Severe deficits in 5-HT2A -mediated neurotransmission in BDNF conditional mutant mice

BDNF is thought to provide critical trophic support for serotonin neurons. In order to determine postnatal effects of BDNF on the serotonin system, we examined a line of conditional mutant mice that have normal brain content of BDNF during prenatal development but later depletion of this neurotrophin in the postnatal period. These mice show a behavioral phenotype that suggests serotonin dysregulation. However, as shown here, the presynaptic serotonin system in the adult conditional mutant mice appeared surprisingly normal from histological, biochemical, and electrophysiological perspectives. By contrast, a dramatic and unexpected postsynaptic 5-HT2A deficit in the mutant mice was found. Electrophysiologically, serotonin neurons appeared near normal except, most notably, for an almost complete absence of expected 5-HT2A -mediated glutamate and GABA postsynaptic potentials normally displayed by these neurons. Further analysis showed that BDNF mutants had much reduced 5-HT2A receptor protein in dorsal raphe nucleus and a similar deficit in prefrontal cortex, a region that normally shows a high level of 5-HT2A receptor expression. Recordings in prefrontal slice showed a marked deficit in 5-HT2A -mediated excitatory postsynaptic currents, similar to that seen in the dorsal raphe. These findings suggest that postnatal levels of BDNF play a relatively limited role in maintaining presynaptic aspects of the serotonin system and a much greater role in maintaining postsynaptic 5-HT2A and possibly other receptors than previously suspected.     

Chronic voluntary ethanol intake hypersensitizes 5‐HT1A autoreceptors in C57BL/6J mice

Alcoholism is a complex disorder involving, among others, the serotoninergic (5‐HT) system, mainly regulated by 5‐HT_1A autoreceptors in the dorsal raphe nucleus. 5‐HT_1A autoreceptor desensitization induced by chronic 5‐HT reuptake inactivation has been associated with a decrease in ethanol intake in mice. We investigated here whether, conversely, chronic ethanol intake could induce 5‐HT_1A autoreceptor supersensitivity, thereby contributing to the maintenance of high ethanol consumption. C57BL/6J mice were subjected to a progressive ethanol intake procedure in a free‐choice paradigm (3–10% ethanol versus tap water; 21 days) and 5‐HT_1A autoreceptor functional state was assessed using different approaches. Acute administration of the 5‐HT_1A receptor agonist ipsapirone decreased the rate of tryptophan hydroxylation in striatum, and this effect was significantly larger (+75%) in mice that drank ethanol than in those drinking water. Furthermore, ethanol intake produced both an increased potency (+45%) of ipsapirone to inhibit the firing of 5‐HT neurons, and a raise (+35%) in 5‐HT_1A autoreceptor‐mediated stimulation of [³⁵S]GTP‐γ‐S binding in the dorsal raphe nucleus. These data showed that chronic voluntary ethanol intake in C57BL/6J mice induced 5‐HT_1A autoreceptor supersensitivity, at the origin of a 5‐HT neurotransmission deficit, which might be causally related to the addictive effects of ethanol intake.     

The mechanism of acute fasting‐induced antidepressant‐like effects in mice

Acute fasting induced antidepressant‐like effects. However, the exact brain region and mechanism of these actions are still largely unknown. Therefore, in this study the antidepressant‐like effects of acute fasting on c‐Fos expression and BDNF levels were investigated. Consistent with our previous findings, immobility time was remarkably shortened by 9 hrs fasting in the forced swimming test. Furthermore, these antidepressant‐like effects of 9 fasting were inhibited by a 5‐HT_2A/2C receptor agonist (±)‐1‐(2, 5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane hydrochloride (DOI), and the effect of DOI was blocked by pretreatment with a selective 5‐HT_2A receptor antagonist ketanserin. Immunohistochemical study has shown that c‐Fos level was significantly increased by 9 hrs fasting in prefrontal cortex but not hippocampus and habenular. Fasting‐induced c‐Fos expression was further enhanced by DOI in prefrontal cortex, and these enhancements were inhibited by ketanserin. The increased BDNF levels by fasting were markedly inhibited by DOI in frontal cortex and hippocampus, and these effects of DOI on BDNF levels were also blocked by ketanserin. These findings suggest that the antidepressant‐like effects of acute fasting may be exerted via 5‐HT_2A receptor and particularly sensitive to neural activity in the prefrontal cortex. Furthermore, these antidepressant‐like effects are also mediated by CREB and BDNF pathway in hippocampus and frontal cortex. Therefore, fasting may be potentially helpful against depression.     

The role of 5‐HT2A receptor and 5‐HT2A/5‐HT1A receptor interaction in the suppression of catalepsy

In the present study, the 5‐HT_2A and 5‐HT_1A receptors functional activity and 5‐HT_2A receptor gene expression were examined in the brain of ASC/Icg and congenic AKR.CBAD13Mit76C mouse strains (genetically predisposed to catalepsy) in comparison with the parental catalepsy‐resistant AKR/J and catalepsy‐prone CBA/Lac mouse strains. The significantly reduced 5‐HT_2A receptor functional activity along with decreased 5‐HT_2A receptor gene expression in the frontal cortex was found in all mice predisposed to catalepsy compared with catalepsy‐resistant AKR/J. 5‐HT_2A agonist DOI (0.5 and 1 mg/kg, i.p.) significantly reduced catalepsy in ASC/Icg and CBA/Lac, but not in AKR.CBAD13Mit76C mice. Essential increase in 5‐HT_1A receptor functional activity was shown in catalepsy‐prone mouse strains in comparison with catalepsy‐resistant AKR/J mice. However, in AKR.CBAD13Mit76C mice it was lower than in ASC/Icg and CBA/Lac mice. The inter‐relation between 5‐HT_2A and 5‐HT_1A receptors in the regulation of catalepsy was suggested. This suggestion was confirmed by prevention of DOI anticataleptic effect in ASC/Icg and CBA/Lac mice by pretreatment with 5‐HT_1A receptor antagonist p‐MPPI (3 mg/kg, i.p.). At the same time, the activation of 5‐HT_2A receptor led to the essential suppression of 5‐HT_1A receptor functional activity, indicating the opposite effect of 5‐HT_2A receptor on pre‐ and postsynaptic 5‐HT_1A receptors. Thus, 5‐HT_2A/5‐HT_1A receptor interaction in the mechanism of catalepsy suppression in mice was shown.     

A single in vivo cocaine administration impairs 5‐HT1B receptor‐induced long‐term depression in the nucleus accumbens

The nucleus accumbens (NAc) is a crucial forebrain nucleus implicated in reward‐based decision‐making. While NAc neurons are richly innervated by serotonergic fibers, information on the functional role of serotonin 5‐hydroxytryptamine (5‐HT) in the NAc is still sparse. Here, we demonstrate that brief application of 5‐HT or 5‐HT_1B receptor agonist CP 93129 induced a long‐term depression (LTD) of glutamatergic transmission in NAc neurons. This LTD was presynaptically mediated and inducible by endogenous 5‐HT. Remarkably, a single cocaine exposure impaired the induction of LTD by 5‐HT or CP 93129. The inhibition was blocked when a selective dopamine D₁ receptor antagonist SCH23390 was coadministered with cocaine. Cocaine treatment resulted in increased phosphorylation of presynaptic proteins, rabphilin 3A and synapsin 1, and significantly attenuated CP 93129‐induced decrease in rabphilin 3A and synapsin 1 phosphorylation. Application of cAMP‐dependent protein kinase inhibitor KT5720 caused a prominent synaptic depression in NAc neurons of mice with a history of cocaine exposure. Our results reveal a novel 5‐HT_1B receptor‐mediated LTD in the NAc and suggest that cocaine exposure may result in elevated phosphorylation of presynaptic proteins involved in regulating glutamate release, which counteracts the presynaptic depressant effects of 5‐HT_1B receptors and thereby impairs the induction of LTD by 5‐HT.     

Gender‐dependent regulation of G‐protein‐gated inwardly rectifying potassium current in dorsal raphe neurons in knock‐out mice devoid of the 5‐hydroxytryptamine transporter

Agonists at G‐protein‐coupled receptors in neurons of the dorsal raphe nucleus (DRN) of knock‐out mice devoid of the serotonin transporter (5‐HTT^?/?) exhibit lower efficacy to inhibit cellular discharge than in wild‐type counterparts. Using patch‐clamp whole‐cell recordings, we found that a G‐protein‐gated inwardly rectifying potassium (GIRK) current is involved in the inhibition of spike discharge induced by 5‐HT_1A agonists (5‐carboxamidotryptamine (5‐CT) and (±)‐2‐dipropylamino‐8‐hydroxy‐1,2,3,4‐tetrahydronaphthalene hydrobromide (8‐OH‐DPAT); 50 nM–30 μM) in both wild‐type and 5‐HTT^?/? female and male mice. These effects were mimicked by 5′‐guanylyl‐imido‐diphosphate (Gpp(NH)p; 400 μM) dialysis into cells with differences between genders. The 5‐HTT^?/? knock‐out mutation reduced the current density induced by Gpp(NH)p in females but not in males. These data suggest that the decreased response of 5‐HT_1A receptors to agonists in 5‐HTT^?/? mutants reflects notably alteration in the coupling between G‐proteins and GIRK channels in females but not in males. Accordingly, gender differences in central 5‐HT neurotransmission appear to depend—at least in part—on sex‐related variations in corresponding receptor‐G protein signaling mechanisms. © 2006 Wiley Periodicals, Inc. J Neurobiol, 2006     

Anxiety and increased 5‐HT1A receptor response in NCAM null mutant mice

Mice deficient in the neural cell adhesion molecule (NCAM) show behavioral abnormalities as adults, including altered exploratory behavior, deficits in spatial learning, and increased intermale aggression. Here, we report increased anxiety‐like behavior of homozygous (NCAM^−/−) and heterozygous (NCAM^+/−) mutant mice in a light/dark avoidance test, independent of genetic background and gender. Anxiety‐like behavior was reduced in both NCAM^+/+ and NCAM^−/− mice by systemic administration of the benzodiazepine agonist diazepam and the 5‐HT_1A receptor agonists buspirone and 8‐OH‐DPAT. However, NCAM^−/− mice showed anxiolytic‐like effects at lower doses of buspirone and 8‐OH‐DPAT than NCAM^+/+ mice. Such increased response to 5‐HT_1A receptor stimulation suggests a functional change in the serotonergic system of NCAM^−/− mice, likely involved in the control of anxiety and aggression. However, 5‐HT_1A receptor binding and tissue content of serotonin and its metabolite 5‐hydroxyindolacetic acid were found unaltered in every brain area of NCAM^−/− mice investigated, indicating that expression of 5‐HT_1A receptors as well as synthesis and release of serotonin are largely unchanged in NCAM^−/− mice. We hypothesize a critical involvement of endogenous NCAM in serotonergic transmission via 5‐HT_1A receptors and inwardly rectifying K⁺ channels as the respective effector systems. © 1999 John Wiley & Sons, Inc. J Neurobiol 40: 343–355, 1999     

Role of maternal 5‐HT1A receptor in programming offspring emotional and physical development

Serotonin_1A receptor (5‐HT_1AR) deficiency has been associated with anxiety and depression and mice with genetic receptor inactivation exhibit heightened anxiety. We have reported that 5‐HT_1AR is not only a genetic but also a maternal ‘environmental’ factor in the development of anxiety in Swiss‐Webster mice. Here, we tested whether the emergence of maternal genotype‐dependent adult anxiety is preceded by early behavioral abnormalities or whether it is manifested following a normal emotional development. Pups born to null or heterozygote mothers had significantly reduced ultrasonic vocalization (USV) between postnatal day (P) 4 and 12, indicating an influence of the maternal genotype. The offspring's own genotype had an effect limited to P4. Furthermore, we observed reduced weight gain in the null offspring of null but not heterozygote mothers, indicating that a complete maternal receptor deficiency compromises physical development of the offspring. Except a short perinatal deficit during the dark period, heterozygote females displayed normal maternal behavior, which, with the early appearance of USV deficit, suggests a role for 5‐HT_1AR during pre‐/perinatal development. Consistent with this notion, adult anxiety in the offspring is determined during the pre‐/perinatal period. In contrast to heterozygote females, null mothers exhibited impaired pup retrieval and nest building that may explain the reduced weight gain of their offspring. Taken together, our data indicate an important role for the maternal 5‐HT_1AR in regulating emotional and physical development of their offspring. Because reduced receptor binding has been reported in depression, including postpartum depression, reduced 5‐HT_1AR function in mothers may influence the emotional development of their offspring.     

Antagonism of 5-HT1A receptors uncovers an excitatory effect of SSRIs on 5-HT neuronal activity, an action probably mediated by 5-HT7 receptors

Both microdialysis and electrophysiology were used to investigate whether another serotonin (5‐HT) receptor subtype next to the 5‐HT_1A autoreceptor is involved in the acute effects of a selective serotonin reuptake inhibitor on 5‐HT neuronal activity. On the basis of a previous study, we decided to investigate the involvement of the 5‐HT₇ receptors. Experiments were performed with the specific 5‐HT₇ antagonist SB 258741 and the putative 5‐HT₇ agonist AS19. In this study WAY 100.635 was used to block 5‐HT_1A receptors. Systemic administration of SB 258741 significantly reduced the effect of combined selective serotonin reuptake inhibitor and WAY 100.635 administration on extracellular 5‐HT in the ventral hippocampus as well as 5‐HT neuronal firing in the dorsal raphe nucleus. In the microdialysis study, co‐administration of AS19 and WAY 100.635 showed a biphasic effect on extracellular 5‐HT in ventral hippocampus, hinting at opposed 5‐HT₇ receptor mediated effects. In the electrophysiological experiments, systemic administration of AS19 alone displayed a bell‐shaped dose–effect curve: moderately increasing 5‐HT neuronal firing at lower doses while decreasing it at higher doses. SB 258741 was capable of blocking the effect of AS19 at a low dose. This is consistent with the pharmacological profile of AS19, displaying high affinity for 5‐HT₇ receptors and moderate affinity for 5‐HT_1A receptors. The data are in support of an excitatory effect of selective serotonin reuptake inhibitors on 5‐HT neuronal activity mediated by 5‐HT₇ receptors. It can be speculated, that the restoration of 5‐HT neuronal firing upon chronic antidepressant treatment, which is generally attributed to desensitization of 5‐HT_1A receptors alone, in fact results from a shift in balance between 5‐HT_1A and 5‐HT₇ receptor function.     

Regulation of GABAergic inhibition by serotonin signaling in prefrontal cortex: molecular mechanisms and functional implications

Serotonergic neurotransmission in prefrontal cortex (PFC) plays a key role in regulating emotion and cognition under normal and pathological conditios. Increasing evidence suggests that serotonin receptors are involved in the complex regulation of GABAergic inhibitory transmission in PFC. Activation of postsynaptic 5-HT₂ receptors in PFC pyramidal neurons inhibits GABA_A-receptor currents via phosphorylation of GABA_A receptor γ2 subunits by RACK1-anchored PKC. In contrast, activation of postsynaptic 5-HT₄ receptors produces an activity-dependent bi-directional regulation of GABA-evoked currents in PFC pyramidal neurons, which is mediated through phosphorylation of GABA_A-receptor β subunits by anchored PKA. On the presynaptic side, GABAergic inhibition is regulated by 5-HT through the activation of 5-HT₂, 5-HT₁, and 5-HT₃ receptors on GABAergic intereneurons. These data provide a molecular and cellular mechanism for serotonin to dynamically regulate synaptic transmission and neuronal excitability in the PFC network, which may underlie the actions of many antidepressant and antipsychotic drugs.     

5‐HT1A Activation Counteracts Cardiovascular But Not Hypophagic Effects of Sibutramine in Rats

The noradrenaline (NA) and serotonin reuptake inhibitor, sibutramine, gives effective weight loss, but full efficacy cannot be attained at approved doses due to cardiovascular side effects. We assessed in rats the contributions of NA and serotonin transporters to sibutramine's hypophagic and cardiovascular effects, and whether selective 5‐hydroxytryptamine (5‐HT_1A) receptor activation could counteract the latter without affecting the former. Food intake was assessed in freely feeding rats and cardiovascular parameters in conscious telemetered rats. Ex vivo radioligand binding was used to estimate brain monoamine transporter occupancy. Sibutramine (1–10 mg/kg p.o.) dose‐dependently reduced food intake; however, 10 mg/kg p.o. markedly elevated blood pressure and heart rate. Sibutramine gave greater occupancy of NA than serotonin reuptake sites. Coadministration of the selective 5‐HT_1A agonist F‐11440 (2.5 mg/kg p.o.) attenuated sibutramine‐induced hypertension and tachycardia without altering its food intake effects. The selective NA reuptake inhibitors, nisoxetine or reboxetine, did not alter food intake alone, but each reduced food intake when combined with F‐11440. These results suggest that sibutramine‐induced hypophagic and cardiovascular effects are largely due to increased brain synaptic NA via NA reuptake inhibition, and that 5‐HT_1A activation can counter the undesirable cardiovascular effects resulting from increased sympathetic activity. Selective NA reuptake inhibitors did not reduce food intake alone but did when combined with 5‐HT_1A activation. Hence increased synaptic serotonin, via serotonin reuptake inhibition or 5‐HT_1A activation, together with increased NA, would appear to produce hypophagia. Thus weight loss with minimal cardiovascular risk could be achieved by 5‐HT_1A activation combined with NA transporter blockade.     

Mass spectrometric characterization of recombinant rat 5‐hydroxytryptamine receptor 1A (5‐HT1AR) expressed in tsA201 human embryonic kidney cells

The 5‐hydroxytryptamine 1A receptor (serotonin 1A receptor; 5‐HT_1AR) is involved in a large series of brain functions, and roles in anxiety, depression, and cognition have been reported. So far, published information on mass spectrometrical characterization of 5‐HT_1AR is limited to the presence of two 5‐HT_1AR peptides in rat's whole brain as observed by in‐solution digestion followed by LC‐MS/MS. Knowledge about the protein sequence and PTMs, however, would have implications for generation of specific antibodies and designing studies on the 5‐HT_1AR at the protein level. A rat recombinant 5‐HT_1AR was extracted from the tsA201 cell line, run using several gel‐based principles with subsequent in‐gel digestion with several proteases, chymotrypsin, trypsin, AspN, proteinase K, and pepsin followed by nano‐LC‐ESI‐MS/MS analysis on a high capacity ion trap and an LTQ Orbitrap Velos. Using two search engines, Mascot and Modiro?, the recombinant 5‐HT_1AR was identified showing 94.55% sequence coverage. A single phosphorylation at S301 was identified and verified by phosphatase treatment and a series of amino acid substitutions were detected. Characterization of 5‐HT_1AR, a key player of brain functions and neurotransmission, was shown and may enable generation of specific antibodies, design of future, and interpretation of previous studies in the rat at the protein level.     

NCAM deficiency in the mouse forebrain impairs innate and learned avoidance behaviours

The neural cell adhesion molecule (NCAM) has been implicated in the development and plasticity of neural circuits and the control of hippocampus‐ and amygdala‐dependent learning and behaviour. Previous studies in constitutive NCAM null mutants identified emotional behaviour deficits related to disturbances of hippocampal and amygdala functions. Here, we studied these behaviours in mice conditionally deficient in NCAM in the postmigratory forebrain neurons. We report deficits in both innate and learned avoidance behaviours, as observed in elevated plus maze and passive avoidance tasks. In contrast, general locomotor activity, trait anxiety or neophobia were unaffected by the mutation. Altered avoidance behaviour of the conditional NCAM mutants was associated with a deficit in serotonergic signalling, as indicated by their reduced responsiveness to (±)‐8‐hydroxy‐2‐(dipropylamino)‐tetralin‐induced hypo-thermia. Another serotonin‐dependent behaviour, namely intermale aggression that is massively increased in constitutively NCAM‐deficient mice, was not affected in the forebrain‐specific mutants. Our data suggest that genetically or environmentally induced changes of NCAM expression in the late postnatal and mature forebrain determine avoidance behaviour and serotonin (5‐HT)_1A receptor signalling.     

5‐HT2A Receptor Gene Promoter Polymorphism in Relation to Abdominal Obesity and Cortisol

Objective: There is considerable evidence that cortisol secretion is associated with obesity. The regulation of the 5‐hydroxytryptamine receptor 2A (5‐HT_2A) gene might play an essential role because it is involved in the control of cortisol secretion. Therefore, we examined the potential impact of the 5‐HT_2A ?1438G/A promoter polymorphism on obesity and estimates of insulin, glucose, and lipid metabolism as well as circulating hormones, including salivary cortisol, in 284 unrelated Swedish men born in 1944. Research Methods and Procedures: The subjects were genotyped by using polymerase chain reaction amplification of the promoter region of the gene for 5‐HT_2A followed by digestion of the reaction product with the restriction enzyme MspI. Results: The frequencies were 0.39 for allele ?1438A and 0.61 for allele ?1438G. Homozygotes for the ?1438G allele had, in comparison with ?1438A/A subjects, higher body mass index, waist‐to‐hip ratio, and abdominal sagittal diameter. Moreover, cortisol escape from 0.25‐mg dexamethasone suppression was found in subjects with the ?1438A/G genotype. Serum leptin, fasting insulin, and glucose, as well as serum lipids, were not different across the ?1438G/A genotype groups. Discussion: From these results, we suggest the possibility that an abnormal production rate of the 5‐HT_2A gene product might lead to the development of abdominal obesity. The pathophysiology could involve stress factors that destabilize the serotonin‐hypothalamic‐pituitary‐adrenal system in those with genetic vulnerability in the serotonin receptor gene.     

Effects of 5‐HT1 and 5‐HT 2 Receptor Agonists on Electromagnetic Field‐Induced Analgesia in Rats

Much evidence demonstrates the antinociceptive effect of magnetic fields (MFs). However, the analgesic action mechanism of the electromagnetic field (EMF) is not exactly understood. The aim of the present study was to investigate the effects of 5‐HT₁ and 5‐HT₂ receptor agonists (serotonin HCl and 2,5‐dimethoxy‐4‐iodoamphetamine [DOI] hydrochloride) on EMF‐induced analgesia. In total, 66 adult male Wistar albino rats with an average body mass of 225 ± 13 g were used in this study. The animals were subjected to repeated exposures of alternating 50 Hz and 5 mT EMF for 2 h a day for 15 days. Prior to analgesia tests, serotonin HCl (5‐HT₁ agonist) 4 mg/kg, WAY 100635 (5‐HT₁ antagonist) 0.04 mg/kg, DOI hydrochloride (5‐HT₂ receptor agonist) 4 mg/kg, and SB 204741 (5‐HT₂ antagonist) 0.5 mg/kg doses were injected into rats. For statistical analysis of the data, analysis of variance was used and multiple comparisons were determined by Tukey’s test. Administration of serotonin HCl MF (5 mT)‐exposed rats produced a significant increase in percent maximal possible effect (% MPE) as compared with EMF group (P < 0.05). On the contrary, injection of WAY 100635 to MF‐exposed rats produced a significant decrease in analgesic activity (P < 0.05). Similarly, the administration of DOI hydrochloride significantly increased % MPE values as compared with the EMF group while SB 204741 reduced it (P < 0.05). In conclusion, our results suggested that serotonin 5‐HT₁ and 5‐HT₂ receptors play an important role in EMF‐induced analgesia; however, further research studies are necessary to understand the mechanism. Bioelectromagnetics. 2019;40:319–330. © 2019 Bioelectromagnetics Society.     

Transient expression of serotonin 5‐HT4 receptors in the mouse developing thalamocortical projections

The serotonin 5‐HT₄ receptor (5‐HT₄‐R) is an unusually complex G‐protein coupled receptor that is likely to play important roles in brain development and that may underlie the comorbidity of central and peripheral abnormalities in some developmental disorders. We studied the expression of 5‐HT₄‐Rs in the developing mouse forebrain at embryonic days 13, 15, 17, and at postnatal days 3 and 14 by using immunohistochemistry, tract tracing, and quantitative RT‐PCR. The developing thalamocortical projections transiently expressed 5‐HT₄‐Rs in the embryonic brain and the 5‐HT₄‐R expression in the forebrain changed from axonal to somatic around birth. From embryonic days 13–17, the forebrain mRNA levels of the 5‐HT_4(a)‐R and 5‐HT_4(b)‐R splice variants increased nine‐ and fivefold, respectively, whereas the levels of the 5‐HT_4(e)‐R and 5‐HT_4(f)‐R variants remained relatively low throughout the studied period of embryonic development. These results suggest that during development 5‐HT₄‐R expression undergoes a dynamic regulation and that this regulation may be important for the normal development of sensory and limbic processing. © 2009 Wiley Periodicals, Inc. Develop Neurobiol, 2010.     

Raphe serotonin neuron‐specific oxytocin receptor knockout reduces aggression without affecting anxiety‐like behavior in male mice only

Serotonin and oxytocin influence aggressive and anxiety‐like behaviors, though it is unclear how the two may interact. That the oxytocin receptor is expressed in the serotonergic raphe nuclei suggests a mechanism by which the two neurotransmitters may cooperatively influence behavior. We hypothesized that oxytocin acts on raphe neurons to influence serotonergically mediated anxiety‐like, aggressive and parental care behaviors. We eliminated expression of the oxytocin receptor in raphe neurons by crossing mice expressing Cre recombinase under control of the serotonin transporter promoter (Slc6a4) with our conditional oxytocin receptor knockout line. The knockout mice generated by this cross are normal across a range of behavioral measures: there are no effects for either sex on locomotion in an open‐field, olfactory habituation/dishabituation or, surprisingly, anxiety‐like behaviors in the elevated O and plus mazes. There was a profound deficit in male aggression: only one of 11 raphe oxytocin receptor knockouts showed any aggressive behavior, compared to 8 of 11 wildtypes. In contrast, female knockouts displayed no deficits in maternal behavior or aggression. Our results show that oxytocin, via its effects on raphe neurons, is a key regulator of resident‐intruder aggression in males but not maternal aggression. Furthermore, this reduction in male aggression is quite different from the effects reported previously after forebrain or total elimination of oxytocin receptors. Finally, we conclude that when constitutively eliminated, oxytocin receptors expressed by serotonin cells do not contribute to baseline anxiety‐like behaviors or maternal care.