Serotonin type 3 receptors stimulate offensive aggression in Syrian hamsters

Hamsters repeatedly exposed to cocaine during adolescence display high levels of offensive aggression compared to saline-treated littermates. The escalated offensive phenotype observed in adolescent cocaine-treated animals is modulated by serotonin (5-HT) signaling and can be suppressed by inhibiting 5-HT type 3 receptors, suggesting that these receptors might play an important role in the aggression-stimulating effects of adolescent cocaine exposure. The current study examined this hypothesis and extended earlier studies investigating the relationship between 5HT(3) receptor neural signaling and the offensive response patterns of aggressive, adolescent cocaine-treated animals compared to non-aggressive, saline-treated littermates. Adolescent cocaine-treated hamsters and saline-treated littermates were tested for offensive aggression after the administration of either the 5-HT(3) antagonist 3-tropanylindole-3-carboxylate methiodide (tropisetron) or the 5-HT(3) agonist 1-(m-chlorophenyl)-biguanide hydrochloride (mCPBG). Tropisetron significantly reduced the high levels of offensive responding observed in adolescent cocaine-treated animals, whereas treatment with the 5-HT(3) receptor agonist mCPBG failed to affect the escalated offensive response. Conversely, tropisetron failed to affect very low, baseline levels of aggressive responding seen in adolescent saline-treated animals, while 5-HT(3) receptor activation via mCPBG triggered highly escalated levels of offensive aggression in these animals. Together, these data support a stimulatory role for 5-HT(3) neural signaling in offensive aggression.     

Serotonin and aggression in children

Research consistently indicates that in animals and adults, reduced central serotonergic (5-HT) function is associated with increased aggression. This relationship has been elucidated via cerebrospinal fluid monoamine metabolite levels, hormonal responses to pharmacologic challenge using serotonergic probes, platelet receptor binding studies, and, more recently, through molecular genetic approaches. In contrast, studies examining the relationship of 5-HT to aggression in children have been characterized by inconsistent findings. The literature examining the relationship between central 5-HT function and aggression is reviewed. Several hypotheses that might account for the discrepancies in the child literature are examined.     

Association of the serotonin transporter and receptor gene polymorphisms in neuropsychiatric symptoms in Alzheimer disease

BACKGROUND: Serotonin has been linked to neuropsychiatric symptoms in Alzheimer disease, mainly agitation/aggression, depression, and psychosis. Neuropsychiatric symptoms have been associated with polymorphisms of the promoter region (5-HTTPR ) and intron 2 of the serotonin transporter gene (5-HTTVNTR) or the 5-HT2A and 5-HT2C receptor genes in some but not all studies. OBJECTIVE: To examine the association of the serotonin promoter, transporter, and receptor genes with neuropsychiatric symptoms in patients with Alzheimer disease. METHODS: The sample included 96 patients with Alzheimer disease from the outpatient clinic of the University of California Los Angeles Alzheimer's Disease Research Center, Los Angeles. The Neuropsychiatric Inventory was used to measure neuropsychiatric symptoms, and blood samples were available for genetic analysis. Based on the literature, we hypothesized that the 5-HT2A and 5-HT2C receptor polymorphisms would be associated with agitation/aggression and psychosis and the 5-HTTPR or 5-HTTVNTR polymorphisms, with agitation/aggression or depression and anxiety. One-way analyses of variance were performed with age, ethnicity, sex, or education as covariates. RESULTS: The 102T genotype of the 5-HT2A receptor was significantly associated with delusions (P =.045) and agitation/aggression (P =.002). We did not replicate previous associations of the 5-HT2C receptor polymorphism with psychosis or of the 5-HTTPR polymorphism with agitation/aggression, psychosis, or depression. We did not find any associations with the 5-HTTVNTR polymorphism and agitation/aggression, depression, or anxiety. CONCLUSIONS: The 5-HT2A receptor polymorphism may contribute to the expression of psychosis and agitation/aggression in patients with Alzheimer disease. Absence of other positive associations may be due to the relatively small sample size and/or potentially small effect size of the polymorphisms and requires further study.     

Higher postmortem prefrontal 5-HT2A receptor binding correlates with lifetime aggression in suicide.

BACKGROUND: In vivo studies find altered serotonin function associated with aggressive and suicidal behaviors. Postmortem studies also reveal serotonergic alterations in suicide subjects but have not reported on the relationship between aggression and the serotonin system. We measured 5-hydroxytryptamine 2A (5-HT(2A)) receptor binding in prefrontal cortex of suicide and nonsuicide subjects and explored the relationship between 5-HT(2A) receptor binding, lifetime aggression, and suicide. METHODS: The 5-HT(2A) receptor binding in coronal sections of prefrontal cortex was quantified by autoradiography with [(3)H] ketanserin in 37 suicide subjects and 73 nonsuicide subjects. The relationship between [(3)H] ketanserin binding and lifetime aggression, rated on the Brown-Goodwin Aggression History Scale, was assessed controlling for age and sex. RESULTS: In suicide subjects, lifetime aggression scores correlated positively with [(3)H] ketanserin binding in all prefrontal Brodmann areas examined, after adjusting for age and sex. This was not the case in nonsuicide subjects. We found no significant differences in aggression scores or [(3)H] ketanserin binding between the suicide subjects and nonsuicide subjects. CONCLUSIONS: The relationship between aggression and 5-HT(2A) receptor binding in suicide subjects, but not in nonsuicide subjects, may reflect differences in the regulation of the 5-HT(2A) receptor related to suicidal behavior and perhaps other proaggressive changes in brains of suicide subjects.     

Molecular dynamics of serotonin and ritanserin interacting with the 5-HT2 receptor.

A three-dimensional model of the serotonin (5-hydroxytrytamine; 5-HT) 5-HT2 receptor was constructed from the amino acid sequence by molecular graphics techniques, molecular mechanics energy calculations and molecular dynamics simulations. The receptor model has 7 alpha helical segments which form a membrane-spanning duct with a putative ligand binding site. Most of the synaptic domains and the ligand binding site were surrounded by negative electrostatic potentials, suggesting that positively charged ligands are attracted to the receptor by electrostatic forces. The cytoplasmic domains, except the C-terminal tail, had mainly positive electrostatic potentials. The molecular dynamics of the receptor-ligand complex was examined in 100 ps simulations with 5-HT or ritanserin at a postulated binding site. During the simulations the helices moved from an initial circular arrangement into a more oval arrangement, and became slightly tilted relative to each other. The protonated ligands neutralized the negative electrostatic potentials around Asp 120 and Asp 155 in the central core of the receptor. 5-HT had only weak interactions with Asp 155 but strong interactions with Asp 120 during the simulations, with the amino group of 5-HT tightly bound to the carboxylic side chain of Asp 120. Ritanserin showed similarly strong interactions with Asp 120 and Asp 155 during the simulations.     

Spinal 5-HT(3) receptor activation induces behavioral hypersensitivity via a neuronal-glial-neuronal signaling cascade

Recent studies indicate that the descending serotonin (5-HT) system from the rostral ventromedial medulla (RVM) in the brainstem and the 5-HT(3) receptor subtype in the spinal dorsal horn are involved in enhanced descending pain facilitation after tissue and nerve injury. However, the mechanisms underlying the activation of the 5-HT(3) receptor and its contribution to facilitation of pain remain unclear. In the present study, activation of spinal 5-HT(3) receptor by intrathecal injection of a selective 5-HT(3) receptor agonist, SR57227, induced spinal glial hyperactivity, neuronal hyperexcitability, and pain hypersensitivity in rats. We found that there was neuron-to-microglia signaling via chemokine fractalkine, microglia to astrocyte signaling via the cytokine IL-18, astrocyte to neuronal signaling by IL-1β, and enhanced activation of GluN (NMDA) receptors in the spinal dorsal horn. In addition, exogenous brain-derived neurotrophic factor-induced descending pain facilitation was accompanied by upregulation of CD11b and GFAP expression in the spinal dorsal horn after microinjection in the RVM, and these events were significantly prevented by functional blockade of spinal 5-HT(3) receptors. Enhanced expression of spinal CD11b and GFAP after hindpaw inflammation was also attenuated by molecular depletion of the descending 5-HT system by intra-RVM Tph-2 shRNA interference. Thus, these findings offer new insights into the cellular and molecular mechanisms at the spinal level responsible for descending 5-HT-mediated pain facilitation during the development of persistent pain after tissue and nerve injury. New pain therapies should focus on prime targets of descending facilitation-induced glial involvement, and in particular the blocking of intercellular signaling transduction between neuron and glia.     

Reduced serotonin 5-HT1A receptor binding in the temporal cortex correlates with aggressive behavior in Alzheimer disease

Previous studies have implicated brain serotonin 5-HT(1A) receptors in several CNS functions, including cognition, mood and emotional states. In Alzheimer disease (AD), cognitive impairment and behavioral symptoms are the main clinical features. However, the biochemical basis of such changes is poorly understood. Results from recent in vivo studies suggest that 5-HT(1A) receptors may be related to aggressive traits in healthy subjects. The present study investigated the state of 5-HT(1A) receptors in the postmortem neocortex of 33 AD patients prospectively assessed for cognition and behavioral symptoms, together with 20 matched controls, by saturation [(3)H]8-OH-DPAT binding assays. 5-HT(1A) receptor binding affinity (K(D)) and density (B(max)) were unchanged in the overall AD group compared with controls. Within the AD group, 5-HT(1A) receptor B(max) in the temporal cortex inversely correlated with aggression and dementia severity. However, multiple regression analyses showed that 5-HT(1A) receptor B(max) remained the best predictor for aggression, while temporal cortical neurofibrillary tangle grading was the best predictor for dementia severity. This suggests that 5-HT(1A) receptor alteration is directly related to aggression in AD, while dementia severity is more strongly related to the neurodegenerative process. Our data indicate further study of 5-HT(1A) receptors as a pharmacological target for the treatment of behavioral symptoms in AD.     

Absence of 5-HT(1B) receptors is associated with impaired impulse control in male 5-HT(1B) knockout mice.

BACKGROUND: Serotonin (5-HT) plays a complex regulatory role in processes like anxiety, depression, aggression, and impulse control. Due to the large amount of serotonergic receptors, knockout mice offer an important opportunity to investigate the role of specific receptors. The 5-HT(1B) receptor is thought to mediate aggression and impulse control. This was studied here in mice lacking 5-HT(1B) receptors (5-HT(1B) KO). METHODS: Wild type and 5-HT(1B) KO mice were exposed to several types of entrained and nonentrained stimuli. With telemetry, body temperature, heart rate, and locomotor activity were measured continuously during the different experiments. RESULTS: To nonentrained stimuli like disturbance stress and confrontation with an intruder, 5-HT(1B) KO mice showed exaggerated physiologic and behavioral responses. These mice displayed behavioral disinhibition, measured as increased social interest and aggression to an intruder mouse. However, in response to well-entrained stimuli like daily light transitions, responses were smaller in 5-HT(1B) KO than in wild type mice, suggesting that hyperreactivity is stimulus specific. CONCLUSIONS: Serotonin 1B receptors are essential in impulse control by inhibiting responses to nonentrained stimuli. Therefore, the 5-HT(1B) KO mouse might be an important additional model for studying aspects of disinhibition in aggression and impulse control.     

GPR30 is necessary for estradiol-induced desensitization of 5-HT1A receptor signaling in the paraventricular nucleus of the rat hypothalamus

Estrogen therapy used in combination with selective serotonin reuptake inhibitor (SSRI) treatment improves SSRI efficacy for the treatment of mood disorders. Desensitization of serotonin 1A (5-HT(1A)) receptors, which takes one to two weeks to develop in animals, is necessary for SSRI therapeutic efficacy. Estradiol modifies 5-HT(1A) receptor signaling and induces a partial desensitization in the paraventricular nucleus (PVN) of the rat within two days, but the mechanisms underlying this effect are currently unknown. The purpose of this study was to identify the estrogen receptor necessary for estradiol-induced 5-HT(1A) receptor desensitization. We previously showed that estrogen receptor β is not necessary for 5-HT(1A) receptor desensitization and that selective activation of estrogen receptor GPR30 mimics the effects of estradiol in rat PVN. Here, we used a recombinant adenovirus containing GPR30 siRNAs to decrease GPR30 expression in the PVN. Reduction of GPR30 prevented estradiol-induced desensitization of 5-HT(1A) receptor as measured by hormonal responses to the selective 5-HT(1A) receptor agonist, (+)8-OH-DPAT. To determine the possible mechanisms underlying these effects, we investigated protein and mRNA levels of 5-HT(1A) receptor signaling components including 5-HT(1A) receptor, Gαz, and RGSz1. We found that two days of estradiol increased protein and mRNA expression of RGSz1, and decreased 5-HT(1A) receptor protein but increased 5-HT(1A) mRNA; GPR30 knockdown prevented the estradiol-induced changes in 5-HT(1A) receptor protein in the PVN. Taken together, these data demonstrate that GPR30 is necessary for estradiol-induced changes in the 5-HT(1A) receptor signaling pathway and desensitization of 5-HT(1A) receptor signaling.     

5-HT7R/G12 signaling regulates neuronal morphology and function in an age-dependent manner

The common neurotransmitter serotonin controls different aspects of early neuronal differentiation, although the underlying mechanisms are poorly understood. Here we report that activation of the serotonin 5-HT(7) receptor promotes synaptogenesis and enhances synaptic activity in hippocampal neurons at early postnatal stages. An analysis of Gα(12)-deficient mice reveals a critical role of G(12)-protein for 5-HT(7) receptor-mediated effects in neurons. In organotypic preparations from the hippocampus of juvenile mice, stimulation of 5-HT(7)R/G(12) signaling potentiates formation of dendritic spines, increases neuronal excitability, and modulates synaptic plasticity. In contrast, in older neuronal preparations, morphogenetic and synaptogenic effects of 5-HT(7)/G(12) signaling are abolished. Moreover, inhibition of 5-HT(7) receptor had no effect on synaptic plasticity in hippocampus of adult animals. Expression analysis reveals that the production of 5-HT(7) and Gα(12)-proteins in the hippocampus undergoes strong regulation with a pronounced transient increase during early postnatal stages. Thus, regulated expression of 5-HT(7) receptor and Gα(12)-protein may represent a molecular mechanism by which serotonin specifically modulates formation of initial neuronal networks during early postnatal development.     

High trait aggression in men is associated with low 5-HT levels,as indexed by 5-HT4 receptor binding

Impulsive aggression has commonly been associated with a dysfunction of the serotonin (5-HT) system: many, but not all, studies point to an inverse relationship between 5-HT and aggression. As cerebral 5-HT₄ receptor (5-HT₄R) binding has recently been recognized as a proxy for stable brain levels of 5-HT, we here test the hypothesis in healthy men and women that brain 5-HT levels, as indexed by cerebral 5-HT₄R, are inversely correlated with trait aggression and impulsivity. Sixty-one individuals (47 men) underwent positron emission tomography scanning with the radioligand [¹¹C]SB207145 for quantification of brain 5-HT₄R binding. The Buss–Perry Aggression Questionnaire (BPAQ) and the Barratt Impulsiveness Scale were used for assessment of trait aggression and trait impulsivity. Among male subjects, there was a positive correlation between global 5-HT₄R and BPAQ total score (P = 0.037) as well as BPAQ physical aggression (P = 0.025). No main effect of global 5-HT₄R on trait aggression or impulsivity was found in the mixed gender sample, but there was evidence for sex interaction effects in the relationship between global 5-HT₄R and BPAQ physical aggression. In conclusion we found that low cerebral 5-HT levels, as indexed by 5-HT₄R binding were associated with high trait aggression in males, but not in females.     

Expression of gLTP in Sympathetic Ganglia of Obese Zucker Rats In Vivo: Molecular Evidence

Long-term potentiation in sympathetic ganglia (gLTP) is similar to LTP of the hippocampal area CA1 in that its expression involves similar changes in signaling molecules. We have shown previously that the stress-prone, hypertensive obese Zucker rats (OZR) expressed gLTP in sympathetic ganglia and that high blood pressure was reduced by treatment with 5-HT(3) receptor antagonists. In the present study, we present additional electrophysiological evidence for the pre-expression of gLTP in sympathetic ganglia from OZR indicated by failure of repetitive stimulation to express gLTP in isolated superior cervical ganglia (SCG) and inhibition of baseline ganglionic transmission by a 5-HT(3) receptor antagonist. We have also investigated the role of key signaling molecules in the expression of gLTP in the hypertensive OZR. Immunoblot analysis showed a significant increase in the levels of phosphorylated (P-)CaMKII and protein kinase C gamma (PKCgamma) in SCG from OZR. The ratio of P-CaMKII to the total CaMKII was markedly increased in OZR ganglia, suggesting increased phosphorylation of this molecule. Additionally, there was a significant decrease in the levels of calcineurin in ganglia. Furthermore, the neural nitric oxide synthase and hemeoxygenase II, which are essential for the expression of gLTP, were significantly elevated in OZR ganglia. The present findings confirm that ganglia from OZR have expressed gLTP and that synaptic plasticity in sympathetic ganglia may involve a molecular cascade similar to that of LTP of the brain hippocampal area CA1.     

Elevated childhood serotonergic function protects against adolescent aggression in disruptive boys

OBJECTIVE: This longitudinal study examined whether responsiveness of the neurotransmitter serotonin (5-HT) in childhood predicts adolescent aggression. METHOD: Boys (N = 33) with disruptive behavior disorders who received assessments of central 5-HT function via the prolactin response to fenfluramine between 1990 and 1994 when they were 7 to 11 years old were re-evaluated clinically on average 6.7 years later. RESULTS: After accounting for baseline aggression, early 5-HT function accounted for a significant proportion of variance in adolescent aggression. This prospective relationship of childhood 5-HT function with adolescent aggression (r = -0.71) and antisocial behavior (r = -0.59) was found primarily in adolescents who were aggressive during childhood. Irrespective of childhood aggression, no child with high 5-HT function was particularly aggressive at follow-up. CONCLUSIONS: Low childhood 5-HT function appears important, but not sufficient, for the emergence of adolescent aggression. However, early high 5-HT function may protect against adolescent violence and aggression.     

New vistas on 5-HT receptors and migraine

1. A number of serotonergic agents have been shown to be effective in the treatment of migraine. At the present time, migraine drug interactions have been analyzed most extensively at 5-hydroxytryptamine1D (5-HT1D), 5-HT2 and 5-HT3 receptor subtypes. 2. This review will summarize the current status of 5-HT receptor subtypes as they relate to anti-migraine agents. 3. The available data suggest that drug interactions with specific 5-HT receptor subtypes may be the basis for their efficacy in both the acute and prophylactic treatment of migraine.     

Inhibition of 5-HT1A receptor-dependent cell survival by cAMP/protein kinase A: role of protein phosphatase 2A and Bax

Serotonergic 5-HT(1A) receptor signaling leading to nuclear factor-kappaB (NF-kappaB) activation appears to be critical for cell survival. Adenylyl cyclase and protein kinase A (AC/PKA) are effectors of the 5-HT(1A) receptor that are inhibited by Galpha(i) subunits. Conversely, Gbetagamma(i) subunits downstream from the 5-HT(1A) receptor participate in the activation of extracellular signal-regulated kinases (ERK1/2), phosphatidylinositol 3-kinase (PI3K), Akt, and NF-kappaB. To model the contribution of pro- and antiapoptotic signaling cascades downstream of activated 5-HT(1A) receptor in cell survival, Chinese hamster ovarian (CHO) cells were employed that exogenously overexpress 5-HT(1A) receptors. Stimulation with the 5-HT(1A) receptor agonist 8-OH-DPAT and pharmacological agonists of AC induced PKA and protein phosphatase 2A (PP2A) activity, which in turn inhibited: Akt activity, IkappaBalpha degradation, nuclear translocation of NF-kappaB, and expression of X-linked inhibitor of apoptosis protein (XIAP/BIRC4). Pharmacological inhibition of PP2A with calyculin A potentiated Akt activity while attenuating ERK1/2 signaling via increased inhibitory phosphorylation of Raf (pSer259). In contrast, increased cAMP levels enhanced Bax translocation to the mitochondria, resulting in the release of cytochrome c, caspase-3 activation, and apoptosis induction. Our data suggest a central role of cAMP/PKA-dependent PP2A in shifting the homeostasis of intracellular signaling downstream of activated 5-HT(1A) receptor toward cell death in biological systems linked to neuropsychiatric disorders.     

Developmentally regulated serotonin 5-HT2B receptors.

Serotonin (5-hydroxytryptamine, 5-HT) binds to numerous cognate receptors to initiate its biological effects. In this review, we have focused on the 5-HT2B receptor to address how signaling and expression of this receptor is specifically implicated in embryonic development and adult health and disease. Transduction of the 5-HT2B signaling is complex, including phospholipase C and A2 stimulation, cGMP production and a mitogenic signal that integrates the tyrosine kinase-signaling pathway. Furthermore, 5-HT, through the 5-HT2B receptors, has the ability to control serotonergic differentiation of committed neuron-like cells. In addition, 5-HT2B receptors are actively involved in the transient action of 5-HT during embryonic morphogenesis. Our recent data presented the first genetic evidence that 5-HT via 5-HT2B receptors regulates cardiac embryonic development and adult functions and suggested that this receptor subtype may be involved in other physiopathological situations. In particular, 5-HT-dependent molecular mechanisms may be involved in embryonic development and postnatal maturation of the enteric nervous system. Also, the involvement of the 5-HT2B receptor in the vascular growth often observed in hypertension is likely. These probably result from reactivation of developmentally regulated receptors in pathological situations. Finally, embryonic functions of 5-HT2 receptors observed in Drosophila gastrulation suggest evolutionary conserved mechanisms.     

Enhancement of Aggression Induced by Isolation Rearing is Associated with a Lack of Central Serotonin

Isolation rearing(IR) enhances aggressive behavior, and the central serotonin(5-hydroxytryptamine,5-HT) system has been linked to IR-induced aggression.However, whether the alteration of central serotonin is the cause or consequence of enhanced aggression is still unknown. In the present study, using mice deficient in central serotonin Tph2-/-and Lmx1 b-/-, we examined the association between central serotonin and aggression with or without social isolation. We demonstrated that central serotonergic neurons are critical for the enhanced aggression after IR. 5-HT depletion in wild-type mice increased aggression. On the other hand, application of 5-HT in Lmx1 b-/-mice inhibited the enhancement of aggression under social isolation conditions. Dopamine was downregulated in Lmx1 b-/-mice. Similar to 5-HT, L-DOPA decreased aggression in Lmx1 b-/-mice. Our results linkthe serotoninergic system directly to aggression and this may have clinical implications for aggression-related human conditions.