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Cited by 31Neuroendocrine regulation and behaviorNeurotransmitter Receptor Influence on BehaviorNeuropeptides and Animal Physiology

Involvement of dopamine, but not norepinephrine, in the sex-specific regulation of juvenile socially rewarding behavior by vasopressin

Open access
Bredewold, Remco, Nascimento, Nara F., Ro, Grace S., Cieslewski, Shannon E., Reppucci, Christina J., Veenema, Alexa H.·2018·Neuropsychopharmacology
DOI 10.1038/s41386-018-0100-2PMC PMC6098123
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Abstract

Social play is a highly rewarding behavior displayed mostly during the juvenile period. We recently showed that vasopressin V1a receptor (V1aR) blockade in the lateral septum (LS) enhances social play in male juvenile rats, but reduces it in females. Here, we determined whether the LS-AVP system modulates dopamine (DA) and/or norepinephrine (NE) neurotransmission in the LS to regulate social play behavior in sex-specific ways. Using microdialysis combined with retrodialysis, we demonstrated that both LS-AVP administration and social play exposure increased extracellular LS-DA release in females, but not in males. Pharmacological blockade of LS-DA receptors reduced social play in both sexes, but required a higher dose in females. This suggests that baseline LS-DA release is sufficient for social play in males, while increased LS-DA release is necessary for social play in females. Administration of a V1aR antagonist into the LS inhibited the social play-induced increase in extracellular LS-DA release in females. Furthermore, co-administration of the DA agonist apomorphine prevented the LS-V1aR blockade-induced decrease in social play in females. This suggests that LS-V1aR blockade reduces social play in females by dampening the rise in LS-DA release. Extracellular LS-NE release was enhanced in response to pharmacological manipulations of the LS-AVP system and to social play in males and/or females, but pharmacological blockade or stimulation of LS-NE receptors did not alter social play in either sex. Overall, we define a mechanism by which the LS-AVP system alters LS-DA neurotransmission differently in males than females resulting in the sex-specific regulation of juvenile social play behavior.

AI snapshot

Written from the paper’s full text.

TL;DR

In juvenile rats, lateral septum (LS) vasopressin V1a receptor blockade regulates social play in sex-specific ways via dopamine, not norepinephrine: LS-AVP and social play increased LS-DA release in females only, and DA receptor blockade reduced play in both sexes. LS-NE release changed with LS-AVP manipulations and social play, but NE receptor drugs did not alter social play.

Key findings

  • LS-AVP retrodialysis increased percent baseline LS-DA release in females but not males (sex × dialysate: F(5,75)=5.60, p<0.001; females p<0.005 during AVP and p<0.001 immediately after vs baseline; males p>0.63). Absolute LS-DA concentrations were higher in females than males immediately after AVP (p<0.05).
  • Social play exposure increased percent baseline LS-DA release in females only (sex × dialysate: F(5,65)=3.19, p<0.05; females p<0.05 for dialysates 3 and 4 vs all others; males p>0.35).
  • Intra-LS DA receptor blockade with cis-(z)-flupenthixol reduced social play duration in males at both 15 and 30 µg/0.5 µl (p<0.01 vs vehicle) but only at 30 µg/0.5 µl in females (p<0.005 vs vehicle). LS-V1aR antagonist decreased social play in females (p<0.01 vs vehicle), and co-administration of the DA agonist apomorphine prevented this decrease.
  • LS-NE release increased in response to LS-AVP (males), social play exposure (females significant; males approached significance), and LS-V1aR antagonist (both sexes), but intra-LS NE agonist or alpha/beta adrenergic antagonists did not significantly alter social play duration in either sex.

Methods

  • Juvenile Wistar rats of both sexes were used: microdialysis experiments at 32 days of age and microinjection behavioral experiments at 30 days of age. Social play was tested by exposing experimental rats to an age- and sex-matched unfamiliar socially housed rat for 10 min.
  • In vivo microdialysis with or without retrodialysis measured extracellular LS-DA and LS-NE release under baseline, LS-AVP administration, social play exposure, and LS-V1aR antagonist treatment; DA and NE were quantified by HPLC with tandem mass spectrometry. Behavioral pharmacology used intra-LS injections of a non-specific DA receptor antagonist, V1aR antagonist ± apomorphine, NE agonist, alpha adrenergic antagonist, or beta adrenergic antagonist, with behavior scored by a blinded researcher.
  • Analyses used repeated-measures two-way ANOVAs (sex × dialysate) with LSD post hoc tests, Student’s t-tests for absolute concentrations, and two-way ANOVAs (sex × drug) or one-way ANOVAs (drug) with Bonferroni post hoc tests; significance was p<0.05.

Limitations

  • Stated: the 10-min microdialysis sampling time may have missed fast and short increases in LS-DA release in males; the authors also note it cannot be excluded that additional drug doses or different types of drugs might alter social play duration.
  • Evident: microdialysis group sizes were small (e.g., females n=6 for AVP DA and males n=6 for V1aR antagonist DA), only juvenile Wistar rats were studied, and the proposed presynaptic V1aR-on-dopaminergic-terminal mechanism was not directly tested.

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

Integrity signals

Registry

Crossref · 10.1038/s41386-018-0100-2

Cites

45 of 45 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

16 of 38 cited sources checked · 8 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Little is known about the sites of action of dopamine and norepinephrine signaling in the brain involved in social play behavior.

    “Despite a few studies using local manipulation of the DA and NE systems [10,11], little is known about the sites of action of DA and NE signaling in the brain involved in social play behavior.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [10] Achterberg EJM, Van Kerkhof LWM, Damsteegt R, Trezza V, Vanderschuren LJMJ. Methylphenidate and atomoxetine inhibit social play behavior through prefrontal and subcortical limbic mechanisms in rats. J Neurosci. 2015;35:161–169. source
    • cites [11] Manduca A, Servadio M, Damsteegt R, Campolongo P, Vanderschuren LJ, Trezza V. Dopaminergic neurotransmission in the nucleus accumbens modulates social play behavior in rats. Neuropsychopharmacology. 2016;41:2215–23. source

      The Introduction (page unavailable) describes uncertainty about where dopamine acts in social play and explains why the authors tested local manipulation in the nucleus accumbens. This supports the dopamine portion of the claim, but the paper does not establish a comparable knowledge gap for norepinephrine. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
  • Premisecitation

    The LS is part of the brain reward system.

    “other studies indicating that the LS is part of the brain reward system.”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [34] Olds J, Milner P. Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain. J Comp Physiol Psychol. 1954;47:419–27. source
    • cites [35] Bishop MP, Elder ST, Heath RG. Intracranial self-stimulation in man. Science. 1963;140:394–6. source
    • cites [36] Luo AH, Tahsili-Fahadan P, Wise RA, Lupica CR, Aston-Jones G. Linking context with reward: a functional circuit from hippocampal CA3 to ventral tegmental area. Science. 2011;333:353–7. source
    • cites [37] Sartor GC, Aston-Jones GS. A septal-hypothalamic pathway drives orexin neurons, which is necessary for conditioned cocaine preference. J Neurosci. 2012;32:4623–31. source
  • Findingown data

    The reduction in social play duration by lateral septum dopamine receptor blockade requires a higher dose in females than in males.

    “LS-DA receptor blockade decreased social play duration (Treatment effect: F (2,40) = 13.5;p < 0.001) at both doses in males (p < 0.01, 15 and 30 µg/0.5 μl vs. vehicle), while it decreased social play duration only at the higher dose in females (p < 0.005, 30 µg/0.5 μl vs. vehicle; Fig. 4a).”
    Quote in the paperSubstantial claim
  • Findingown data

    Extracellular LS-NE release increases in both male and female juvenile rats in response to LS-V1aR antagonist treatment.

    “The percent of baseline NE release increased in males and females in response to AVP retrodialysis (b), during social play exposure (e), and during V1aR antagonist retrodialysis (h).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Pharmacological blockade of lateral septum dopamine receptors reduces social play duration in both male and female juvenile rats.

    “LS-DA receptor blockade decreased social play duration (Treatment effect: F (2,40) = 13.5;p < 0.001) at both doses in males (p < 0.01, 15 and 30 µg/0.5 μl vs. vehicle), while it decreased social play duration only at the higher dose in females (p < 0.005, 30 µg/0.5 μl vs. vehicle; Fig. 4a).”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 13
  • May combine two claims. 17
  • The quote only partly states this claim. 2

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

    Premisecitation

    Systemic administration of drugs enhancing dopamine signaling increases reinforcement responding for social play, and these effects are blocked by non-specific dopamine receptor antagonists.

    “systemic administration of drugs enhancing DA signaling increased reinforcement responding for social play, and these effects were blocked by administration of non-specific DA receptor antagonists [9].”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [9] Achterberg EJM, van Kerkhof LWM, Servadio M, van Swieten MM, Houwing DJ, Aalderink M, Driel NV, Trezza V, Vanderschuren LJMJ. Contrasting roles of dopamine and noradrenaline in the motivational properties of social play behavior in rats. Neuropsychopharmacology. 2016;41:858–68. source

  • May combine two claims.

    Premisecitation

    Pharmacological blockade of the vasopressin V1a receptor in the lateral septum enhances social play in male juvenile rats but reduces it in females.

    “We recently showed that vasopressin V1a receptor (V1aR) blockade in the lateral septum (LS) enhances social play in male juvenile rats, but reduces it in females.”
    • Also stated in: § INTRODUCTION · plain
      “Specifically, pharmacological blockade of the AVP V1a receptor (V1aR) in the LS increased social play behavior in juvenile male rats but decreased it in females [12,13].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [12] Veenema AH, Bredewold R, De Vries GJ. Sex-specific modulation of juvenile social play by vasopressin. Psychoneuroendocrinology. 2013;38:2554–61. source
    • cites [13] Bredewold R, Smith CJ, Dumais KM, Veenema AH. Sex-specific modulation of juvenile social play behavior by vasopressin and oxytocin depends on social context. Front Behav Neurosci. 2014;16.8:216. source

      The Results (Modulation of social play behavior by AVP) report that V1aR antagonist treatment enhanced social play in males and reduced it in females when tested in the home cage. The Discussion specifies that these effects were absent in a novel cage, a context limitation omitted from the citing sentence. (LLM, conf=0.87)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Premisecitation

    Systemic administration of the norepinephrine reuptake inhibitor atomoxetine decreases responding for social play and decreases the expression of social play.

    “systemic administration of the NE reuptake inhibitor atomoxetine decreased responding for social play and decreased the expression of social play [9].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [9] Achterberg EJM, van Kerkhof LWM, Servadio M, van Swieten MM, Houwing DJ, Aalderink M, Driel NV, Trezza V, Vanderschuren LJMJ. Contrasting roles of dopamine and noradrenaline in the motivational properties of social play behavior in rats. Neuropsychopharmacology. 2016;41:858–68. source

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

    Premisecitation

    The LS is necessary for the formation of cocaine conditioned place preference in rats.

    “is necessary for the formation of cocaine conditioned place preference in rats [36,37].”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [36] Luo AH, Tahsili-Fahadan P, Wise RA, Lupica CR, Aston-Jones G. Linking context with reward: a functional circuit from hippocampal CA3 to ventral tegmental area. Science. 2011;333:353–7. source

      The paper’s Abstract (page not available) identifies the lateral septum as part of the CA3–LS–VTA circuit and reports that inactivating the cd-LS–to–VTA component blocked context-induced reinstatement of extinguished cocaine-seeking. It does not establish that the LS is necessary for the formation of cocaine conditioned place preference; reinstatement and preference formation are different outcomes. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [37] Sartor GC, Aston-Jones GS. A septal-hypothalamic pathway drives orexin neurons, which is necessary for conditioned cocaine preference. J Neurosci. 2012;32:4623–31. source

      In Results, Experiment 3 (page unavailable), rats were conditioned before the rostral lateral septum (LSr) was inactivated, and inactivation before the CPP test attenuated cocaine preference. The Discussion describes the LSr pathway as critical for the expression of preference. These findings support a role in expressing cocaine CPP, but do not establish that the LS is necessary for its formation. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

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

    Premisecitation

    In juvenile male rats, enhancing NE signaling by using NE reuptake inhibitors administered into the basolateral amygdala and habenula reduces social play.

    “enhancing NE signaling by using NE reuptake inhibitors reduced social play in juvenile male rats (females were not tested) when administered into other brain regions such as the basolateral amygdala and habenula [10].”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [10] Achterberg EJM, Van Kerkhof LWM, Damsteegt R, Trezza V, Vanderschuren LJMJ. Methylphenidate and atomoxetine inhibit social play behavior through prefrontal and subcortical limbic mechanisms in rats. J Neurosci. 2015;35:161–169. source

  • May combine two claims.

    Premisecitation

    Male and female rats show very dense V1aR binding in the dorsal and intermediate LS, with females having even denser binding than males.

    “Male and female rats show very dense V1aR binding in the dorsal and intermediate LS, with females having even denser binding than males [39,40].”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [39] Smith CJ, Poehlmann ML, Li S, Ratnaseelan AM, Bredewold R, Veenema AH. Age and sex differences in oxytocin and vasopressin V1a receptor binding densities in the rat brain: focus on the social decision-making network. Brain Struct Funct. 2017;222:981–1006. source

      The Results section, “Sex differences in V1aR binding density” (page unavailable), reports higher V1aR binding in females than males in the dorsal lateral septum. The paper does not establish the claim of very dense V1aR binding in both dorsal and intermediate lateral septum: its Table 1 identifies intermediate lateral septum binding as OTR, not V1aR. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [40] Veenema AH, Bredewold R, De Vries GJ. Vasopressin regulates social recognition in juvenile and adult rats of both sexes, but in sex- and age-specific ways. Horm Behav. 2012;61:50–56. source

      Experiment 4 (Results; page unavailable) reports significantly higher lateral-septum V1aR binding density in females than males. The Discussion describes abundant septal binding in juvenile rats of both sexes. Our copy does not establish the claimed very dense binding specifically in the dorsal and intermediate lateral septum. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    DA neurotransmission in the nucleus accumbens modulates social play behavior.

    “DA neurotransmission in the nucleus accumbens was also found to modulate social play behavior.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [11] Manduca A, Servadio M, Damsteegt R, Campolongo P, Vanderschuren LJ, Trezza V. Dopaminergic neurotransmission in the nucleus accumbens modulates social play behavior in rats. Neuropsychopharmacology. 2016;41:2215–23. source

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

    Premisecitation

    Increased extracellular LS-DA release has been observed in response to systemic application of cocaine in rats and morphine in mice.

    “Increased extracellular LS-DA release has been observed in response to systemic application of drugs of abuse such as cocaine in rats and morphine in mice [32,33]”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [32] Reddy IA, Pino JA, Weikop P, Osses N, Sørensen G, Bering T, Valle C, Bluett RJ, Erreger K, Wortwein G, Reyes JG, Graham D, Stanwood GD, Hackett TA, Patel S, Fink-Jensen A, Torres GE, Galli A. Glucagon-like peptide 1 receptor activation regulates cocaine actions and dopamine homeostasis in the lateral septum by decreasing arachidonic acid levels. Transl Psychiatry. 2016;6:e809. source

      The Results section (page unavailable) reports that cocaine increased extracellular lateral-septum dopamine in mice and that the results were paralleled in rats. But cocaine was perfused locally through a microdialysis probe, not administered systemically; the systemic injection was the GLP-1R agonist Ex-4. The morphine-in-mice finding is separately cited in the citing sentence and is not attributed to this paper. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [33] Sotomayor R, Forray MI, Gysling K. Acute morphine administration increases extracellular DA levels in the rat lateral septum by decreasing the GABAergic inhibitory tone in the ventral tegmental area. J Neurosci Res. 2005;81:132–9. source

  • May combine two claims.

    Premisecitation

    In juvenile male rats, administration of a D1 receptor antagonist, a D2 receptor antagonist, or the non-specific DA receptor antagonist alpha-flupenthixol reduces social play behavior.

    “administration of a D1 receptor antagonist, a D2 receptor antagonist, or the non-specific DA receptor antagonist alpha-flupenthixol reduced social play behavior in juvenile male rats (females were not tested [11]).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [11] Manduca A, Servadio M, Damsteegt R, Campolongo P, Vanderschuren LJ, Trezza V. Dopaminergic neurotransmission in the nucleus accumbens modulates social play behavior in rats. Neuropsychopharmacology. 2016;41:2215–23. source

      The Discussion reports that intra-NAc α-flupenthixol, the D1 antagonist SCH-23390, and the D2 antagonist eticlopride reduced social play in rats isolated for 24 hours or 7 days before testing. It also says these drugs did not generally reduce social play after brief isolation, a condition the citing sentence omits. The Animals section identifies the rats as male; females were not tested. Page numbers were unavailable in our copy. (LLM, conf=0.90)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    In female juvenile rats, LS-AVP administration increases the percent of baseline extracellular LS-DA release; no such increase occurs in males.

    “The percent of baseline DA release increased in females, but not in males, in response to AVP retrodialysis (b)”
    • Also stated in: § DISCUSSION · plain
      “an increase in the percent of baseline LS-DA release in response to LS-AVP administration or social play exposure was seen in females only.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In female juvenile rats, social play exposure increases the percent of baseline extracellular LS-DA release; no such increase occurs in males.

    “The percent of baseline DA release increased in females, but not in males, in response to AVP retrodialysis (b) and social play exposure (e)”
    • Also stated in: § DISCUSSION · plain
      “an increase in the percent of baseline LS-DA release in response to LS-AVP administration or social play exposure was seen in females only.”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Social play exposure increases extracellular lateral septum norepinephrine release in both sexes, significantly in females and with an effect approaching significance in males.

    “LS-NE release increased in both sexes in response to social play exposure.The percent of baseline LS-NE release increased in response to social play exposure (dialysate effect: F (5,70) = 4.92; p < 0.005).”
    Quote in the paperNot a substantial claim

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

    Premisereasoning

    All studies thus far focused on male rats and it is unclear whether dopamine and norepinephrine are similarly involved in social play behavior in females.

    “In addition, all studies thus far focused on male rats and it is unclear whether DA and NE are similarly involved in social play behavior in females.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    LS-DA neurotransmission, but not LS-NE neurotransmission, is involved in the sex-specific regulation of social play behavior by the LS-AVP system.

    “Here, we demonstrate that LS-DA, but not LS-NE, neurotransmission is involved in the sex-specific regulation of social play behavior by the LS-AVP system.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Social play behavior is rewarding in juvenile rats.

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

    Premisecitation

    The lateral septum receives dopaminergic input from the ventral tegmental area and adrenergic input from the locus coeruleus.

    “The LS receives dopaminergic input from the ventral tegmental area (VTA) and adrenergic input from the locus coeruleus [15,16].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15] Lindvall O. Mesencephalic dopaminergic afferents to the lateral septal nucleus of the rat. Brain Res. 1975;87:89–95. source
    • cites [16] Lindvall O, Stenevi U. Dopamine and noradrenaline neurons projecting to the septal area in the rat. Cell Tiss Res. 1978;190:383–407. source

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

    Premisecitation

    Electrophysiological stimulation of the ventral tegmental area excites lateral septum neurons and application of dopamine receptor antagonists in the lateral septum inhibits this effect.

    “Electrophysiological stimulation of the VTA excites LS neurons and application of DA receptor antagonists in the LS inhibits this effect [17].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Assaf SY, Miller JJ. Excitatory action of the mesolimbic dopamine system on septal neurones. Brain Res. 1977;129:353–60. source

  • May combine two claims.

    Premisecitation

    Bath application of arginine vasopressin reduces the dopamine-induced or norepinephrine-induced inhibition of spontaneous lateral septum neuronal activity.

    “In support, bath application of arginine vasopressin (AVP) reduced the DA-induced or NE-induced inhibition of spontaneous LS neuronal activity [18].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Joëls M, Urban IJ. Monoamine-induced responses in lateral septal neurons: influence of iontophoretically applied vasopressin. Brain Res. 1985;344:120–6. source

  • May combine two claims.

    Interpretationreasoning

    Baseline lateral septum dopamine release is sufficient for social play in males, while increased lateral septum dopamine release is necessary for social play in females.

    “This suggests that baseline LS-DA release is sufficient for social play in males, while increased LS-DA release is necessary for social play in females.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    The additional inputs to the lateral septum may include vasopressinergic efferents from the bed nucleus of the stria terminalis and medial amygdala.

    “These inputs may include vasopressinergic efferents from the bed nucleus of the stria terminalis and medial amygdala [20][21][22].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20][21][22]

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

  • May combine two claims.

    Interpretationown data

    Lateral septum dopamine, but not lateral septum norepinephrine, neurotransmission plays a critical role in the sex-specific regulation of social play behavior by the lateral septum vasopressin system.

    “Altogether, these findings demonstrate a critical role for LS-DA, but not LS-NE, neurotransmission in the sex-specific regulation of social play behavior by the LS-AVP system.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. The quote only partly states this claim.

    Study design and conductown data

    Microdialysis probe and microinjection placements were correctly located in the lateral septum of male and female juvenile rats.

    “Microdialysis probe and microinjection placements in the lateral septum of male and female juvenile rats.”
    • Also stated in: § CONCLUSIONS · hedged
      “indicating in blue the areas marking correct placement of a microdialysis probe (a) or a microinjection (b) in the lateral septum.”
    Quote in the paperSubstantial claim

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

    Interpretationreasoning

    Social play exposure triggers activation of VTA-DA neurons projecting to both the LS and nucleus accumbens.

    “Thus, it is plausible that social play exposure triggers activation of VTA-DA neurons projecting to both the LS and nucleus accumbens.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    The LS is associated with electrical self-stimulation in rats and humans.

    “the LS is associated with electrical self-stimulation in rats and humans [34,35]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [34] Olds J, Milner P. Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain. J Comp Physiol Psychol. 1954;47:419–27. source
    • cites [35] Bishop MP, Elder ST, Heath RG. Intracranial self-stimulation in man. Science. 1963;140:394–6. source

  • May combine two claims.

    Premisecitation

    Treatment with 6-hydroxydopamine reduces LS-DA and LS-NE concentrations as well as LS-AVP binding.

    “treatment with 6-hydroxydopamine, a neurotoxin that selectively destroys DA and NE neurons in the brain, reduced LS-DA and LS-NE concentrations as well as LS-AVP binding [41].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Ishizawa H, Tabakoff B, Mefford IN, Hoffman PL. Reduction of arginine vasopressin binding sites in mouse lateral septum by treatment with 6-hydroxydopamine. Brain Res. 1990;507:189–94. source

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

    Interpretationcitation

    LS-DA neurotransmission plays a role in the positive and reinforcing effects of drug taking.

    “suggesting a role for LS-DA neurotransmission in the positive and reinforcing effects of drug taking.”
    Quote in the paperNot a substantial claim
25 of 25

  • The paper relies on this without support.

    Social play behavior is rewarding in juvenile rats.

    “sex differences in the LS neural circuitry mediating a socially rewarding behavior.”
    “rewarding aspects of social play behavior in females only.”

  • The paper relies on this without support.

    The V1aR antagonist d(CH2)5-[Tyr(Me)2]AVP specifically blocks V1aR.

    “Administration of the V1aR antagonist (d(CH 2 ) 5 -[Tyr(Me) 2 ]AVP at 10 ng/0.5 µl (V1aR-a) reduced social play duration compared to vehicle treatment (Veh) in females”

  • The paper relies on this without support.

    Apomorphine enhances LS-DA signaling.

    “enhancing LS-DA signaling by local administration of the DA agonist apomorphine prevented the decrease in social play behavior induced by LS-V1aR blockade in females”
3 of 3

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • ConsistentF(5, 75) = 5.6reported p < .001 · recomputed p < .001

    “F (5,75) = 5.60, p < .001”

  • ConsistentF(5, 65) = 3.19reported p < .05 · recomputed p = .012

    “F (5,65) = 3.19, p < .05”

  • ConsistentF(5, 55) = 2.8reported p < .05 · recomputed p = .025

    “F (5,55) = 2.80, p < .05”

  • ConsistentF(5, 30) = 1.51reported p = .22 · recomputed p = .216

    “F (5,30) = 1.51, p = .22”

  • ConsistentF(5, 25) = 1.63reported p = .19 · recomputed p = .189

    “F (5,25) = 1.63, p = .19”

5 of 5

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.

  • Conflicting claims about the lower apomorphine dose

    Minor

    The results say that either apomorphine dose prevented the V1aR antagonist-induced decrease in social play, but the Fig. 4 caption says the 0.2 μg dose did not prevent it.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Pellis SM, Pellis VC. Book The PlayfulBrain: Venturing to the Limits of Neuroscience. Oxford: Oneworld Publications; 2009.

Cited by

Sorted by citations

Related

Authors
Bredewold, R., Nascimento, N. F., Ro, G. S., Cieslewski, S. E., Reppucci, C. J., & Veenema, A. H.
Affiliations
  • Michigan State University (US)
  • Boston College (US)
Corresponding author
Bredewold, Remco
ORCID
Venue
Neuropsychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2018-05-22
Volume
43
Issue
10
Pages
2109-2117
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
DOI
10.1038/s41386-018-0100-2
PMC
PMC6098123
OpenAlex
W2804053821
Semantic Scholar
0749de6431d7a46bac7cee84b6d70d36adccca23
Cited by
31
References
45
Citations by year
2026: 5 · 2025: 1 · 2024: 6 · 2023: 4 · 2022: 2 · 2021: 4 · 2020: 3 · 2019: 3 · 2018: 3
FWCI
4.19
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Neuropsychopharmacology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (submittedVersion)
  • PubMed Central (submittedVersion)
Funders
  • National Science Foundation (1253386)
  • National Institutes of Health (R01MH102456)
  • National Institute of Mental Health (R01 MH102456)
  • Division of Integrative Organismal Systems
Topics
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords
vasopressin, V1a receptor, dopamine, norepinephrine, lateral septum, social play, juvenile social behavior, sex differences, neurotransmitter release, apomorphine, dopamine receptors, norepinephrine receptors, reward
MeSH terms
Animals, Dopamine, Female, Male, Norepinephrine, Play and Playthings, Reward, Sex Characteristics, Social Behavior, Vasopressins, Rats, Wistar, Receptors, Vasopressin, Microdialysis, Septum of Brain, Rats

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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