Brain Glutamate Dynamics Predict Positive Agency in Healthy Women

Contributions of brain glutamate to conscious emotion are not well understood. Here we evaluate the relationship of experimentally-induced change in neocortical glutamate (ΔGlu) and subjective states in well individuals. Drug challenge with d-amphetamine (AMP; 20 mg oral), methamphetamine (MA; Desoxyn^®, 20 mg oral), and placebo (PBO) was conducted on three separate test days in a within-subjects double blind design. Proton magnetic resonance spectroscopy (MRS) quantified neurometabolites in the right dorsal anterior cingulate cortex (dACC) 140-150 m post-drug and PBO. Subjective states were assessed at half hour intervals over 5.5-hours on each session, yielding 3,792 responses per participant (91,008 responses overall, N=24 participants). Self-reports were reduced by principal components analysis to a single factor score of AMP- and MA-induced Positive Agency (ΔPA) in each participant. We found drug-induced ΔGlu related positively with ΔPA (ΔGluMA r=+.44, p<.05, N=21), with large effects in females (ΔGluMA r=+.52, p<.05; ΔGluAMP r=+.61, p<.05, N=11). States related to ΔGlu in females included rise in subjective stimulation, vigor, friendliness, elation, positive mood, positive affect (r's=+.51 to +.74, p<.05), and alleviation of anxiety (r=-.61, p<.05, N=11). Self-reports correlated with DGlu to the extent they loaded on ΔPA (r=.95 AMP, p=5×10^-10; r=.63 MA, p=.0015, N=11), indicating coherence of ΔGlu effects. Timing data indicated Glu shaped emotion both concurrently and prospectively, with no relationship to pre-MRS emotion (ΔGluAMP r=+.59 to +.65, p's<.05; ΔGluMA r=+.53, p<.05, N=11). Together these findings indicate substantive, mechanistic contributions of neocortical Glu to positive agentic states in healthy individuals, most readily observed in women.