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

Thursday, May 12, 2016: 11:30 AM-1:30 PM
Hall A (Baltimore Convention Center)
J. L. Findon1, R. H. Wichers2, J. Horder3, E. Daly2, R. A. Edden4, D. G. Murphy2 and G. M. McAlonan5, (1)Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, England, United Kingdom, (2)Sackler Institute for Translational Neurodevelopment, Department of Forensic and Neurodevelopmental Sciences,, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom, (3)Institute of Psychiatry, King's College London, London, England, United Kingdom of Great Britain and Northern Ireland, (4)Johns Hopkins University School of Medicine, Baltimore, MD, (5)Department of Forensic and Neurodevelopmental Science, IoPPN, KCL, London, United Kingdom
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.