Searching for neural and behavioral parameters that predict anti‐aggressive effects of chronic SSRI treatment in rats

Rationale: Only a subset of impulsive aggressive patients benefits from selective serotonin reuptake inhibitor (SSRI) treatment, confirming contradictory results about the association between serotonin (5‐hydroxytryptamine, 5‐HT) and aggression. This shows the need to define behavioral characteristics within this subgroup to move towards individualized pharmacological treatment of impulsive aggression. Methods: Here we submitted an outbred strain of Long Evans rats to a crossover design treatment regimen with the SSRI citalopram, to test its anti‐aggressive effect. Behavioral characteristics were baseline aggression, anxiety parameters as measured in the elevated plus maze and open field and cue responsivity as indicated by sign vs. goal tracking behavior. 5‐HT1A receptor densities as measured by ex vivo [18F]MPPF binding were determined in the dorsal raphe nucleus, dentate gyrus, orbitofrontal cortex, infralimbic cortex and prelimbic cortex, because of the receptors’ involvement in the therapeutic delay of SSRIs and aggression. Results: We found statistically significant increased variance in aggressive behavior after citalopram treatment. However, none of the selected parameters predicted the citalopram treatment effect. Conclusion: Since aggression after citalopram treatment decreased in a subgroup of animals and increased in the other, future research should focus on other possible predictors to support treatment strategies in aggressive patients. HIGHLIGHTSIn an outbred strain of Long Evans rats aggressive behavior varied from 0 to 37%.Aggressive behavior after chronic citalopram treatment showed increased variance.Anxiety and cue responsivity parameters did not predict the effect of citalopram.Regional brain 5‐HT1A receptor densities did not predict the treatment effect.

• Publication year

  2018

• Venue

  Neuropharmacology

• Publication date

  2018-09-11

• Fields of study

  Medicine, Psychology

• Identifiers
  DOI 10.1016/j.neuropharm.2018.09.012PMID 30217738
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Mouse strain differences in SSRI sensitivity correlate with serotonin transporter binding and function

  2017cited by this paper
• Untangling the neurobiology of coping styles in rodents: Towards neural mechanisms underlying individual differences in disease susceptibility.

  2017cited by this paper
• Serotonin and arginine–vasopressin mediate sex differences in the regulation of dominance and aggression by the social brain

  2016cited by this paper
• The neurobiology of aggression and violence

  2015cited by this paper
• Differential effects of chronic fluoxetine on the behavior of dominant and subordinate naked mole-rats.

  2014cited by this paper
• The Resident-intruder Paradigm: A Standardized Test for Aggression, Violence and Social Stress

  2013cited by this paper
• Excessive aggression as model of violence: a critical evaluation of current preclinical methods

  2013influential reference
• Revisiting the serotonin-aggression relation in humans: a meta-analysis.

  2013cited by this paper
• Suppression of Serotonin Neuron Firing Increases Aggression in Mice

  2013cited by this paper
• Intermittent explosive disorder as a disorder of impulsive aggression for DSM-5.

  2012cited by this paper
• Neonatal fibroblast growth factor treatment enhances cocaine sensitization.

  2012cited by this paper
• Aggression in schizophrenia.

  2011cited by this paper
• Testosterone, cortisol, and serotonin as key regulators of social aggression: A review and theoretical perspective

  2011cited by this paper
• 5HT(1A) and 5HT(1B) receptors of medial prefrontal cortex modulate anxiogenic-like behaviors in rats.

  2011cited by this paper
• High novelty-seeking predicts aggression and gene expression differences within defined serotonergic cell groups.

  2011cited by this paper
• Personality predictors of antiaggressive response to fluoxetine: inverse association with neuroticism and harm avoidance

  2011cited by this paper
• Prescription Drugs Associated with Reports of Violence Towards Others

  2010cited by this paper
• An Animal Model of Genetic Vulnerability to Behavioral Disinhibition and Responsiveness to Reward-Related Cues: Implications for Addiction

  2010cited by this paper
• 5-HT1A autoreceptor levels determine vulnerability to stress and response to antidepressants.

  2010cited by this paper
• Reducing Impulsivity in Repeat Violent Offenders: An Open Label Trial of a Selective Serotonin Reuptake Inhibitor

  2010cited by this paper
• A double-blind, randomized, placebo-controlled trial of fluoxetine in patients with intermittent explosive disorder.

  2009cited by this paper
• MDMA-induced serotonergic neurotoxicity enhances aggressiveness in low- but not high-aggressive rats.

  2009cited by this paper
• Aggression is related to frontal serotonin‐1A receptor distribution as revealed by PET in healthy subjects

  2009cited by this paper
• The effect of increased serotonergic neurotransmission on aggression: a critical meta-analytical review of preclinical studies

  2009cited by this paper
• Individual differences in the attribution of incentive salience to a reward-related cue: influence on cocaine sensitization.

  2008cited by this paper
• Differential regulation of serotonin-1A receptor-stimulated [35S]GTP gamma S binding in the dorsal raphe nucleus by citalopram and escitalopram.

  2008cited by this paper
• Long-term citalopram maintenance in mice: selective reduction of alcohol-heightened aggression

  2008cited by this paper
• Serotonin transporter deficiency in rats improves inhibitory control but not behavioural flexibility

  2007cited by this paper
• Low inborn anxiety correlates with high intermale aggression: link to ACTH response and neuronal activation of the hypothalamic paraventricular nucleus.

  2007cited by this paper
• Differential role of the 5-HT1A receptor in aggressive and non-aggressive mice: an across-strain comparison.

  2007cited by this paper
• Differential responsiveness to fluoxetine during puberty.

  2006cited by this paper
• Selective Breeding for Divergence in Novelty-seeking Traits: Heritability and Enrichment in Spontaneous Anxiety-related Behaviors

  2006cited by this paper
• Do similar neural systems subserve aggressive and sexual behaviour in male rats? Insights from c-Fos and pharmacological studies.

  2005cited by this paper
• Reduction in 5‐HT1A receptor density, 5‐HT1A mRNA expression, and functional correlates for 5‐HT1A receptors in genetically defined aggressive rats

  2005cited by this paper
• Association between suicide attempts and selective serotonin reuptake inhibitors: systematic review of randomised controlled trials

  2005cited by this paper
• The effects of dopaminergic/serotonergic reuptake inhibition on maternal behavior, maternal aggression, and oxytocin in the rat.

  2005cited by this paper
• Animal models of depressive illness: the importance of chronic drug treatment.

  2005cited by this paper
• Serotonin and Aggression

  2004cited by this paper
• Citalopram, a selective serotonin reuptake inhibitor: Clinical antidepressive and long-term effect — a phase II study

  2004cited by this paper
• The genetic basis of neuroticism.

  2004cited by this paper
• Fluoxetine increases relative metabolic rate in prefrontal cortex in impulsive aggression

  2004cited by this paper
• Antidepressants in chronic unpredictable mild stress (CUMS)-induced deficit of fighting behavior.

  2004cited by this paper
• Serotonin-Induced Increases in Adult Cell Proliferation and Neurogenesis are Mediated Through Different and Common 5-HT Receptor Subtypes in the Dentate Gyrus and the Subventricular Zone

  2004cited by this paper
• Effects of chronic treatment with escitalopram or citalopram on extracellular 5‐HT in the prefrontal cortex of rats: role of 5‐HT1A receptors

  2004cited by this paper
• Chronic fluoxetine induces opposite changes in G protein coupling at pre and postsynaptic 5-HT1A receptors in rat brain.

  2003cited by this paper
• Increased extracellular serotonin level in rat hippocampus induced by chronic citalopram is augmented by subchronic lithium: neurochemical and behavioural studies in the rat

  2003cited by this paper
• Requirement of Hippocampal Neurogenesis for the Behavioral Effects of Antidepressants

  2003cited by this paper
• In socially isolated mice, the reversal of brain allopregnanolone down-regulation mediates the anti-aggressive action of fluoxetine

  2003cited by this paper
• The R-enantiomer of citalopram counteracts escitalopram-induced increase in extracellular 5-HT in the frontal cortex of freely moving rats.

  2003cited by this paper
• Fluoxetine treatment decreases territorial aggression in a coral reef fish.

  2003cited by this paper
• Escitalopram, the S-(+)-enantiomer of citalopram, is a selective serotonin reuptake inhibitor with potent effects in animal models predictive of antidepressant and anxiolytic activities

  2003cited by this paper
• Chronic fluoxetine treatment selectively uncouples raphe 5-HT(1A) receptors as measured by [(35)S]-GTP gamma S autoradiography.

  2002cited by this paper
• Reduced aggression in mice lacking the serotonin transporter

  2002cited by this paper
• Differential Regulation of 5-HT1A Receptor-G Protein Interactions in Brain Following Chronic Antidepressant Administration

  2002cited by this paper
• SSRI treatment of borderline personality disorder: a randomized, placebo-controlled clinical trial for female patients with borderline personality disorder.

  2002cited by this paper
• Chronic fluoxetine treatment selectively uncouples raphe 5‐HT1A receptors as measured by [35S]‐GTPγS autoradiography

  2002cited by this paper
• Inverse relationship between serotonin 5-HT(1A) receptor binding and anxiety: a [(11)C]WAY-100635 PET investigation in healthy volunteers.

  2001cited by this paper
• In vivo steady‐state pharmacokinetic outcome following clinical and toxic doses of racemic citalopram to rats

  2001cited by this paper
• Reduction of intraspecific aggression in adult rats by neonatal treatment with a selective serotonin reuptake inhibitor.

  2001cited by this paper
• Measuring normal and pathological anxiety-like behaviour in mice: a review.

  2001cited by this paper
• Enhanced sensitivity of postsynaptic serotonin-1A receptors in rats and mice with high trait aggression.

  2001cited by this paper
• Fenfluramine challenge in unipolar depression with and without anger attacks.

  2000cited by this paper
• Desensitisation of 5-HT autoreceptors upon pharmacokinetically monitored chronic treatment with citalopram.

  2000cited by this paper
• Impulsivity, aggression, and serotonin: a molecular psychobiological perspective.

  2000cited by this paper
• Adverse Reactions of Selective Serotonin Reuptake Inhibitors

  1999cited by this paper
• The effects of tryptophan depletion and loading on laboratory aggression in men: time course and a food-restricted control

  1999cited by this paper
• Fluoxetine and impulsive aggressive behavior in personality-disordered subjects.

  1997cited by this paper
• Interaction studies of 5-HT1A receptor antagonists and selective 5-HT reuptake inhibitors in isolated aggressive mice.

  1997cited by this paper
• Effects of Fluoxetine on Aggressive Behavior of Adult Inpatients with Mental Retardation and Epilepsy

  1995cited by this paper
• Effect of fluoxetine on anger in symptomatic volunteers with borderline personality disorder.

  1995cited by this paper
• Serotonin receptors and animal models of aggressive behavior.

  1995cited by this paper
• Citalopram, a selective serotonin reuptake inhibitor, in the treatment of aggression in schizophrenia

  1995cited by this paper
• Isolation-induced aggression in mice: effects of 5-hydroxytryptamine uptake inhibitors and involvement of postsynaptic 5-HT1A receptors.

  1994cited by this paper
• Thigmotaxis as an index of anxiety in mice. Influence of dopaminergic transmissions.

  1994cited by this paper
• Regional serotonin and dopamine activity: Sensitivity to amphetamine and aggressive behavior in mice

  1990cited by this paper
• Central Serotonin and Impulsive Aggression

  1989cited by this paper
• The effect of raising or lowering tryptophan levels on aggression in vervet monkeys.

  1987cited by this paper
• Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat.

  1985cited by this paper
• Blockade by antidepressants and related compounds of biogenic amine uptake into rat brain synaptosomes: most antidepressants selectively block norepinephrine uptake.

  1984cited by this paper
• Low cerebrospinal fluid 5-hydroxyindoleacetic acid concentration differentiates impulsive from nonimpulsive violent behavior.

  1983cited by this paper
• The Rat Brain in Stereotaxic Coordinates

  1983cited by this paper
• The Rat Brain in Stereotaxic Coordinates

  1983cited by this paper
• Citalopram--pharmacological profile of a specific serotonin uptake inhibitor with antidepressant activity.

  1982cited by this paper
• Effect of serotonergic drugs on the aggressiveness induced by delta 9-tetrahydrocannabinol in rem-sleep-deprived rats.

  1982cited by this paper
• Aggression in humans correlates with cerebrospinal fluid amine metabolites.

  1979cited by this paper
• Effect of stress and para-chlorophenylalanine upon brain serotonin, 5-hydroxyindoleacetic acid and catecholamines in grouped and isolated mice.

  1968cited by this paper
• Brain serotonin metabolism in isolated aggressive mice.

  1968cited by this paper

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• Revisiting the Role of Serotonin in Attention-Deficit Hyperactivity Disorder: New Insights from Preclinical and Clinical Studies

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• Chronic exposure to imipramine induces a switch from depression-like to mania-like behavior in female serotonin transporter knockout rats: Role of BDNF signaling in the infralimbic cortex.

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• Prescribing Patterns of Psychotropic Drugs and Risk of Violent Behavior: A Prospective, Multicenter Study in Italy

  2020cites this paper
• The development of the serotonergic and dopaminergic systems during chicken mid-late embryogenesis.

  2019cites this paper