Oxytocin microinjected into the central amygdaloid nuclei exerts anti-aggressive effects in male rats

We recently demonstrated that acute and chronic intracerebroventricular enhancement of brain OXT levels induces potent anti-aggressive and pro-social explorative effects during social challenges. However, the exact anatomical location in the brain where OXT exerts its action is still elusive. In the present study, we targeted two critical brain areas, i.e. the central amygdala (CeA) and the dorsal raphe (DR), both containing high levels of OXT receptors (OXTRs) and constituting important nodes of the neural circuitry related to aggression. Behavioral effects of local micro-infusion of OXT and OXTR antagonist, L368.899, (alone and combined) were evaluated in resident male rats during confrontations with an unfamiliar male intruder. Our results show that OXT microinjected into the CeA markedly reduced resident's offensive behavior and facilitated social exploration, without affecting other non-aggressive behaviors. The receptor specificity of the behavioral effects was verified when a micro-infusion of a selective OXTR antagonist nullified the changes. Pharmacological blockade of CeA OXTRs per se was without clear behavioral effects suggesting that endogenous OXT within the CeA does not play a major inhibitory role on offensiveness. Anatomical specificity was also supported by the absence of relevant behavioral effects when OXT was microinjected into more medial sub-regions of the amygdala. Likewise, within the DR neither OXT nor OXTR exerted significant effects on offensive aggression, while microinjection of the 5-HT1A autoreceptor agonist in this region significantly suppressed aggression. In conclusion, our results point at the CeA as an important brain site of action for the anti-aggressive and pro-social explorative effects induced by exogenous enhancement of brain OXT levels.

[1]  Markus Heinrichs,et al.  Oxytocin, vasopressin, and human social behavior , 2009, Frontiers in Neuroendocrinology.

[2]  Christian Büchel,et al.  Different amygdala subregions mediate valence-related and attentional effects of oxytocin in humans , 2010, Proceedings of the National Academy of Sciences.

[3]  Matthias Gamer,et al.  Oxytocin increases amygdala reactivity to threatening scenes in females , 2012, Psychoneuroendocrinology.

[4]  S. D. de Boer,et al.  Activation of serotonergic neurotransmission during the performance of aggressive behavior in rats. , 2003, Behavioral neuroscience.

[5]  P. Veinante,et al.  Distribution of oxytocin‐ and vasopressin‐binding sites in the rat extended amygdala: a histoautoradiographic study , 1997, The Journal of comparative neurology.

[6]  P. R. Wiepkema,et al.  University of Groningen The Organization of Intraspecific Agonistic Behaviour in the Rat , 2002 .

[7]  T. W. Greidanus,et al.  Penetration of neurohypophyseal hormones from plasma into cerebrospinal fluid (CSF): Half-times of disappearance of these neuropeptides from CSF , 1983, Brain Research.

[8]  K. Phan,et al.  Amygdala and Orbitofrontal Reactivity to Social Threat in Individuals with Impulsive Aggression , 2007, Biological Psychiatry.

[9]  M. Kavaliers,et al.  Neuroendocrinology of social information processing in rats and mice , 2009, Frontiers in Neuroendocrinology.

[10]  L. Young,et al.  Oxytocin, vasopressin and pair bonding: implications for autism , 2006, Philosophical Transactions of the Royal Society B: Biological Sciences.

[11]  Joseph E LeDoux,et al.  Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[12]  Peter Kirsch,et al.  Oxytocin Modulates Neural Circuitry for Social Cognition and Fear in Humans , 2005, The Journal of Neuroscience.

[13]  R. Malenka,et al.  Social reward requires coordinated activity of accumbens oxytocin and 5HT , 2013, Nature.

[14]  A. Argiolas,et al.  Oxytocin injected into the ventral subiculum or the posteromedial cortical nucleus of the amygdala induces penile erection and increases extracellular dopamine levels in the nucleus accumbens of male rats , 2009, The European journal of neuroscience.

[15]  M. Millan,et al.  S 15535: a highly selective benzodioxopiperazine 5-HT1A receptor ligand which acts as an agonist and an antagonist at presynaptic and postsynaptic sites respectively. , 1993, European journal of pharmacology.

[16]  S. D. de Boer,et al.  5-HT1A and 5-HT1B receptor agonists and aggression: a pharmacological challenge of the serotonin deficiency hypothesis. , 2005, European journal of pharmacology.

[17]  P. Jones,et al.  Oxytocin and neurophysin in plasma and CSF during suckling in the guinea-pig. , 1982, Neuroendocrinology.

[18]  S. D. de Boer,et al.  The Vicious Cycle Towards Violence: Focus on the Negative Feedback Mechanisms of Brain Serotonin Neurotransmission , 2009, Front. Behav. Neurosci..

[19]  Sabine C. Herpertz,et al.  Effects of intranasal oxytocin on emotional face processing in women , 2010, Psychoneuroendocrinology.

[20]  B. Jacobs,et al.  Structure and function of the brain serotonin system. , 1992, Physiological reviews.

[21]  M. Ludwig,et al.  Vasopressin, oxytocin, and social odor recognition , 2012, Hormones and Behavior.

[22]  Stefano Parmigiani,et al.  Escalated aggressive behavior: dopamine, serotonin and GABA. , 2005, European journal of pharmacology.

[23]  C. Büchel,et al.  Oxytocin and reduction of social threat hypersensitivity in women with borderline personality disorder. , 2013, The American journal of psychiatry.

[24]  M. Althaus,et al.  Acute and repeated intranasal oxytocin administration exerts anti-aggressive and pro-affiliative effects in male rats , 2015, Psychoneuroendocrinology.

[25]  C. Stockmeier.  Neurobiology of Serotonin in Depression and Suicide a , 1997, Annals of the New York Academy of Sciences.

[26]  Martin K. Schwarz,et al.  Evoked Axonal Oxytocin Release in the Central Amygdala Attenuates Fear Response , 2012, Neuron.

[27]  M. Heinrichs,et al.  Neuropeptides and social behaviour: effects of oxytocin and vasopressin in humans. , 2008, Progress in brain research.

[28]  R. Nelson,et al.  Interaction of nitric oxide and serotonin in aggressive behavior , 2003, Hormones and Behavior.

[29]  Kae Nakamura,et al.  Reward-Dependent Modulation of Neuronal Activity in the Primate Dorsal Raphe Nucleus , 2008, The Journal of Neuroscience.

[30]  N. Sousa,et al.  A Trans-Dimensional Approach to the Behavioral Aspects of Depression , 2008, Front. Behav. Neurosci..

[31]  T. Insel,et al.  The neurobiology of attachment , 2001, Nature Reviews Neuroscience.

[32]  V. Arango,et al.  Serotonin brain circuits involved in major depression and suicide. , 2002, Progress in brain research.

[33]  Zhibin Zhang,et al.  Agonistic encounters and brain activation in dominant and subordinate male greater long-tailed hamsters , 2010, Hormones and Behavior.

[34]  H. Zingg,et al.  Mapping oxytocin receptor gene expression in the mouse brain and mammary gland using an oxytocin receptor–LacZ reporter mouse , 2003, Neuroscience.

[35]  C. Patrick,et al.  Role of Serotonin and Dopamine System Interactions in the Neurobiology of Impulsive Aggression and its Comorbidity with other Clinical Disorders. , 2008, Aggression and violent behavior.

[36]  P. Veinante,et al.  Vasopressin and Oxytocin Excite Distinct Neuronal Populations in the Central Amygdala , 2005, Science.

[37]  T. Insel,et al.  Oxytocin in the Amygdala Facilitates Maternal Aggression , 1992, Annals of the New York Academy of Sciences.

[38]  S. D. de Boer,et al.  Individual Variation in Aggression of Feral Rodent Strains: A Standard for the Genetics of Aggression and Violence? , 2003, Behavior genetics.

[39]  A. Takahashi,et al.  GABAB Receptor Modulation of Serotonin Neurons in the Dorsal Raphé Nucleus and Escalation of Aggression in Mice , 2010, The Journal of Neuroscience.

[40]  R. Stoop,et al.  Oxytocin enhances the inhibitory effects of diazepam in the rat central medial amygdala , 2010, Neuropharmacology.

[41]  K. Miczek,et al.  Social and neural determinants of aggressive behavior: pharmacotherapeutic targets at serotonin, dopamine and γ-aminobutyric acid systems , 2002, Psychopharmacology.

[42]  John C Gore,et al.  Amygdala hyperreactivity in borderline personality disorder: implications for emotional dysregulation , 2003, Biological Psychiatry.

[43]  A. Lucion,et al.  Effects of oxytocin microinjected into the central amygdaloid nucleus and bed nucleus of stria terminalis on maternal aggressive behavior in rats , 2005, Physiology & Behavior.

[44]  Tadashi Kimura,et al.  Evidence That Oxytocin Exerts Anxiolytic Effects via Oxytocin Receptor Expressed in Serotonergic Neurons in Mice , 2009, The Journal of Neuroscience.

[45]  S. Maier,et al.  Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus , 2005, Nature Neuroscience.

[46]  T. Dietrich,et al.  Evidence of abnormal amygdala functioning in borderline personality disorder: a functional MRI study , 2001, Biological Psychiatry.

[47]  U. Fischbacher,et al.  Oxytocin Shapes the Neural Circuitry of Trust and Trust Adaptation in Humans , 2008, Neuron.

[48]  B. Leonard,et al.  The effect of testosterone and cyproterone acetate on the concentration of γ-aminobutyric acid in brain areas of aggressive and non-aggressive mice , 1977, Pharmacology Biochemistry and Behavior.

[49]  A. Takahashi,et al.  Neurogenetics of aggressive behavior: studies in rodents. , 2014, Current topics in behavioral neurosciences.

[50]  N. Singewald,et al.  Extracellular amino acid levels in the paraventricular nucleus and the central amygdala in high- and low-anxiety dams rats during maternal aggression: Regulation by oxytocin , 2007, Stress.

[51]  M. G. Terenzi,et al.  Oxytocin-induced excitation of neurones in the rat central and medial amygdaloid nuclei , 2005, Neuroscience.

[52]  M. Althaus,et al.  Antiaggressive activity of central oxytocin in male rats , 2013, Psychopharmacology.

[53]  T. Baskerville,et al.  Interactions between dopamine and oxytocin in the control of sexual behaviour. , 2008, Progress in brain research.

[54]  S. Boer,et al.  Patterns of violent aggression-induced brain c-fos expression in male mice selected for aggressiveness , 2006, Physiology & Behavior.

[55]  M. Althaus,et al.  Chronic enhancement of brain oxytocin levels causes enduring anti-aggressive and pro-social explorative behavioral effects in male rats , 2014, Hormones and Behavior.

[56]  T. Durroux,et al.  Pharmacology of Oxytocin and Vasopressin Receptors in the Central and Peripheral Nervous System a , 1992, Annals of the New York Academy of Sciences.

[57]  J. Johns,et al.  An oxytocin antagonist infused into the central nucleus of the amygdala increases maternal aggressive behavior. , 2003, Behavioral neuroscience.

[58]  Zuoxin Wang,et al.  Nucleus accumbens oxytocin and dopamine interact to regulate pair bond formation in female prairie voles , 2003, Neuroscience.

[59]  T. Insel,et al.  Oxytocin and complex social behavior: species comparisons. , 1993, Psychopharmacology bulletin.

[60]  J. Palacios,et al.  Pharmacological characteristics and anatomical distribution of [3H]oxytocin-binding sites in the wistar rat brain studied by autoradiography , 1987, Neuroscience.

[61]  R. Hen,et al.  Serotonin receptors and animal models of aggressive behavior. , 1995, Pharmacopsychiatry.

[62]  A. Douglas,et al.  Brain Oxytocin Correlates with Maternal Aggression: Link to Anxiety , 2005, The Journal of Neuroscience.

[63]  C. M. Coppens,et al.  The Resident-intruder Paradigm: A Standardized Test for Aggression, Violence and Social Stress , 2013, Journal of visualized experiments : JoVE.

[64]  U. Fischbacher,et al.  Oxytocin increases trust in humans , 2005, Nature.

[65]  D. Dorsa,et al.  Social Interaction Deficits Caused by Chronic Phencyclidine Administration are Reversed by Oxytocin , 2005, Neuropsychopharmacology.

[66]  E. Tribollet,et al.  Vasopressin and oxytocin receptors in the central nervous system. , 1996, Critical reviews in neurobiology.

[67]  I. Neumann.  Brain Oxytocin: A Key Regulator of Emotional and Social Behaviours in Both Females and Males , 2008, Journal of neuroendocrinology.

[68]  D. Slattery,et al.  The Neuropeptide Oxytocin Facilitates Pro-Social Behavior and Prevents Social Avoidance in Rats and Mice , 2011, Neuropsychopharmacology.

[69]  J. Goodson.  The vertebrate social behavior network: Evolutionary themes and variations , 2005, Hormones and Behavior.

[70]  Jai-Yoon Sul,et al.  Serotonergic neuron regulation informed by in vivo single‐cell transcriptomics , 2014, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[71]  C. Montag,et al.  Imaging oxytocin × dopamine interactions: an epistasis effect of CD38 and COMT gene variants influences the impact of oxytocin on amygdala activation to social stimuli , 2013, Front. Neurosci..

[72]  L. Resstel,et al.  Involvement of medial prefrontal cortex neurons in behavioral and cardiovascular responses to contextual fear conditioning , 2006, Neuroscience.

[73]  K. Miczek,et al.  GABAA/α1 receptor agonists and antagonists: effects on species-typical and heightened aggressive behavior after alcohol self-administration in mice , 2004, Psychopharmacology.

[74]  P. Jones,et al.  Differential clearance of neurophysin and neurohypophysial peptides from the cerebrospinal fluid in conscious guinea pigs. , 1982, Neuroendocrinology.

[75]  K. Miczek,et al.  Anti-aggressive effects of agonists at 5-HT1B receptors in the dorsal raphe nucleus of mice , 2007, Psychopharmacology.

[76]  B. Rusak,et al.  Circadian and light regulation of oxytocin and parvalbumin protein levels in the ciliated ependymal layer of the third ventricle in the C57 mouse , 2005, Neuroscience.

[77]  Nicolas Singewald,et al.  Release of Oxytocin in the Rat Central Amygdala Modulates Stress-Coping Behavior and the Release of Excitatory Amino Acids , 2005, Neuropsychopharmacology.