¹McGill University, Integrated Program in Neuroscience, Montreal, Canada, ²McGill University, Psychology, Montreal, Canada, ³McGill University, Psychiatry, Montreal, Canada, ⁴Université de Montréal, Départment de Psychiatrie et d’Addictologie, Montreal, Canada, ⁵McGill University, McConnell Brain Imaging Centre, Montreal, Canada, ⁶Université de Montréal, School of Psychoeducation, Montreal, Canada, ⁷Université de Québec à Montréal, Psychology, Montreal, Canada, ⁸Université de Laval, Psychology, Quebec City, Canada, ⁹Université de Montréal, Department of Social and Preventative Medicine, Montreal, Canada

Background: Type 5 metabotropic glutamate receptors (mGluR5) affect experience-dependent neuroplasticity and the readiness for future plasticity, influencing the ability to adapt to changing environments. Across drug- and stress-related disorders, the availability of these receptors is reported to be altered, but results have been inconsistent.

Aims & Objectives: To investigate these effects more thoroughly, we conducted repeat positron emission tomography (PET) scans in young adults before and after they developed a mental health disorder.

Method: ​PET scans with the selective mGluR5 ligand, [¹¹C]ABP688, were conducted in longitudinally followed youth at ages 18 (Wave-1, n=59) and 25 (Wave-2, n=44). Binding potential (BPND) values were derived for 11 striatal and extrastriatal regions of interest (ROIs). Linear mixed-effects models examined effects of Group (Emerging DSM-5 Disorder vs Control), Time, and ROI, including all two- and three-way interactions. The analyses tested for longitudinal changes in BPND and examined effects of within-person and between-person drug use, stress, and drug use × stress interactions. Mediation analyses tested whether lifetime drug occasions mediated the association between adolescent behavioral and emotional volatility (externalizing, EXT) and Wave-2 [¹¹C]ABP688 BPND values, with indirect effects evaluated using 5,000 bootstrap samples. Post hoc comparisons were Bonferroni-corrected.

Results: From Wave-1 to Wave-2, some participants developed mood (n=9), anxiety (n=9), ADHD (n=3), OCD (n=1), and substance use disorders (n=6). Both healthy controls and the emerging DSM-5 disorder group showed decreases in BPND over the seven-year follow-up, but, across ROI, these declines were greater in the DSM-5 group (Group x Wave interaction, p=.007). As previously reported, tobacco smokers exhibited lower BPND values than non-smokers and this was seen in all regions (β = −0.044, p = .004). After controlling for smoking, lower BPND values were also predicted by higher than average illicit drug use occasions (β = −1.02 × 10-4, p = .005), and larger Wave-1 to Wave-2 increases in drug use predicted larger decreases in BPND (β = −7.43 × 10-5, p < .001). Lower Wave-2 BPND values were also associated with higher Wave-2 stress (β = −0.009, p < .001) and this negative association was amplified by greater increases in drug use (interaction β = −2.97 × ß = -2.97 x 10-5, p < .001). Mediation analyses indicated that higher adolescent EXT scores were indirectly associated with lower Wave-2 [¹¹C]ABP688 BPND across ROIs via higher lifetime drug use (e.g., ventral striatum indirect effect a x b = -0.0224, 95% bootstrap CI [−0.0554, −0.0011]).

Discussion & Conclusions: This study provides the first longitudinal evidence in humans that decreases in mGluR5 availability are related to a wide range of mental health problems. The effects are related to stress yet, across diagnoses, are largely driven by cumulative substance use.