Interaction between disinhibition and restraint: Implications for body weight and eating disturbance

An increase in obesity is usually accompanied by an increase in eating disturbances. Susceptibility to these states may arise from different combinations of underlying traits: Three Factor Eating Questionnaire (TFEQ) Restraint and Disinhibition. Two studies were conducted to examine the interaction between these traits; one on-line study (n=351) and one laboratory-based study (n=120). Participants completed a battery of questionnaires and provided self-report measures of body weight and physical activity. A combination of high Disinhibition and high Restraint was associated with a problematic eating behaviour profile (EAT-26), and a higher rate of smoking and alcohol consumption. A combination of high Disinhibition and low Restraint was associated with a higher susceptibility to weight gain and a higher sedentary behaviour. These data show that different combinations of Disinhibition and Restraint are associated with distinct weight and behaviour outcomes.

Psycho-markers of weight loss. The roles of TFEQ Disinhibition and Restraint in exercise-induced weight management

Eating behaviour traits, namely Disinhibition and Restraint, have the potential to exert an effect on food intake and energy balance. The effectiveness of exercise as a method of weight management could be influenced by these traits. Fifty eight overweight and obese participants completed 12-weeks of supervised exercise. Each participant was prescribed supervised exercise based on an expenditure of 500 kcal/session, 5 d/week for 12-weeks. Following 12-weeks of exercise there was a significant reduction in mean body weight (-3.26 ± 3.63 kg), fat mass (FM: -3.26 ± 2.64 kg), BMI (-1.16 ± 1.17 kg/m2)and waist circumference (WC: -5.0 ± 3.23 cm). Regression analyses revealed a higher baseline Disinhibition score was associated with a greater reduction in BMI and WC, while Internal Disinhibition was associated with a larger decrease in weight, %FM and WC. Neither baseline Restraint or Hunger were associated with any of the anthropometric markers at baseline or after 12-weeks. Furthermore, after 12-weeks of exercise, a decrease in Disinhibition and increase in Restraint were associated with a greater reduction in WC, whereas only Restraint was associated with a decrease in weight. Post-hoc analysis of the sub-factors revealed a decrease in External Disinhibition and increase in Flexible Restraint were associated with weight loss. However, an increase in Rigid Restraint was associated with a reduction in %FM and WC. These findings suggest that exercise-induced weight loss is more marked in individuals with a high level of Disinhibition. These data demonstrate the important roles that Disinhibition and Restraint play in the relationship between exercise and energy balance.

Elucidating the neuropsychological profile of apathetic syndrome and disinhibition syndrome in a brain-injured population in Oman

The purpose of this study was to compare the neuropsychological performance of two frontal dysexecutive phenotypes - disinhibited&' syndrome (DS) and &'apathetic&' syndrome (AS) following a traumatic brain injury in a non-western population, Oman. Methods: The study compared the performance of DS and AS in neuropsychological measures including those tapping into verbal reasoning ability/working memory/attention planning/goal-directed behavior and affective ranges. Results: The present analysis showed that DS and AS participants did not differ on indices measuring working memory/attention and affective ranges. However, the two cohorts differed significantly in measures of planning/goal-directed behaviour. Conclusion: This study lays the groundwork for further scrutiny in delineating the different characteristics of what has been previously labelled as frontal dysexecutive phenotype. This study indicates that DS and AS are marked with specific neuropsychological deficits.

Anabolic-androgenic steroid treatment induces behavioral disinhibition and downregulation of serotonin receptor messenger RNA in the prefrontal cortex and amygdala of male mice

Nandrolone is an anabolic-androgenic steroid (AAS) that is highly abused by individuals seeking enhanced physical strength or body appearance. Supraphysiological doses of this synthetic testosterone derivative have been associated with many physical and psychiatric adverse effects, particularly episodes of impulsiveness and overt aggressive behavior. As the neural mechanisms underlying AAS-induced behavioral disinhibition are unknown, we investigated the status of serotonergic system-related transcripts in several brain areas of mice receiving prolonged nandrolone administration. Male C57BL/6J mice received 15 mg/kg of nandrolone decanoate subcutaneously once daily for 28 days, and different sets of animals were used to investigate motor-related and emotion-related behaviors or 5-HT-related messenger RNA (mRNA) levels by real-time quantitative polymerase chain reaction. AAS-injected mice had increased body weight, were more active and displayed anxious-like behaviors in novel environments. They exhibited reduced immobility in the forced swim test, a higher probability of being aggressive and more readily attacked opponents. AAS treatment substantially reduced mRNA levels of most investigated postsynaptic 5-HT receptors in the amygdala and prefrontal cortex. Interestingly, the 5-HT(1B) mRNA level was further reduced in the hippocampus and hypothalamus. There was no alteration of 5-HT system transcript levels in the midbrain. In conclusion, high doses of AAS nandrolone in male mice recapitulate the behavioral disinhibition observed in abusers. Furthermore, these high doses downregulate 5-HT receptor mRNA levels in the amygdala and prefrontal cortex. Our combined findings suggest these areas as critical sites for AAS-induced effects and a possible role for the 5-HT(1B) receptor in the observed behavioral disinhibition.

Effect of lithium on behavioral disinhibition induced by electrolytic lesion of the median raphe nucleus

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

The inotropic peptide ?ARKct improves ?AR responsiveness in normal and failing cardiomyocytes through G(??)-mediated L-type calcium current disinhibition

The G(βγ)-sequestering peptide β-adrenergic receptor kinase (βARK)ct derived from the G-protein-coupled receptor kinase (GRK)2 carboxyl terminus has emerged as a promising target for gene-based heart failure therapy. Enhanced downstream cAMP signaling has been proposed as the underlying mechanism for increased β-adrenergic receptor (βAR) responsiveness. However, molecular targets mediating improved cardiac contractile performance by βARKct and its impact on G(βγ)-mediated signaling have yet to be fully elucidated.

Nerve Injury-Induced Neuropathic Pain Causes Disinhibition of the Anterior Cingulate Cortex

Neuropathic pain caused by peripheral nerve injury is a debilitating neurological condition of high clinical relevance. On the cellular level, the elevated pain sensitivity is induced by plasticity of neuronal function along the pain pathway. Changes in cortical areas involved in pain processing contribute to the development of neuropathic pain. Yet, it remains elusive which plasticity mechanisms occur in cortical circuits. We investigated the properties of neural networks in the anterior cingulate cortex (ACC), a brain region mediating affective responses to noxious stimuli. We performed multiple whole-cell recordings from neurons in layer 5 (L5) of the ACC of adult mice after chronic constriction injury of the sciatic nerve of the left hindpaw and observed a striking loss of connections between excitatory and inhibitory neurons in both directions. In contrast, no significant changes in synaptic efficacy in the remaining connected pairs were found. These changes were reflected on the network level by a decrease in the mEPSC and mIPSC frequency. Additionally, nerve injury resulted in a potentiation of the intrinsic excitability of pyramidal neurons, whereas the cellular properties of interneurons were unchanged. Our set of experimental parameters allowed constructing a neuronal network model of L5 in the ACC, revealing that the modification of inhibitory connectivity had the most profound effect on increased network activity. Thus, our combined experimental and modeling approach suggests that cortical disinhibition is a fundamental pathological modification associated with peripheral nerve damage. These changes at the cortical network level might therefore contribute to the neuropathic pain condition.

Mechanisms underlying kainate receptor-mediated disinhibition in the hippocampus

Kainate (KA) receptor activation depresses stimulus-evoked γ-aminobutyric acid (GABA-mediated) synaptic transmission onto CA1 pyramidal cells of the hippocampus and simultaneously increases the frequency of spontaneous GABA release through an increase in interneuronal spiking. To determine whether these two effects are independent, we examined the mechanism by which KA receptor activation depresses the stimulus-evoked, inhibitory postsynaptic current (IPSC). Bath application of the α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA)/KA receptor agonist KA in the presence of the AMPA receptor antagonist GYKI 53655 caused a large increase in spontaneous GABA release and a coincident depression of the evoked IPSC. The depressant action on the evoked IPSC was reduced, but not abolished, by the GABAB receptor antagonist SCH 50911, suggesting that the KA-induced increase in spontaneous GABA release depresses the evoked IPSC through activation of presynaptic GABAB receptors. KA had no resolvable effect on the potassium-induced increase in miniature IPSC frequency, suggesting that KA does not act through a direct effect on the release machinery or presynaptic calcium influx. KA caused a decrease in pyramidal cell input resistance, which was reduced by GABAA receptor antagonists. KA also caused a reduction in the size of responses to iontophoretically applied GABA, which was indistinguishable from the SCH 50911-resistant, residual depression of the evoked IPSC. These results suggest that KA receptor activation depresses the evoked IPSC indirectly by increasing interneuronal spiking and GABA release, leading to activation of presynaptic GABAB receptors, which depress GABA release, and postsynaptic GABAA receptors, which increase passive shunting.

Neural correlates of impaired self-awareness of apathy, disinhibition and dysexecutive deficits in cocaine-dependent individuals

Cocaine addiction is characterized by impaired self-awareness about cognitive and motivational deficits, leading to poor treatment outcomes. However, there is still limited understanding of the neurophysiological underpinnings of this impairment. We aimed to establish if impaired self-awareness is underpinned by brain structural phenotypes among cocaine-dependent individuals (CDI). Sixty-five CDI and 65 designated informants completed the Frontal Systems Behavior Scale, and a subsample of 40 CDI were scanned via magnetic resonance imaging. We applied multiple regression models to establish the association between levels of self-awareness indexed by Frontal Systems Behavior Scale's discrepancy scores (i.e. informant ratings minus self-reports of apathy, disinhibition and dysexecutive deficits) and gray matter volumes indexed by magnetic resonance imaging voxel-based measures within five brain regions of interest: anterior cingulate cortex, orbitofrontal cortex (OFC), striatum, insula and dorsolateral prefrontal cortex (DLPFC). We also examined the neural underpinnings of underestimation versus overestimation of deficits, by splitting the CDI group according to the positive or negative value of their discrepancy scores. We found that poorer self-awareness of apathy deficits was associated with greater gray matter volume in the dorsal striatum, and poorer self-awareness of disinhibition deficits was associated with greater gray matter volume in the OFC in the whole sample. More underestimation and more overestimation of executive deficits were linked to lower DLPFC volume. We show that impaired self-awareness of cognitive and motivational deficits in cocaine addiction has a neural underpinning, implicating striatum, OFC and DLPFC structural phenotypes.

The consequences of substance use among gay and bisexual men : a consensual qualitative research analysis

- Background Substance use is common among gay/bisexual men and is associated with significant health risks (e.g. HIV transmission). The consequences of substance use, across the range of substances commonly used, have received little attention. The purpose of this study is to map participant’s beliefs about the effects of substance use to inform prevention, health promotion and clinical interventions. - Methods Participants were interviewed about experiences regarding their substance use and recruited through medical and sexual health clinics. Data were collected though a consumer panel and individual interviews. Responses regarding perceived consequences of substance use were coded using Consensual Qualitative Research (CQR) methodology. - Results Most participants reported lifetime use of alcohol, cannabis, stimulants and amyl nitrite, and recent alcohol and cannabis use. A wide range of themes were identified regarding participant’s thoughts, emotions and behaviours (including sexual behaviours) secondary to substance use, including: cognitive functioning, mood, social interaction, physical effects, sexual activity, sexual risk-taking, perception of sexual experience, arousal, sensation, relaxation, disinhibition, energy/activity level and numbing. Analyses indicated several consequences were consistent across substance types (e.g. cognitive impairment, enhanced mood), whereas others were highly specific to a given substance (e.g. heightened arousal post amyl nitrite use). - Conclusions Prevention and interventions need to consider the variety of effects of substance use in tailoring effective education programs to reduce harms. A diversity of consequences appear to have direct and indirect impacts on decision-making, sexual activity and risk-taking. Findings lend support for the role of specific beliefs (e.g. expectancies) related to substance use on risk-related cognitions, emotions and behaviours.

Negative mood regulation expectancies, frontal lobe related behaviors and alcohol use

Negative mood regulation (NMR) expectancies have been linked to substance problems in previous research, but the neurobiological correlates of NMR are unknown. In the present study, NMR was examined in relation to self-report indices of frontal lobe functioning, mood and alcohol use in 166 volunteers of both genders who ranged in age from 17 to 43 years. Contrary to expectations based on previous findings in addicts and problem drinkers, scores on the NMR scale did not differ between Low Risk and High Risk drinkers as defined by the Alcohol Use Disorders Identification Test (AUDIT). However, NMR scores were significantly negatively correlated with all three indices of frontal lobe dysfunction on the Frontal Systems Behavior Scale (FrSBe) Self-Rating Form as well as with all three indices of negative mood on the Depression Anxiety Stress Scales (DASS), which in turn were all positively correlated with FrSBe. Path analyses indicated that NMR partially mediated the direct effects of frontal lobe dysfunction (as indexed by FrSBe) on DASS Stress and DASS Depression. Further, the High Risk drinkers scored significantly higher on the Disinhibition and Executive Dysfunction indices of the FrSBe than did Low Risk drinkers. Results are consistent with the notion that NMR is a frontal lobe function.