Regulation of Brain Excitatory/Inhibitory Balance through the Mu-Opioid System Depends on the Extent of Autistic Symptoms

Background: There is accumulating evidence that ASD involves an imbalance between excitatory (E) glutamate and inhibitory (I) GABA transmission. E/I balance can be modulated through multiple signalling pathways, including the opioid system. For example, genetic abnormalities in the mu-opioid receptor gene are linked to ASD; and the social behaviour abnormalities of the mu-opioid receptor ‘null’ mouse can be rescued by a glutamate acting drug (mGluR4 positive allosteric modulator; Becker et al, 2014). However, whether E/I balance can be regulated through the mu-opioid system in adults with and without ASD has not been directly examined. 

Objectives: To provide Proof of Concept evidence for a difference in E/I response to mu-opioid activation in adults with and without symptoms of ASD. 

Methods: We used MEGAPRESS proton magnetic resonance spectroscopy ([¹H]-MRS) to measure levels of Glx (glutamate + glutamine) and GABA from the dorsomedial pre-frontal cortex of 19 unmedicated adult men with (n=8) and without (n=11) ASD. Individuals were scanned twice, once after oral administration of 12.5mg of tianeptine (a mu-opioid receptor agonist; Gassaway et al, 2014) and once following matched placebo in a randomised double blind procedure. Scans were at least 8 days apart to ensure full washout of the drug. An ‘Inhibitory Index’ was defined as GABA/(GABA + GLx), and the percentage (tianeptine-induced) change in Inhibitory Index from baseline (placebo) was calculated. ASD symptoms were rated in the entire cohort using the Autism Quotient (AQ). We conducted a preliminary analysis of group differences in the change in Inhibitory Index; and tested the prediction that the change in Inhibitory Index would be correlated with the extent of autistic symptoms rated using the Autism Quotient (AQ) across the entire cohort.

Results: There was a trend-level group difference in the tianeptine induced change in the inhibitory index (p = 0.08). This masked a highly significant negative correlation between AQ score and the change in inhibitory index (r = -.617, p < 0.01). Scrutiny of this relationship revealed that there was essentially ‘no change’ in inhibitory index in individuals with AQ = 24, a recognised population ‘cut-off’ score for ASD. However, tianeptine decreased the inhibitory index in individuals with AQ > 24; and those with the highest AQ scores had the greatest decrease. In contrast, tianeptine increased the inhibitory index in individuals with AQ < 24; and those with the lowest AQ had the greatest increase. 

Conclusions: Thus, E/I balance can be shifted acutely in the adult brain through the mu-opioid system. However, the direction and extent of E/I change depends on the extent of autistic features measured using the AQ. This study is still in progress. A larger sample size will allow us to assess whether modification of E/I balance through the mu-opioid system could provide a means to identify more ‘pharmacologically homogeneous’ sub-groups of people with ASD. It may also support further work to confirm the mu-opioid system as a treatment target for ASD.  In that event, repurposing well-tolerated drugs with a known safety profile, including tianeptine, should be explored.