Functional consequences of a rare human serotonergic 5-HT1A receptor variant
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PROVIDER: S-EPMC10547147 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description:Mental disorders are caused by genetic and environmental factors. We here show that deficiency of an isoform of dopamine D2 receptor (D2R), D2LR, causes stress vulnerability in mouse. This occurs through dysfunction of serotonin [5-hydroxytryptamine (5-HT)] 1A receptor (5-HT1AR) on serotonergic neurons in the mouse brain. Exposure to forced swim stress significantly increased anxiety- and depressive-like behaviors in D2LR knock-out (KO) male mice compared with wild-type mice. Treatment with 8-OH-DPAT, a 5-HT1AR agonist, failed to alleviate the stress-induced behaviors in D2LR-KO mice. In forced swim-stressed D2LR-KO mice, 5-HT efflux in the medial prefrontal cortex was elevated and the expression of genes related to 5-HT levels was upregulated by the transcription factor PET1 in the dorsal raphe nucleus. Notably, D2LR formed a heteromer with 5-HT1AR in serotonergic neurons, thereby suppressing 5-HT1AR-activated G-protein-activated inwardly rectifying potassium conductance in D2LR-KO serotonergic neurons. Finally, D2LR overexpression in serotonergic neurons in the dorsal raphe nucleus alleviated stress vulnerability observed in D2LR-KO mice. Together, we conclude that disruption of the negative feedback regulation by the D2LR/5-HT1A heteromer causes stress vulnerability.SIGNIFICANCE STATEMENT Etiologies of mental disorders are multifactorial, e.g., interactions between genetic and environmental factors. In this study, using a mouse model, we showed that genetic depletion of an isoform of dopamine D2 receptor, D2LR, causes stress vulnerability associated with dysfunction of serotonin 1A receptor, 5-HT1AR in serotonergic neurons. The D2LR/5-HT1AR inhibitory G-protein-coupled heteromer may function as a negative feedback regulator to suppress psychosocial stress.
| S-EPMC6750932 | biostudies-literature
Project description:G protein-coupled receptors are known to play a key role in many cellular signal transduction processes, including those mediating serotonergic signaling in the nervous system. Several factors have been shown to regulate the activity of these receptors, including membrane potential and the concentration of sodium ions. Whether voltage and sodium regulate the activity of serotonergic receptors is unknown. Here, we used Xenopus oocytes as an expression system to examine the effects of voltage and of sodium ions on the potency of one subtype of serotonin (5-hydroxytryptamine [5-HT]) receptor, the 5-HT1A receptor. We found that the potency of 5-HT in activating the receptor is voltage dependent and that it is higher at resting potential than under depolarized conditions. Furthermore, we found that removal of extracellular Na+ resulted in a decrease of 5-HT potency toward the 5-HT1A receptor and that a conserved aspartate in transmembrane domain 2 is crucial for this effect. Our results suggest that this allosteric effect of Na+ does not underlie the voltage dependence of this receptor. We propose that the characterization of modulatory factors that regulate this receptor may contribute to our future understanding of various physiological functions mediated by serotonergic transmission.
| S-EPMC9136116 | biostudies-literature
Project description:Serotonergic innervation of the spinal cord in mammals has multiple roles in the control of motor, sensory and visceral functions. In rats, functional consequences of spinal cord injury at thoracic level can be improved by a substitutive transplantation of serotonin (5-HT) neurons or regeneration under the trophic influence of grafted stem cells. Translation to either pharmacological and/or cellular therapies in humans requires the mapping of the spinal cord 5-HT innervation and its receptors to determine their involvement in specific functions. Here, we have performed a preliminary mapping of serotonergic processes and serotonin-lA (5-HT(1A)) receptors in thoracic and lumbar segments of the human spinal cord. As in rodents and non-human primates, 5-HT profiles in human spinal cord are present in the ventral horn, surrounding motoneurons, and also contact their presumptive dendrites at lumbar level. 5-HT(1A) receptors are present in the same area, but are more densely expressed at lumbar level. 5-HT profiles are also present in the intermediolateral region, where 5-HT(1A) receptors are absent. Finally, we observed numerous serotonergic profiles in the superficial part (equivalent of Rexed lamina II) of the dorsal horn, which also displayed high levels of 5-HT(1A) receptors. These findings pave the way for local specific therapies involving cellular and/or pharmacological tools targeting the serotonergic system.
| S-EPMC3219094 | biostudies-literature
Project description:RationaleProblematic patterns of gambling are characterised by loss of control and persistent gambling often to recover losses. However, little is known about the mechanisms that mediate initial choices to begin gambling and then continue to gamble in the face of losing outcomes.ObjectivesThese experiments first assessed gambling and loss-chasing performance under different win/lose probabilities in C57Bl/6 mice, and then investigated the effects of antagonism of 5-HT2CR with SB242084, 5-HT1AR agonism with 8-OH-DPAT and modafinil, a putative cognitive enhancer.ResultsAs seen in humans and other species, mice demonstrated the expected patterns of behaviour as the odds for winning were altered increasing gambling and loss-chasing when winning was more likely. SB242084 decreased the likelihood to initially gamble, but had no effects on subsequent gambling choices in the face of repeated losses. In contrast, 8-OH-DPAT had no effects on choosing to gamble in the first place, but once started 8-OH-DPAT increased gambling choices in a dose-sensitive manner. Modafinil effects were different to the serotonergic drugs in both decreasing the propensity to initiate gambling and chase losses.ConclusionsWe present evidence for dissociable effects of systemic drug administration on different aspects of gambling behaviour. These data extend and reinforce the importance of serotonergic mechanisms in mediating discrete components of gambling behaviour. They further demonstrate the ability of modafinil to reduce gambling behaviour. Our work using a novel mouse paradigm may be of utility in modelling the complex psychological and neurobiological underpinnings of gambling problems, including the analysis of genetic and environmental factors.
| S-EPMC7239826 | biostudies-literature
Project description:BackgroundThe serotonin 5-HT1A receptor (5-HT1AR) and metabotropic glutamate receptor 4 (mGlu4) have been implicated as sites of antipsychotic drug action. 5-HT1AR belongs to the A class of G protein-coupled receptors (GPCRs); mGlu4 is a representative of class C GPCRs. Both receptors preferentially couple with Gi protein to inhibit cAMP formation. The present work aimed to examine the possibility of mGlu4 and 5-HT1A receptor cross-talk, the phenomenon that could serve as a molecular basis of the interaction of these receptor ligands observed in behavioral studies.MethodsFirst, in vitro studies were performed to examine the pharmacological modulation of interaction of the mGlu4 and 5-HT1A receptors in the T-REx 293 cell line using SNAP- or HALO-tag and cAMP accumulation assay. Next, the colocalization of these two receptors was examined in some regions of the mouse brain by applying RNAScope dual fluorescence in situ hybridization, immunohistochemical labeling, and proximity ligation assay (PLA).ResultsThe ex vivo and in vitro results obtained in the present work suggest the existence of interactions between mGlu4 and 5-HT1A receptors. The changes were observed in cAMP accumulation assay and were dependent on expression and activation of mGlu4R in T-REx 293cell line. Moreover, the existence of spots with proximity expression of both receptors were showed by PLA, immunofluorescence labeling and RNAscope methods.ConclusionThe existence of interactions between mGlu4 and 5-HT1A receptors may represent another signaling pathway involved in the development and treatment psychiatric disorders such as schizophrenia or depression.
| S-EPMC7550284 | biostudies-literature
Project description:IntroductionAbuse or misuse of tobacco, e-cigarettes, or antidepressants may have serious clinical consequences during adolescence, a sensitive period during brain development when the distinct neurobiology of adolescent serotonin (5-HT) and dopamine (DA) systems create unique behavioral vulnerabilities to drugs of abuse.MethodsUsing a pharmacological approach, we modeled the behavioral and neurochemical effects of subchronic (4-day) nicotine (60µg/kg, i.v.) or fluoxetine (1mg/kg, i.v.) exposure in adolescent and adult male rats.ResultsNicotine and fluoxetine significantly enhance quinpirole-induced locomotor activity and initial cocaine self-administration in adolescents, but not adults. These effects were blocked by serotonin 5-HT1A receptor antagonists, WAY-100,635 (100 µg/kg, i.v.) or S-15535 (300 µg/kg, i.v.). Neurochemical and anatomical autoradiographic analysis of 8-OH-DPAT-stimulated [35S]GTPγS reveal that prior exposure to nicotine and fluoxetine results in both overlapping and distinct effects on regional 5-HT1A receptor activity. Both fluoxetine and nicotine enhance adolescent 5-HT1A receptor activity in the primary motor cortex (M1), whereas fluoxetine alone targets prefrontal cortical neurocircuitry and nicotine alone targets the amygdala.DiscussionGiven their different pharmacological profiles, comparison between WAY-100,635 and S-15535 indicates that postsynaptic 5-HT1A receptors mediate the behavioral effects of prior nicotine and fluoxetine exposure. In addition, within the adolescent M1, maladaptive changes in 5-HT signaling and 5-HT1A activity after nicotine or fluoxetine exposure may potentiate hyper-responsiveness to dopaminergic drugs and prime adolescent vulnerability for future substance abuse.
| S-EPMC11196788 | biostudies-literature
Project description:Mounting evidence suggests that the serotonin system serves in signal transmission to regulate insulin secretion in pancreatic islets of Langerhans. Among the 5-HT receptor subtype found in pancreatic islets, serotonin receptor 1A (5-HT1A ) demonstrates a unique ability to inhibit β-cell insulin secretion. We report the design, synthesis, and characterization of two novel fluorescent probes for the 5-HT1A receptor. The compounds were prepared by conjugating the scaffold of the 5-HT1A receptor agonist 8-OH-DPAT with two fluorophores suitable for live-cell imaging. Compound 5a {5-(dimethylamino)-N-[5-[(8-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino]pentyl]naphtalen-1-sulfonammide} showed high affinity for the 5-HT1A receptor (Ki =1.8 nM). Fluoroprobe 5a was able to label the 5-HT1A receptor in pancreatic islet cell cultures in a selective manner, as the fluorescence emission was significantly attenuated by co-administration of the 5-HT1A receptor antagonist WAY-100635. Thus, fluoroprobe 5a showed useful properties to further characterize this unique receptor's role.
| S-EPMC9127068 | biostudies-literature
Project description: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-HT1A receptors within the BLA in mutual-reward choices. Rats received daily injections of either 50 or 25 ng of the 5-HT1A 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-HT1A receptor agonist 8-OH-DPAT have the potential to increase mutual-reward choices in a social setting without affecting other behavioral parameters.
| S-EPMC7538979 | biostudies-literature
Project description:There are no approved pharmacotherapies for fragile X syndrome (FXS), a rare neurodevelopmental disorder caused by a mutation in the FMR1 promoter region that leads to various symptoms, including intellectual disability and auditory hypersensitivity. The gene that encodes inhibitory serotonin 1A receptors (5-HT1ARs) is differentially expressed in embryonic brain tissue from individuals with FXS, and 5-HT1ARs are highly expressed in neural systems that are disordered in FXS, providing a rationale to focus on 5-HT1ARs as targets to treat symptoms of FXS. We examined agonist-labeled 5-HT1AR densities in male and female Fmr1 knockout mice and found no differences in whole-brain 5-HT1AR expression in adult control compared to Fmr1 knockout mice. However, juvenile Fmr1 knockout mice had lower whole-brain 5-HT1AR expression than age-matched controls. Consistent with these results, juvenile Fmr1 knockout mice showed reduced behavioral responses elicited by the 5-HT1AR agonist (R)-8-OH-DPAT, effects blocked by the selective 5-HT1AR antagonist, WAY-100635. Also, treatment with the selective 5-HT1AR agonist, NLX-112, dose-dependently prevented audiogenic seizures (AGS) in juvenile Fmr1 knockout mice, an effect reversed by WAY-100635. Suggestive of a potential role for 5-HT1ARs in regulating AGS, compared to males, female Fmr1 knockout mice had a lower prevalence of AGS and higher expression of antagonist-labeled 5-HT1ARs in the inferior colliculus and auditory cortex. These results provide preclinical support that 5-HT1AR agonists may be therapeutic for young individuals with FXS hypersensitive to auditory stimuli.
| S-EPMC11426339 | biostudies-literature
Project description:Serotonin receptors are involved in a number of physiological functions and regulate aggression, anxiety, appetite, cognition, learning, memory, mood, nausea, sleep, and thermoregulation. Here we report synthesis and detailed structural and behavioral studies of three indole derivatives: D2AAK5, D2AAK6, and D2AAK7 as serotonin 5-HT1A and 5-HT2A receptor ligands. X-ray studies revealed that the D2AAK5 compound crystallizes in centrosymmetric triclinic space group with one molecule in the asymmetric unit. The main interaction between the ligands and the receptors is the salt bridge between the protonatable nitrogen atom of the ligands and the conserved Asp (3.32) of the receptors. The complexes were stable in the molecular dynamic simulations. MD revealed that the studied ligands are relatively stable in their binding sites, with the exception of D2AAK7 in the serotonin 5-HT1A receptor. D2AAK7 exerts anxiolytic activity in the EPM test, while D2AAK5 has a beneficial effect on the memory processes in the PA test.
| S-EPMC9823611 | biostudies-literature