Impulsive behaviour induced by both NMDA receptor antagonism and GABAA receptor activation in rat ventromedial prefrontal cortex

Murphy, Emily R.; Fernando, Anushka B. P.; Urcelay, Gonzalo P.; Robinson, Emma; Mar, Adam C.; Theobald, David E. H.; Dalley, Jeffrey W.; Robbins, Trevor W.

doi:10.1007/s00213-011-2572-1

Cited by 97 publications

(89 citation statements)

References 44 publications

(58 reference statements)

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“…Our findings of positive correlations of the BIS-11 total impulsivity score with Glu/tCr and a trend for a negative correlation with GABA adds further support for the involvement of glutamatergic and GABAergic mechanisms in the expression of impulsivity (Hayes et al, 2014;Jupp et al, 2013;Murphy et al, 2012 ). In a group-wise correlation analyses, the Glu/tCr correlations hold for the BPD group.…”

Section: Discussionsupporting

confidence: 72%

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Impulsivity and Aggression in Female BPD and ADHD Patients: Association with ACC Glutamate and GABA Concentrations

Ende

Cackowski

Eijk

et al. 2015

Neuropsychopharmacol

118

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Borderline personality disorder (BPD) and attention-deficit-hyperactivity disorder (ADHD) are both characterized by high impulsivity and difficulties in controlling anger and aggression. In BPD, comorbid ADHD may further increase impulsivity. For both disorders, altered MR spectroscopy levels of the neurotransmitters glutamate and GABA as well as some correlations with impulsivity were previously reported. The objective of this study was to investigate the neurotransmitters glutamate and GABA in relation to impulsivity and aggression as expressed in the anterior cingulate cortex (ACC) in groups of female patients with BPD and ADHD, respectively. Associations of glutamate and GABA levels with further BPD (symptom severity) and ADHD aspects (hyperactivity and inattention) were exploratively evaluated. 1H MR spectra were acquired at 3T to determine glutamate to total creatine ratios (Glu/tCr) and GABA levels from the ACC in a BPD group (n = 26), an ADHD group (n = 22), and a healthy control (HC) group (n = 30); all participants were females. Both patient groups showed higher scores on self-reported impulsivity, anger, and aggression compared with HCs. ACC GABA levels were significantly lower in ADHD than HC. Although measures of impulsivity were positively related to glutamate and negatively to GABA, for aggression only a negative correlation with GABA could be demonstrated. These data provide human in vivo evidence for the role of ACC Glu/tCr and GABA in impulsivity and aggression. If distinct associations of Glu/tCr and GABA for BPD and ADHD can be confirmed in future studies, this might yield implications for more specific pharmacological treatments.

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Section: Discussionsupporting

confidence: 72%

“…Despite these studies, Hayes argues that there is still a lack of research on GABA in the general context of impulsivity (Hayes et al, 2014). In rodents, Murphy et al recently reported implications for glutamatergic and GABAergic mechanisms in the infralimbic cortex in the expression of impulsivity (Murphy et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Impulsivity and Aggression in Female BPD and ADHD Patients: Association with ACC Glutamate and GABA Concentrations

Ende

Cackowski

Eijk

et al. 2015

Neuropsychopharmacol

118

View full text Add to dashboard Cite

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“…Activation of the mPFC is required for suppression of impulsive action (Dalley et al, 2011;Murphy et al, 2012) and cocaine-seeking behavior (Koya et al, 2009;LaLumiere et al, 2012). Our observation that 5-HT 2C R knockdown in the mPFC resulted in elevated impulsive action and cocaine cue reactivity suggests that loss of the 5-HT 2C R inactivates the mPFC suppression circuit to drive aggregate expression of these behaviors.…”

Section: Discussionmentioning

confidence: 85%

Functional Status of the Serotonin 5-HT2C Receptor (5-HT2CR) Drives Interlocked Phenotypes that Precipitate Relapse-Like Behaviors in Cocaine Dependence

Anastasio

Stutz

Fox

et al. 2013

Neuropsychopharmacol

154

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Relapse vulnerability in cocaine dependence is rooted in genetic and environmental determinants, and propelled by both impulsivity and the responsivity to cocaine-linked cues ('cue reactivity'). The serotonin (5-hydroxytryptamine, 5-HT) 5-HT 2C receptor (5-HT 2C R) within the medial prefrontal cortex (mPFC) is uniquely poised to serve as a strategic nexus to mechanistically control these behaviors. The 5-HT 2C R functional capacity is regulated by a number of factors including availability of active membrane receptor pools, the composition of the 5-HT 2C R macromolecular protein complex, and editing of the 5-HT 2C R pre-mRNA. The one-choice serial reaction time (1-CSRT) task was used to identify impulsive action phenotypes in an outbred rat population before cocaine self-administration and assessment of cue reactivity in the form of lever presses reinforced by the cocaine-associated discrete cue complex during forced abstinence. The 1-CSRT task reliably and reproducibly identified high impulsive (HI) and low impulsive (LI) action phenotypes; HI action predicted high cue reactivity. Lower cortical 5-HT 2C R membrane protein levels concomitant with higher levels of 5-HT 2C R:postsynaptic density 95 complex distinguished HI rats from LI rats. The frequency of edited 5-HT 2C R mRNA variants was elevated with the prediction that the protein population in HI rats favors those isoforms linked to reduced signaling capacity. Genetic loss of the mPFC 5-HT 2C R induced aggregate impulsive action/cue reactivity, suggesting that depressed cortical 5-HT 2C R tone confers vulnerability to these interlocked behaviors. Thus, impulsive action and cue reactivity appear to neuromechanistically overlap in rodents, with the 5-HT 2C R functional status acting as a neural rheostat to regulate, in part, the intersection between these vulnerability behaviors.

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“…Preclinical studies suggest that reductions in or lower levels of GABA are associated with greater impulsivity (Boy et al 2011; Murphy et al 2012; Paine et al 2011). We have previously shown that [ 11 C]Ro15‐4513 is sensitive to GABA levels, and since it is an inverse benzodiazepine agonist, lower levels of GABA would be associated with higher [ 11 C]Ro15‐4513 binding.…”

Section: Discussionmentioning

confidence: 99%

“…As the main inhibitory neurotransmitter in the human brain, the role of GABAergic functioning in impulsivity is attracting attention with growing preclinical evidence supporting its involvement (Hayes et al 2014). For instance, a GABA agonist and antagonist in the prefrontal cortex of rats increased and reduced, respectively, impulsive responses in the 5‐choice serial reaction time task (Murphy et al 2012; Paine et al 2011). GABA A receptor binding is lower in the anterior cingulate cortex of high‐impulsive rats compared with low‐impulsive rats and is inversely correlated with impulsive responding (Jupp et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Evidence for GABA‐A receptor dysregulation in gambling disorder: correlation with impulsivity

et al. 2016

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As a behavioural addiction, gambling disorder (GD) provides an opportunity to characterize addictive processes without the potentially confounding effects of chronic excessive drug and alcohol exposure. Impulsivity is an established precursor to such addictive behaviours, and GD is associated with greater impulsivity. There is also evidence of GABAergic dysregulation in substance addiction and in impulsivity. This study therefore investigated GABAA receptor availability in 15 individuals with GD and 19 healthy volunteers (HV) using [11C]Ro15‐4513, a relatively selective α5 benzodiazepine receptor PET tracer and its relationship with impulsivity. We found significantly higher [11C]Ro15‐4513 total distribution volume (VT) in the right hippocampus in the GD group compared with HV. We found higher levels of the ‘Negative Urgency’ construct of impulsivity in GD, and these were positively associated with higher [11C]Ro15‐4513 VT in the amygdala in the GD group; no such significant correlations were evident in the HV group. These results contrast with reduced binding of GABAergic PET ligands described previously in alcohol and opiate addiction and add to growing evidence for distinctions in the neuropharmacology between substance and behavioural addictions. These results provide the first characterization of GABAA receptors in GD with [11C]Ro15‐4513 PET and show greater α5 receptor availability and positive correlations with trait impulsivity. This GABAergic dysregulation is potential target for treatment.

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Impulsive behaviour induced by both NMDA receptor antagonism and GABAA receptor activation in rat ventromedial prefrontal cortex

Cited by 97 publications

References 44 publications

Impulsivity and Aggression in Female BPD and ADHD Patients: Association with ACC Glutamate and GABA Concentrations

Impulsivity and Aggression in Female BPD and ADHD Patients: Association with ACC Glutamate and GABA Concentrations

Functional Status of the Serotonin 5-HT2C Receptor (5-HT2CR) Drives Interlocked Phenotypes that Precipitate Relapse-Like Behaviors in Cocaine Dependence

Evidence for GABA‐A receptor dysregulation in gambling disorder: correlation with impulsivity

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