. The E-I balance of neuronal networks is linked to the action of numerous neuromodulators such as dopamine and 5-HT. We investigated the role of D2-receptors in tuning the E-I balance in a mouse model of anxiety, the 5-HT1A-receptor KO mice. We focused on synaptic plasticity of excitation and inhibition on layer 5 pyramidal neurons. We show that D2-receptor activation decreases the excitation and favors HFS-induced LTD of excitatory synapses via the activation of GSK3β. This effect is absent in 5-HT1A-receptor KO mice. Our data show that the fine control of excitatory transmission by GSK3β requires recruitment of D2-receptors and depends on the presence of 5-HT1A-receptors. In psychiatric disorders in which the number of 5-HT1A-receptors decreased, therapies should reconsider how serotonin and dopamine receptors interact and control neuronal network activity., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The neuropeptides vasopressin and corticotropin-releasing factor facilitate, while serotonin inhibits, aggression. How the brain is wired to coordinate interactions between these functionally opposed neurotransmitters to control behavioral states is poorly understood., Methods: Pair-bonded male prairie voles (Microtus ochrogaster) were infused with a retrograde tracer, Fluoro-Gold, and tested for affiliation and aggression toward a female partner or novel female subject. Subsequent immunocytochemical experiments examined neuronal activation using Fos and neurochemical/neuroreceptor profiles on brain areas involved in these social behaviors. Finally, a series of behavioral pharmacologic and real-time in vivo brain microdialysis experiments were performed on male prairie voles displaying affiliation or aggression., Results: We localized a subpopulation of excitatory vasopressin neurons in the anterior hypothalamus that may gate corticotropin-releasing factor output from the amygdala to the anterior hypothalamus and then the lateral septum to modulate aggression associated with mate guarding. Conversely, we identified a subset of inhibitory serotonergic projection neurons in the dorsal raphe that project to the anterior hypothalamus and may mediate the spatiotemporal release of neuropeptides and their interactions in modulating aggression and affiliation., Conclusions: Together, this study establishes the medial extended amygdala as a major neural substrate regulating the switch between positive and negative affective states, wherein several neurochemicals converge and interact to coordinate divergent social behaviors., Competing Interests: All authors report no biomedical financial interests or potential conflicts of interest., (Published by Elsevier Inc.)

The serotonergic tone of the dorsal raphe (DR) is regulated by 5-HT 1A receptors, which negatively control serotonergic activity via the activation of G protein-coupled inwardly rectifying K + (GIRK) channels. In addition, DR activity is modulated by local GABAergic transmission, which is believed to play a key role in the development of mood-related disorders. Here, we sought to characterize the role of GIRK2 subunit-containing channels on the basal electrophysiological properties of DR neurons and to investigate whether the presynaptic and postsynaptic activities of 5-HT 1A , GABA B , and GABA A receptors are affected by Girk2 gene deletion. Whole-cell patch-clamp recordings in brain slices from GIRK2 knockout mice revealed that the GIRK2 subunit contributes to maintenance of the resting membrane potential and to the membrane input resistance of DR neurons. 5-HT 1A and GABA B receptor-mediated postsynaptic currents were almost absent in the mutant mice. Spontaneous and evoked GABA A receptor-mediated transmissions were markedly reduced in GIRK2 KO mice, as the frequency and amplitude of spontaneous IPSCs were reduced, the paired-pulse ratio was increased and GABA-induced whole-cell currents were decreased. Similarly, the pharmacological blockade of GIRK channels with tertiapin-Q prevented the 5-HT 1A and GABA B receptor-mediated postsynaptic currents and increased the paired-pulse ratio. Finally, deletion of the Girk2 gene also limited the presynaptic inhibition of GABA release exerted by 5-HT 1A and GABA B receptors. These results indicate that the properties and inhibitory activity of DR neurons are highly regulated by GIRK2 subunit-containing channels, introducing GIRK channels as potential candidates for studying the pathophysiology and treatment of affective disorders., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Previous studies have shown that partial and full 5-HT 1A receptor agonists reduce antipsychotic-induced catalepsy. Consequently, some antipsychotics combining balanced efficacy between dopamine (DA) D 2 antagonism or partial agonism and 5-HT 1A receptor agonism have a low propensity to induce extrapyramidal side effects (EPS), as reflected by low cataleptogenic activity in rodents. In the present experiments, we attempted to explore the importance of pre- and postsynaptic 5-HT 1A agonistic properties of brexpiprazole and aripiprazole in the context of neurological side-effect liabilities. Additional measures of prefrontal cortical serotonin (5-HT) and DA levels using microdialysis were used to support that brexpiprazole has a preferential agonist effect on presynaptic 5-HT 1A receptors. Brexpiprazole (3.0 and 10mg/kg, p.o.) as well as aripiprazole (8.0 and 30mg/kg, p.o.) failed to induce catalepsy in rats. Brexpiprazole (10mg/kg, p.o.) significantly reduced the cataleptic response induced by haloperidol (0.63mg/kg, s.c.), while aripiprazole (1.0-100mg/kg, p.o.) failed to reverse the effect of haloperidol and only showed a numeric decrease at 10mg/kg, (p.o.). When 5-HT 1A receptors were blocked by the selective antagonist, WAY100635 (1.0mg/kg, s.c.), cataleptogenic properties of brexpiprazole (10mg/kg; p.o), but not aripiprazole (8.0 and 30mg/kg, p.o.) were unmasked. The ("biased") 5-HT 1A receptor agonists F15599 (postsynaptic preference) and F13714 (presynaptic preference) had differential effects on haloperidol-induced catalepsy: F13714 (0.16mg/kg, s.c.) counteracted catalepsy, whereas F15599 (0.040mg/kg, s.c.) had no significant effect at regionally-selective doses. These data support a role of presynaptic 5-HT 1A receptors in the anticataleptic effect of brexpiprazole. The selective 5-HT 2A antagonist M100907 (0.10mg/kg, s.c.) had no effect on haloperidol-induced catalepsy, arguing against a major role of 5-HT 2A receptors in the cataleptogenic profile of brexpiprazole. The findings with brexpiprazole were supported using microdialysis studies: Brexpiprazole (3.0 and 10mg/kg, p.o.) decreased extracellular 5-HT levels in the medial prefrontal cortex (mPFC), while it failed to affect extracellular DA in the same samples, suggesting that the 5-HT 1A agonist properties of brexpiprazole may be preferentially presynaptic. In conclusion, these results confirm that brexpiprazole and aripiprazole have low propensities to induce EPS. However, the low EPS risk of brexpiprazole is more likely dependent on its agonist properties on presynaptic 5-HT 1A receptors, while that of aripiprazole is less sensitive to 5-HT 1A receptor antagonism., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Serotonin receptors 5-HT1A and 5-HT7 are involved in the development of various psychopathologies. Some data indicate that there is an interplay between 5-HT1A 5-HT7 receptors that could be implicated in the regulation of their function. This work analyzed the effects of chronic 5-HT7 activation on the functional activity of 5-HT7 and 5-HT1A receptors, on the corresponding protein levels, and on the expression of genes encoding 5-HT7 and 5-HT1A receptors in the mouse brain. Chronic administration of the 5-HT7 selective agonist LP44 (20.5 nmol, i.c.v., 14 days) produced considerable desensitization of both 5-HT7 and 5-HT1A receptors. In LP44-treated mice, the hypothermic responses mediated by both 5-HT7 and 5-HT1A receptors were attenuated. Moreover, the levels of 5-HT1A receptor protein in the midbrain and the frontal cortex of LP44-treated mice were significantly decreased. However, the brain levels of 5-HT7 receptor protein did not differ between LP44-treated and control mice. Chronic LP44 treatment did not alter the expression of the 5-HT7 and 5-HT1A receptor genes in all investigated brain structure. These data suggest that 5-HT7 receptors participate in the posttranscriptional regulation of the 5-HT1A receptors functioning.

Serotonin (5-HT) deficiency occurs in a number of brain disorders that affect cognitive function. However, a direct causal relationship between 5-HT hypo-transmission and memory and underlying mechanisms has not been established. We used mice with a constitutive depletion of 5-HT brain levels (Pet1KO mice) to analyze the contribution of 5-HT to different forms of learning and memory. Pet1KO mice exhibited a striking deficit in novel object recognition memory, a hippocampal-dependent task. No alterations were found in tasks for social recognition, procedural learning, or fear memory. Viral delivery of designer receptors exclusively activated by designer drugs was used to selectively silence the activity of 5-HT neurons in the raphe. Inhibition of 5-HT neurons in the median raphe, but not the dorsal raphe, was sufficient to impair object recognition in adult mice. In vivo electrophysiology in behaving mice showed that long-term potentiation in the hippocampus of 5-HT-deficient mice was altered, and administration of the 5-HT1A agonist 8-OHDPAT rescued the memory deficits. Our data suggest that hyposerotonergia selectively affects declarative hippocampal-dependent memory. Serotonergic projections from the median raphe are necessary to regulate object memory and hippocampal synaptic plasticity processes, through an inhibitory control mediated by 5-HT1A receptors.

Spinal afferents such as nociceptive afferents and group III-IV muscle afferents are known to exert an acute excitatory effect on breathing when activated. Here, we report the surprising existence of latent spinal afferents which exerted tonic inhibitory influence on breathing subliminally in anesthetized rats, an effect which was reversed upon activation of serotonin-1A receptors (5-HT 1A Rs) in lumbar spinal cord, lesion of pontine lateral parabrachial nucleus or suppression of the adjacent Kölliker-Fuse nucleus with NMDA receptor blockade. Small-interfering RNA knockdown of 5-HT 1A Rs in lumbar spinal cord unequivocally localized the site of 5-HT 1A R-mediated gating of these respiratory-inhibiting interoceptive afferents to relay neurons in the spinal superficial dorsal horn at the lumbar level and not cervical spinal or supraspinal levels. Our results reveal a novel somatosensory/viscerosensory mechanism which exerts tonic inhibitory influence on homeostatic regulation of breathing independent from the classical chemoreflex excitatory pathways, and suggest a hitherto unrecognized therapeutic target in spinal dorsal horn for 5-HT 1A R-based treatment of a variety of respiratory abnormalities.

The nucleus incertus (NI), a brainstem structure with diverse anatomical connections, is implicated in anxiety, arousal, hippocampal theta modulation, and stress responses. It expresses a variety of neurotransmitters, neuropeptides and receptors such as 5-HT1A, D2 and CRF1 receptors. We hypothesized that the NI may play a role in the neuropharmacology of buspirone, a clinical anxiolytic which is a 5-HT1A receptor partial agonist and a D2 receptor antagonist. Several preclinical studies have reported a biphasic anxiety-modulating effect of buspirone but the precise mechanism and structures underlying this effect are not well-understood. The present study implicates the NI in the anxiogenic effects of a high dose of buspirone. Systemic buspirone (3 mg/kg) induced anxiogenic effects in elevated plus maze, light-dark box and open field exploration paradigms in rats and strongly activated the NI, as reflected by c-Fos expression. This anxiogenic effect was reproduced by direct infusion of buspirone (5 μg) into the NI, but was abolished in NI-CRF-saporin-lesioned rats, indicating that the NI is present in neural circuits driving anxiogenic behaviour. Pharmacological studies with NAD 299, a selective 5-HT1A antagonist, or quinpirole, a D2/D3 agonist, were conducted to examine the receptor system in the NI involved in this anxiogenic effect. Opposing the 5-HT1A agonism but not the D2 antagonism of buspirone in the NI attenuated the anxiogenic effects of systemic buspirone. In conclusion, 5-HT1A receptors in the NI contribute to the anxiogenic effect of an acute high dose of buspirone in rats and may be functionally relevant to physiological anxiety., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)