Attenuation of dopamine‐induced GABA release in problem gamblers

Abstract

Introduction We have previously shown that an interaction between medial prefrontal and parietal cortices is instrumental in promoting self‐awareness via synchronizing oscillations in the gamma range. The synchronization of these oscillations is modulated by dopamine release. Given that such oscillations result from intermittent GABA stimulation of pyramidal cells, it is of interest to determine whether the dopaminergic system regulates GABA release directly in cortical paralimbic regions. Here, we test the hypothesis that the regulation of the GABA‐ergic system by the dopaminergic system becomes attenuated in problem gamblers resulting in addictive behaviors and impaired self‐awareness. Methods [ 11 C]Ro15‐4513 PET, a marker of benzodiazepine α 1/ α 5 receptor availability in the GABA receptor complex, was used to detect changes in synaptic GABA levels after oral doses of 100mg L‐dopa in a double‐blind controlled study of male problem gamblers ( N = 10) and age‐matched healthy male controls ( N = 10). Results The mean reduction of cortical gray matter GABA/BDZ receptor availability induced by L‐dopa was significantly attenuated in the problem gambling group compared to the healthy control group ( p = 0.0377). Conclusions Our findings demonstrate that: (a) Exogenous dopamine can induce synaptic GABA release in healthy controls. (b) This release is attenuated in frontal cortical areas of males suffering from problem gambling, possibly contributing to their loss of inhibitory control. This suggests that dysfunctional dopamine regulation of GABA release may contribute to problem gambling and gambling disorder.

The Molecular Organization of Self-awareness: Paralimbic Dopamine-GABA Interaction

“…In other words: dopamine increases GABA binding directly in the human paralimbic cortex, concomitantly with increased self-awareness and conscious experience (Lou et al, 2016). The effect is faltering in problem gambling, reflecting faltering self-monitoring and self-awareness (Møller et al, 2019). This development brings the properties of the GABA receptor molecule into focus.…”

“…interaction between dopamine and GABA receptors in gambling disorder, a prime example of dysfunctional self-monitoring and self-control (Møller et al, 2019). Related to this, a number of studies suggest that altered GABA neurotransmission plays an important role in substance addiction (Lingford-Hughes et al, 2012 or gambling (Mick et al, 2017).…”

“…In later childhood and adulthood, disturbance of the paralimbic network is linked to severe pathology. Thus, deficient GABA neurotransmission is prominent in disorders with poor self-awareness and self-monitoring such as addiction (Lingford-Hughes et al, 2012Mick et al, 2017;Møller et al, 2019), autism (Hashemi et al, 2017), anosognosia, hallucinations, and delusions (Therriault et al, 2018), progressing to schizophrenia (Rikandi et al, 2018) major depression (Rikandi et al, 2018), and/or dementia (Lin et al, 2015). Even in the vegetative state (also termed unresponsive wakefulness syndrome, Laureys et al, 2010), recovery of the paralimbic network is tightly linked to clinical recovery (Thibaut et al, 2019).…”

“…To determine if deficient GABA neurotransmission in pathology could be a primary event or secondary to toxic or pathological effects in more complex disorders, we examined if deficient dopamine-GABA neurotransmission was present in a relatively mono-symptomatic disorder such as gambling disorder (Møller et al, 2019). This was indeed the case.…”

Motor cortex dysfunction in problem gamblers

“…BF 10 = 3.913.Given stronger SICI has been associated with higher spMEP amplitudes,37 we determined whether differences in spMEP amplitudes could explain why gamblers displayed significantly less SICI than controls. A contrast comparing gamblers (at-risk gamblers and problem gamblers combined) with controls showed no significant difference in spMEP amplitude, F 1, 61 = 1.412, P = .239, η p 2 = 0.0231, BF 01 = 1.68.…”