Methylphenidate Dose-Dependently Affects Aggression and Improves Fear Extinction and Anxiety in BALB/cJ Mice.
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ABSTRACT:
SUBMITTER: Jager A
PROVIDER: S-EPMC6823535 | biostudies-literature | 2019
REPOSITORIES: biostudies-literature
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Project description:RATIONALE:A promising strategy to prevent a return of fear after exposure-based therapy in anxiety disorders is to pharmacologically enhance the extinction memory consolidation presumed to occur after exposure. Accumulating evidence suggests that the effect of a number of pharmacological consolidation enhancers depends on a successful fear reduction during exposure. Here, we employed the dopamine precursor L-DOPA to clarify whether its documented potential to enhance extinction memory consolidation is dependent on successful fear extinction. METHODS:In two double-blind, randomized and placebo-controlled experiments (experiment 1: N = 79, experiment 2: N = 32) comprising fear conditioning (day 1), extinction followed by administration of 150 mg L-DOPA or placebo (day 2) and a memory test (day 3) in healthy male adults, conditioned responses were assessed as differential skin conductance responses. We tested whether the effect of L-DOPA on conditioned responses at test depended on conditioned responses at the end of extinction in an experiment with a short (10 trials, experiment 1) and long (25 trials, experiment 2) extinction session. RESULTS:In both experiments, the effect of L-DOPA was dependent on conditioned responses at the end of extinction. That is, post-extinction L-DOPA compared to placebo administration reduced conditioned responses at test only in participants showing a complete reduction of conditioned fear at the end of extinction. CONCLUSION:The results support the potential use of L-DOPA as a pharmacological adjunct to exposure treatment, but point towards a common boundary condition for pharmacological consolidation enhancers: a successful reduction of fear in the exposure session.
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Project description:Anterior cingulate cortex (ACC) and midcingulate cortex (MCC) have been implicated in the regulation of aggressive behaviour. For instance, patients with conduct disorder (CD) show increased levels of aggression accompanied by changes in ACC and MCC volume. However, accounts of ACC/MCC changes in CD patients have been conflicting, likely due to the heterogeneity of the studied populations. Here, we address these discrepancies by studying volumetric changes of ACC/MCC in the BALB/cJ mouse, a model of aggression, compared to an age- and gender-matched control group of BALB/cByJ mice. We quantified aggression in BALB/cJ and BALB/cByJ mice using the resident-intruder test, and related this to volumetric measures of ACC/MCC based on Nissl-stained coronal brain slices of the same animals. We demonstrate that BALB/cJ behave consistently more aggressively (shorter attack latencies, more frequent attacks, anti-social biting) than the control group, while at the same time showing an increased volume of ACC and a decreased volume of MCC. Differences in ACC and MCC volume jointly predicted a high amount of variance in aggressive behaviour, while regression with only one predictor had a poor fit. This suggests that, beyond their individual contributions, the relationship between ACC and MCC plays an important role in regulating aggressive behaviour. Finally, we show the importance of switching from the classical rodent anatomical definition of ACC as cingulate area 2 and 1 to a definition that includes the MCC and is directly homologous to higher mammalian species: clear behaviour-related differences in ACC/MCC anatomy were only observed using the homologous definition.
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Project description:The fear conditioning and extinction neurocircuitry has been extensively studied in healthy and clinical populations, with a particular focus on posttraumatic stress disorder. Despite significant overlap of symptoms between posttraumatic stress disorder and anxiety disorders, the latter has received less attention. Given that dysregulated fear levels characterize anxiety disorders, examining the neural correlates of fear and extinction learning may shed light on the pathogenesis of underlying anxiety disorders.To investigate the psychophysiological and neural correlates of fear conditioning and extinction recall in anxiety disorders and to document how these features differ as a function of multiple diagnoses or anxiety severity.This investigation was a cross-sectional, case-control, functional magnetic resonance imaging study at an academic medical center. Participants were healthy controls and individuals with at least 1 of the following anxiety disorders: generalized anxiety disorder, social anxiety disorder, specific phobia, and panic disorder. The study dates were between March 2013 and May 2015.Two-day fear conditioning and extinction paradigm.Skin conductance responses, blood oxygenation level-dependent responses, trait anxiety scores from the State Trait Anxiety Inventory-Trait Form, and functional connectivity.This study included 21 healthy controls (10 women) and 61 individuals with anxiety disorders (36 women). P values reported for the neuroimaging results are all familywise error corrected. Skin conductance responses during extinction recall did not differ between individuals with anxiety disorders and healthy controls (?p2?=?0.001, P?=?.79), where ?p2 is partial eta squared. The anxiety group had lower activation of the ventromedial prefrontal cortex (vmPFC) during extinction recall (?p2?=?0.178, P?=?.02). A similar hypoactive pattern was found during early conditioning (?p2?=?0.106, P?=?.009). The vmPFC hypoactivation was associated with anxiety symptom severity (r?=?-0.420, P?=?.01 for conditioning and r?=?-0.464, P?=?.004 for extinction recall) and the number of co-occuring anxiety disorders diagnosed (?p2?=?0.137, P?=?.009 for conditioning and ?p2?=?0.227, P?=?.004 for extinction recall). Psychophysiological interaction analyses revealed that the fear network connectivity differed between healthy controls and the anxiety group during fear learning (?p2 range between 0.088 and 0.176 and P range between 0.02 and 0.003) and extinction recall (?p2 range between 0.111 and 0.235 and P range between 0.02 and 0.002).Despite no skin conductance response group differences during extinction recall, brain activation patterns between anxious and healthy individuals differed. These findings encourage future studies to examine the conditions longitudinally and in the context of treatment trials to improve and guide therapeutics via advanced neurobiological understanding of each disorder.
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