Exogenous dopamine reduces GABA receptor availability in the human brain

Abstract

BackgroundWhile it has recently been shown that dopamine release stimulates conscious self‐monitoring through the generation of gamma oscillations in medial prefrontal/anterior cingulate cortex, and that the GABAergic system is effective in producing such oscillations, interaction of the two transmitter systems has not been demonstrated in humans. We here hypothesize that dopamine challenge stimulates the GABA system directly in the medial prefrontal/anterior cingulate region in the human brain.MethodsPositron emission tomography (PET) with the GABA receptor α1/α5 subtype ligand [11C] Ro15‐4513 was used to detect changes in GABA receptor availability after clinical oral doses of levodopa in a double blind controlled study.ResultsWe here provide the first direct evidence for such coupling in the cerebral cortex, in particular in the medial prefrontal anterior cingulate region, by showing that exogenous dopamine decreases [11C] Ro15‐4513 binding widely in the human brain compatible with a fall in α1 subtype availability in GABA complexes due to increased GABA activity.

Attenuation of dopamine‐induced GABA release in problem gamblers

“…As reported previously (Lou, Rosenstand et al, ), exogenous dopamine activates GABA neurotransmission in healthy controls. After placebo, highest [ 11 C]Ro15‐4513 BDZ ligand binding was seen in medial prefrontal/anterior cingulate cortex and left and right insula.…”

“…Hoerbelt, Lindsley, and Fleck () have demonstrated that the dopaminergic system regulates GABA receptors directly in the striatum using the patch‐clamp technique. In our previous report (Lou, Rosenstand et al, ) we showed that dopaminergic activation of GABA release occurs directly throughout the paralimbic cortex, in particular in the medial prefrontal cortex. This binding is compromised in individuals suffering from problem gambling—as shown here.…”

“…Using a combination of an oral L‐dopa challenge to exogenously raise brain dopamine and measurements of GABA A /BDZ receptor availability with [ 11 C]Ro15‐4513 PET, we obtained evidence that rises in synaptic dopamine activated GABA neurotransmission and enhanced gamma synchronization and self‐awareness in humans. The L‐dopa‐induced increases in GABA release result in increased GABA receptor occupancy predominantly in the medial prefrontal/anterior cingulate region crucial for self‐awareness (Joensson et al, ; Lou, Rosenstand et al, ). GABA‐A receptors and alpha‐1 subunits are ubiquitous in gray matter.…”

“…This synchronization is known to facilitate self‐awareness (Lou, Changeux et al, ) and its reduction is associated with impaired self‐awareness and may also be instrumental in the development of an addiction to gambling and allied problems. Levels of synaptic GABA are regulated by dopamine release and it is GABA activation that leads to the periodic inhibition of pyramidal cells that results in synchronization of oscillatory activity across brain regions (Lou, Rosenstand et al, ). We, therefore, propose that attenuation of the normal dopamine regulation of GABA neurotransmission may underlie impaired self‐control and self‐awareness, both of which are characteristically present in individuals suffering from gambling disorder.…”

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

“…With this ligand, we were able to detect changes in dopamineinduced GABA binding under different physiological conditions at well-defined brain sites (Lou et al, 2016). It was found that GABA ligand binding was maximal in the medial anterior paralimbic region (cingulate gyrus), indicating empty GABA binding sites in these locations.…”