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Cited by 13Neuroendocrine regulation and behaviorNeuropeptides and Animal PhysiologyNeurotransmitter Receptor Influence on Behavior

Vasopressin regulates social play behavior in sex-specific ways through glutamate modulation in the lateral septum

Open access
Bredewold, Remco, Washington, Catherine, Veenema, Alexa H.·2025·Neuropsychopharmacology
DOI 10.1038/s41386-024-01987-zPMC PMC11845679

Published version of a preprint

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Abstract

Understanding the neural basis of social play in juvenile rats may ultimately help restore social play deficits in autistic children. We previously found that administration of a vasopressin (AVP) V1a receptor (V1aR) antagonist into the lateral septum (LS) increased social play behavior in male juvenile rats and decreased it in females. Here, we demonstrate that glutamate, but not GABA, is involved in this sex-specific regulation. First, we found a sex difference in extracellular LS glutamate/GABA ratio (lower in females) that was eliminated by V1aR antagonist infusion in the LS that caused an increase in glutamate release in females only. Second, infusion of the glutamate receptor agonist L-glutamic acid into the LS mimicked the V1aR antagonist-induced decrease in female social play while preventing the increase in male social play. Third, infusion of the glutamate receptor antagonists AP-5 and CNQX into the LS prevented the V1aR antagonist-induced decrease in female social play. Fourth, there were no sex differences in extracellular GABA release in the LS upon either V1aR antagonist infusion or in social play expression upon infusion of the GABA-A receptor agonist muscimol into the LS, suggesting that GABA is not involved in the sex-specific regulation of social play by the LS-AVP system. Last, we found no sex differences in the type (GAD1/2, somatostatin, calbindin 1, Sox9) of V1aR-expressing LS cells, suggesting other cellular mechanisms mediating the sex-specific effects on glutamate release in the LS by the LS-AVP system. In conclusion, we demonstrate that the LS-AVP system regulates social play sex-specifically via glutamatergic neurotransmission. These findings have relevance for potential sex-specific effects of AVP-based treatment of social deficits in children.

AI snapshot

Written from the paper’s full text.

TL;DR

In juvenile rats, lateral septum (LS) vasopressin V1a receptor blockade regulates social play sex-specifically via glutamate, not GABA: it increases LS glutamate release in females but not males, and glutamate manipulations prevent or mimic the opposing behavioral effects. No sex differences were found in LS Avpr1a+ cell types expressing GABAergic, somatostatin, calbindin, or astrocyte markers.

Key findings

  • Males had higher baseline extracellular LS glutamate concentrations and glutamate/GABA ratios than females (p < 0.05); V1aR antagonist eliminated these sex differences (baseline p = 0.42; social play p = 0.21; ratio V1aR-A p = 0.06; V1aR-A + play p = 0.36). Extracellular GABA concentrations did not differ by sex (p ≥ 0.49).
  • V1aR antagonist increased percentage glutamate release in females before social play (dialysate 3 vs baseline p < 0.01; vs vehicle p < 0.05) but not in males (treatment effect F(1,15) = 0.15; p = 0.71); social play increased glutamate release in both sexes.
  • L-glutamic acid into the LS reduced social play duration in both sexes (F(1,32) = 22.4; p < 0.001; males p < 0.01; females p < 0.001), with a stronger effect in females (sex effect F(1,32) = 4.56; p < 0.05). It prevented the V1aR antagonist-induced increase in social play in males (V1aR-A vs vehicle p < 0.01; V1aR-A + L-GLU vs V1aR-A p < 0.005; vs vehicle p = 1.00) and mimicked the V1aR antagonist-induced decrease in females.
  • AP-5 + CNQX prevented the V1aR antagonist-induced decrease in social play in females (treatment effect F(1,24) = 5.28; p < 0.05; AP-5/CNQX vs V1aR-A p < 0.05; vs vehicle p = 1.00). Muscimol reduced social play in both sexes (F(1,26) = 17.3; p < 0.001; males p < 0.005; females p < 0.05). No sex differences were found in percentages of Avpr1a+ LS cells co-expressing Gad1/Gad2, Sst, Calb1, or Sox9.

Methods

  • Juvenile male and female Wistar rats underwent a 10-min social play test with an unfamiliar age- and sex-matched stimulus rat; behavior was scored blind from video.
  • Experiment 1 used LS microdialysis/retrodialysis with vehicle (n = 8/sex) or V1aR antagonist d(CH2)5Tyr(Me2)AVP (males n = 9; females n = 10), with glutamate and GABA quantified by HPLC-MS/MS. Experiment 2 used LS microinfusions of L-glutamic acid, AP-5, CNQX, muscimol, and/or V1aR antagonist before social play. Experiment 3 used fluorescent in situ hybridization (RNAscope) for Avpr1a with Gad1, Gad2, Sst, Calb1, and Sox9 in juvenile rats (n = 5–7/sex; tables report n = 4–7/sex).
  • Analyses used one-way, two-way, and repeated-measures ANOVAs with LSD or Bonferroni post hoc tests; significance set at p < 0.05.

Limitations

  • The paper states that further research is required to uncover the cellular mechanism by which LS-V1aR activation alters LS glutamate release and regulates social play sex-specifically; no sex differences were found in the V1aR-expressing cell types examined.
  • Evident from the text: all experiments were in juvenile Wistar rats, so direct relevance to humans or ASD is not established; microdialysis measures extracellular concentrations rather than synaptic release; and some experiments used small group sizes (e.g., n = 8–10 per group in microdialysis).
  • Evident from the text: the social play test used single-housed experimental rats and a 10-min exposure, and the pharmacological manipulations cannot identify the precise presynaptic or postsynaptic source of glutamate.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/s41386-024-01987-z

Cites

94 of 94 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

38 of 63 cited sources checked · 26 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Of the AVP, glutamate, and GABA systems in the LS, AVP and glutamate regulate social play behavior in sex-specific ways.

    “Of these three systems, AVP and glutamate regulated social play behavior in sex-specific ways.”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites Veenema et al., 2013 source

      The Discussion (page unavailable) reports that blocking AVP V1a receptors in the lateral septum increased social play in juvenile males but decreased it in females. The paper does not report that glutamate regulates social play in a sex-specific way, so it supports only the AVP part of the claim. (LLM, conf=0.89)

      Experimental — accuracy not yet measured
    • cites Bredewold et al., 2014 source

      The Discussion conclusion (page not provided) states that AVP and OXT in the lateral septum regulate social play in juvenile rats in sex-specific, context-dependent ways. It supports the AVP portion, but does not support attributing a sex-specific glutamate effect to this paper; the other system it identifies is oxytocin, not glutamate. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites Bredewold et al., 2015 source
  • Premisecitation

    Deficits in social play in ASD are likely due to disrupted reward-seeking tendencies, especially in social contexts.

    “Children diagnosed with autism spectrum disorder (ASD) show deficits in social play (Mundy, 1995;Jordan, 2003) which are likely due to disrupted reward-seeking tendencies, especially in social contexts (Chevallier et al., 2012;Kohls et al., 2012Kohls et al., , 2013)).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites Chevallier et al., 2012 source
    • cites Kohls et al., 2012 source

      The Discussion’s “Social motivation theory of ASD” section proposes that impaired social ‘wanting’ causes reduced social-seeking behavior, particularly in social contexts. That supports the proposed mechanism, but the passage does not specifically connect it to deficits in social play. No page number is available in our copy. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
    • cites Kohls et al., 2013 source

      The Introduction links reduced interest in social interactions in ASD to a hypothesized reward-circuit dysfunction, and the Discussion reports altered responses to social rewards in children with ASD. The paper does not examine social play specifically, so it supports the proposed mechanism for social difficulties but not its application to play deficits in particular. (LLM, conf=0.82)

      Experimental — accuracy not yet measured
  • Premisecitation

    The LS plays a critical role in juvenile social play behavior in rats and hamsters.

    “More specifically, the LS plays a critical role in juvenile social play behavior as demonstrated in both rats and hamsters (Beatty et al., 1982;Cheng & Delville, 2009;Veenema et al., 2013, Bredewold et al., 2014, 2015).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Beatty et al., 1982 source
    • cites Cheng & Delville, 2009 source
    • cites Veenema et al., 2013 source

      The Results (Experiment 2; page unavailable) report that injections of a V1aR antagonist into the lateral septum changed juvenile social play in rats, with opposite effects in males and females. This supports a role for the LS in rat social play, but the paper did not study hamsters, so it does not establish that part of the cited sentence. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
  • Premisecitation

    Social play among juvenile peers facilitates the acquisition of social and cognitive competence in humans, non-human primates, and rats.

    “Social play among juvenile peers has been shown to facilitate the acquisition of social and cognitive competence in humans, non-human primates, and rats (Palagi et al., 2016;Pellegrini, 1988;Suomi & Harlow, 1972;Sigman & Ruskin, 1999;Hol et al., 1999;Guralnick et al., 2006;Cordoni & Palagi, 2011;Van Den Berg et al., 1999).”
    Quote in the paperNot a substantial claim1 of 3 sources checked
    • cites Palagi et al., 2016 source

      The indexed copy contains repository metadata and a PDF listing (Abstract > 1.1 Articolo in rivista), but no accessible passage from the paper addressing this claim. Searches for juvenile peer play and the acquisition of social or cognitive competence returned only repository-page text, so the claim cannot be checked against our copy. (LLM, conf=0.76)

      Experimental — accuracy not yet measured
    • cites Pellegrini, 1988 source
    • cites Suomi & Harlow, 1972 source
  • Premisecitation

    AVP via V1aR activation directly excites LS GABAergic interneurons.

    “and directly excites LS GABAergic interneurons (Allaman-Exertier et al., 2007).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Allaman-Exertier et al., 2007 source

      The Results report that vasopressin directly excites lateral septal neurons through V1A receptors. The Discussion says that identifying those neurons as GABAergic interneurons is a hypothesis; the authors’ preliminary attempt to verify their GABAergic identity failed. The cited paper therefore does not establish that the directly excited cells are GABAergic interneurons. (LLM, conf=0.91)

      Experimental — accuracy not yet measured
  • May combine two claims. 17
  • Classified as probably not a substantial claim. 21

  • May combine two claims.

    Premisecitation

    Administration of a V1aR antagonist into the LS increases social play levels in males and decreases it in females.

    “In detail, administration of the AVP V1a receptor (V1aR) antagonist into the LS increased social play levels in males and decreased it in females (Veenema et al., 2013, Bredewold et al., 2014) while administration of glutamate receptor antagonists into the LS decreased social play levels in females, while no changes in social play levels were seen in males (Bredewold et al., 2015).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites Veenema et al., 2013 source
    • cites Bredewold et al., 2014 source

      The Results (Modulation of social play behavior by AVP, Treatment effects) report that V1aR antagonist treatment increased social play in males and decreased it in females in the home cage. The citing sentence omits that condition: the Discussion (context-specific effects) says these effects were absent in a novel cage. (LLM, conf=0.89)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    AVP, glutamate, and GABA systems in the LS each modulate social play behavior in both male and female juvenile rats.

    “We previously showed that arginine-vasopressin (AVP), glutamate, and GABA systems in the LS each modulate social play behavior in both male and female juvenile rats (Veenema et al., 2013, Bredewold et al., 2014, 2015).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites Veenema et al., 2013 source
    • cites Bredewold et al., 2014 source

      The Results (Modulation of social play behavior by AVP) report that manipulating the lateral-septal AVP system changed social play in male and female juvenile rats, with effects dependent on sex and context. This paper examines AVP and oxytocin, not whether glutamate or GABA systems in the lateral septum modulate social play; those parts of the sentence are not supported by this source. Page numbers are unavailable in our copy. (LLM, conf=0.90)

      Experimental — accuracy not yet measured
    • cites Bredewold et al., 2015 source

      The Discussion reports that LS GABA-A receptor blockade reduced social play in both juvenile males and females, and it describes earlier findings that LS vasopressin-receptor blockade affected both sexes. But it reports that glutamate-receptor blockade reduced social play in females and did not alter it in males, so this source does not support the claim that all three systems modulate play in both sexes. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    The lateral septum (LS) is a key brain region involved in social behavior, motivation, and reward.

    “The lateral septum (LS) is a key brain region involved in social behavior, motivation, and reward (Clarke and File, 1982;Goodson et al., 1997;Beiderbeck et al., 2007;Scotti et al., 2011;Luo et al., 2011;McDonald et al., 2012;Veenema et al., 2012;Lukas et al., 2013;Harasta et al., 2015).”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites Clarke and File, 1982 source
    • cites Goodson et al., 1997 source

      The Abstract (page not provided) describes the lateral septum’s role in social behavior and reports that lesions altered aggression in zebra finches and song associated with courtship or aggression in field sparrows. It does not address motivation or reward, so it supports only the social-behavior part of the claim. (LLM, conf=0.87)

      Experimental — accuracy not yet measured
    • cites Beiderbeck et al., 2007

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In humans, a higher excitatory/inhibitory ratio is thought to contribute to the pathophysiology of various neurological and psychiatric disorders, including ASD.

    “In humans, a higher excitatory/inhibitory ratio is thought to contribute to the pathophysiology of various neurological and psychiatric disorders, including ASD (Nelson & Valakh, 2015;Rubenstein & Merzenich, 2003;Robertson et al., 2016).”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites Nelson & Valakh, 2015 source
    • cites Rubenstein & Merzenich, 2003 source
    • cites Robertson et al., 2016 source

      The available copy contains the title and reference links, but no substantive passage about excitatory/inhibitory ratios or their role in ASD or other disorders. Searches for excitation–inhibition balance and psychiatric disorders returned no relevant text, so the claim cannot be checked against this copy. (LLM, conf=0.72)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    A higher excitation/inhibition ratio during development is linked to neuroplasticity and the acquisition of new cognitive skills.

    “This contrasts with another study showing that a higher excitation/inhibition ratio during development is linked to neuroplasticity and the acquisition of new cognitive skills (Cohen Kadosh et al., 2015).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Cohen Kadosh et al., 2015 source

  • Classified as probably not a substantial claim.

    Premisecitation

    The compensation theory postulates that some sex differences in the brain may serve to prevent sex differences in behavior allowing males and females to display similar behaviors despite major sex differences.

    “This theory postulates that some sex differences in the brain may serve to prevent sex differences in behavior allowing males and females to display similar behaviors despite major sex”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites De Vries & Boyle, 1998 source
    • cites De Vries, 2004 source

  • May combine two claims.

    Premisecitation

    Administration of glutamate receptor antagonists into the LS decreases social play levels in females, while no changes are seen in males.

    “In detail, administration of the AVP V1a receptor (V1aR) antagonist into the LS increased social play levels in males and decreased it in females (Veenema et al., 2013, Bredewold et al., 2014) while administration of glutamate receptor antagonists into the LS decreased social play levels in females, while no changes in social play levels were seen in males (Bredewold et al., 2015).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Bredewold et al., 2015 source

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Drug doses were chosen based on previous microinjection studies in rats inducing changes in behavior.

    “Drug doses were chosen based on previous microinjection studies in rats inducing changes in behavior (Veenema et al., 2012(Veenema et al., , 2013;;Bredewold et al., 2015;Stanley et al., 1993;Numan et al., 2010).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites Veenema et al., 2012 source
    • cites Veenema et al., 2013 source
    • cites Bredewold et al., 2015 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    AVP acts on presynaptically expressed V1aR to modulate glutamate release in the parabrachial nucleus and the nucleus of the solitary tract.

    “in vitro studies have suggested that AVP acts on presynaptically expressed V1aR to modulate glutamate release in other brain regions, namely the parabrachial nucleus and the nucleus of the solitary tract (Chen & Pittman, 1999;Bailey et al., 2006).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites Chen & Pittman, 1999 source
    • cites Bailey et al., 2006 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Bath application of a V1aR antagonist increased glutamate release from solitary tract neurons.

    “Interestingly, bath application of a V1aR antagonist increased glutamate release from solitary tract neurons (Bailey et al., 2006)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Bailey et al., 2006 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Calb1 is almost exclusively expressed in GABAergic neurons in the LS.

    “Calb1 is almost exclusively expressed in GABAergic neurons in the LS (Zhao et al., 2013)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Zhao et al., 2013 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Suppressed activity of Sst-expressing neurons in the dorsal LS is associated with improved social discrimination behavior in mice.

    “while suppressed activity of Sst-expressing neurons in the dorsal LS is associated with improved social discrimination behavior (Borie et al., 2021) in mice.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Borie et al., 2021 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Similar effects of bicuculline and muscimol on neuronal activation have been reported before.

    “Yet, similar effects of bicuculline and muscimol on neuronal activation have been reported before (Yoon et al., 2010).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Yoon et al., 2010 source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Glutamate release and glutamate re-uptake in the brain are both regulated by astrocytes.

    “Glutamate release and glutamate re-uptake in the brain are both regulated by astrocytes (Mahmoud et al., 2019).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Mahmoud et al., 2019 source

  • Classified as probably not a substantial claim.

    Premisecitation

    Sox9 is a reliable marker of astrocytes.

    “which is a reliable marker of astrocytes (Sun et al., 2017)”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites Sun et al., 2017 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Presynaptic V1aR activation leads to an inhibition of glutamate release.

    “suggesting that presynaptic V1aR activation leads to an inhibition of glutamate release.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites Bailey et al., 2006 source

  • May combine two claims.

    Findingown data

    In females, V1aR antagonist and the combined treatment of V1aR antagonist and L-glutamic acid reduced social play duration compared to vehicle.

    “In females, V1aR antagonist (p < 0.05) and the combined treatment of the V1aR antagonist and L-glutamic acid (p < 0.005) reduced social play duration compared to vehicle (Fig. 3C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    L-glutamic acid administration into the LS decreases social play behavior in both sexes, with a stronger effect in females.

    “Indeed, we found that mimicking the increase in glutamate by administration of L-glutamic acid into the LS decreased social play in females.”
    • Also stated in: § DISCUSSION · plain
      “However, L-glutamic acid administration into the LS induced a decrease in social play behavior in males, an effect seen in females too”
    • Also stated in: § DISCUSSION · plain
      “(A)The non-specific glutamate receptor agonist L-glutamic acid (L-GLU; 600 nM/0.5 ml) decreased social play duration in both sexes, with a stronger effect in females compared with males.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    V1aR antagonist administration into the LS reduced social play duration, and this effect was abolished by simultaneous administration of AP-5 and CNQX.

    “Bonferroni posthoc testing revealed that V1aR antagonist administration into the LS reduced social play duration (V1aR-A vs vehicle: p < 0.05) and this effect was abolished by simultaneous administration of AP-5 and CNQX (AP-5+CNQX vs vehicle: p = 1.00;AP-5/CNQX vs V1aR-A: p < 0.05; Fig 3D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Sst-expressing cells (>50% in dorsal LS; >40% in intermediate LS) and Calb1-expressing cells (almost 40% in dorsal LS; almost 30% in intermediate LS) represent most Avpr1a-expressing cells in the LS.

    “Notably, Sstexpressing cells (>50% in dorsal LS; >40% in intermediate LS) and Calb1-expressing cells (almost 40% in dorsal LS; almost 30% in intermediate LS) represent most Avpr1a-expressing cells in the LS”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    There was a sex effect on social play duration, driven by L-glutamic acid inducing a shorter duration of social play in females compared to males.

    “Furthermore, there was a sex effect on social play duration (Sex effect: F(1,32) = 4.56; p < 0.05) which is driven by L-glutamic acid inducing a shorter duration of social play in females compared to males (p < 0.05; Fig. 3A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Extracellular glutamate concentration is higher in males than in females under baseline conditions and during social play.

    “(A-B) Extracellular glutamate concentration is higher in males than in females under baseline conditions (basal; A-B) and during social play (play; B)”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    ASD shows robust sex differences in incidence, symptoms severity, and treatment responses.

    “Moreover, ASD shows robust sex differences in incidence, symptoms severity, and treatment responses (Rutter et al., 2003).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Rutter et al., 2003 source

  • May combine two claims.

    Interpretationown data

    The observed female-specific increase in extracellular LS-glutamate release upon LS-V1aR blockade likely resulted in altered LS neuronal excitability, which in turn may have contributed to the decrease in social play seen after LS-V1aR blockade in females.

    “The observed female-specific increase in extracellular LS-glutamate release upon LS-V1aR blockade likely resulted in altered LS neuronal excitability, which in turn, may have contributed to the decrease in social play seen after LS-V1aR blockade in females.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Rats with incorrect microdialysis probe placement were removed from the analysis.

    “Rats with incorrect probe placement were removed from the analysis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    The studies on excitatory/inhibitory ratio in humans are primarily performed in male subjects, while the study linking higher excitation/inhibition ratio to neuroplasticity used females only.

    “Interestingly, the former studies are primarily performed in male subjects, while the latter used females only.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    V1aRs are expressed on GABAergic interneurons, which are the main cell type in the LS.

    “The latter could be mediated directly by V1aRs expressed on GABAergic interneurons, which are the main cell type in the LS (Risold & Swanson, 1997a;Garrido Sanabria et al., 2006).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Risold & Swanson, 1997a source
    • cites Garrido Sanabria et al., 2006 source

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Rats with incorrect cannula placement were removed from the analysis.

    “Rats with incorrect cannula placement were removed from the analysis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    In the social play test, behavior was analyzed by a researcher blind to the treatment condition.

    “All tests were videotaped for subsequent analysis of behavior by a researcher blind to the treatment condition using JWatcher (http://www.jwatcher.ucla.edu/).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    The HPLC-MS/MS assay had a lower limit of quantitation of 0.8 nM on column for GABA and 0.02 μM on column for glutamate, and inter-day variation of 6.68 %CV for GABA and 3.77 %CV for glutamate.

    “Lower limit of quantitation was 0.8 nM on column for GABA and 0.02 µM on column for glutamate and inter-day variation were 6.68 %CV for GABA and 3.77 %CV for glutamate.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Vehicle and drug injections were given in a counterbalanced order over two consecutive days.

    “received one vehicle injection and one drug injection in a counterbalanced order over two consecutive days.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Glutamate is a downstream substrate by which LS-V1aR blockade reduced social play behavior in females, an effect that can be mimicked in males.

    “This strongly suggests that glutamate is a downstream substrate by which LS-V1aR blockade reduced social play behavior in females, an effect that can be mimicked in males.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    GABA-A receptor activation presumably will result in decreased LS neuronal output while GABA-A receptor blockade will allow for increased LS output.

    “GABA-A receptor activation presumably will result in decreased LS neuronal output while GABA-A receptor blockade will allow for increased LS output (Sheehan et al., 2004).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Sheehan et al., 2004 source
33 of 33

  • The paper relies on this without support.

    Social play behavior is rewarding.

    “Given the rewarding nature of social play behavior”

  • The paper relies on this without support.

    Social play behavior plays a critical role in the development of social competence.

    “and its critical role in the development of social competence”
2 of 2

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Repeated-measures degrees of freedom do not match the treated-male sample size

    Minor

    The methods report nine V1aR-antagonist-treated males. For six dialysates from nine rats, the within-subject error degrees of freedom would be 5 × (9 − 1) = 40, not 35; the pooled male analysis also reports degrees of freedom consistent with including all nine treated males.

    Reported 35 · recomputed 40

  • Figure caption gives a different L-glutamic acid dose

    Minor

    The methods specify 600 nmol of L-glutamic acid per injection, whereas the Fig. 3 caption specifies 600 nM per 0.5 ml. Those are not equivalent doses.

  • Figure caption injection volumes differ from the methods

    Minor

    The methods specify 0.5 μl injections, but the Fig. 3 caption gives 0.5 ml for muscimol and other treatments-a thousandfold larger volume.

  • GABA comparison is labeled as glutamate release

    Minor

    The statement refers to Fig. 2F, which the figure caption identifies as a comparison of GABA release. It also conflicts with the reported female-specific increase in glutamate release.

4 of 4

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Authors
Bredewold, R., Washington, C., & Veenema, A. H.
Affiliations
Michigan State University (US)
Corresponding author
Veenema, Alexa H.
ORCID
Venue
Neuropsychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2024-09-20
Volume
50
Issue
4
Pages
630-639
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
DOI
10.1038/s41386-024-01987-z
PMC
PMC11845679
OpenAlex
W4402713372
Semantic Scholar
6ea89bc850ecdafac1abdefc26ce00adcd18d998
Cited by
13
References
94
Citations by year
2025: 7 · 2024: 5 · 2023: 1
FWCI
5.76
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuropsychopharmacology (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
Funders
  • Brain and Behavior Research Foundation (17382)
  • U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (R01MH102456)
  • National Science Foundation (IOS1253386)
Topics
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords
vasopressin, V1a receptor, lateral septum, social play, sex differences, glutamate, glutamatergic neurotransmission, GABA, young rats, autism spectrum disorder, social dysfunction, glutamate receptor antagonists, muscimol

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-12.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-12.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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