Hypothalamic glutamate levels following serotonergic stimulation: A pilot study using 7-Tesla magnetic resonance spectroscopy in healthy volunteers

Introduction and purpose

Functional proton magnetic resonance spectroscopy (MRS) can be applied to measure pharmacodynamic effects of central nervous system (CNS)-active drugs. The serotonin precursor 5-hydroxytryptophan (5-HTP), administered together with carbidopa and granisetron to improve kinetics and reduce adverse effects, acutely enhances central serotonergic neurotransmission and induces hypothalamus-pituitary-adrenal-(HPA) axis activation. We studied the hypothalamic levels of glutamate/glutamine (Glx), choline (Chol), N-acetyl-aspartate (NAA) and creatine using 7-Tesla (7 T) MRS, and adrenocorticotropic hormone (ACTH) and cortisol in peripheral blood, after the administration of the 5-HTP function test in healthy volunteers.

Methods

A randomized, double blind, placebo-controlled, two-way cross-over study was performed in 12 healthy males with a 7 day wash-out period. After administration of the oral 5-HTP function test, ACTH and cortisol were measured over 4 h and MRS scans at 7 T were performed every 30 min over 3 h measuring Glx:Creatine, Chol:Creatine and NAA:Creatine ratios.

Results

In the hypothalamus, the administration of 5-HTP had no effect on the average Glx, Chol or NAA levels over 180 min but induced a significant decrease of Glx at 60 min on post-hoc analysis. 5-HTP-induced significant ACTH release reaching an E_max of 60.2 ng/L at 80 min followed by cortisol with an E_max of 246.4 ng/mL at 110 min.

Conclusions

The reduction in hypothalamic Glx levels after serotonergic stimulation is compatible with activation of excitatory neurons in this region, which is expected to cause depletion of local glutamate stores. The hypothalamic MRS-response reached its maximum prior to subsequent increases of ACTH and cortisol, which support the functional relevance of hypothalamic Glx-depletion for activation of the HPA-axis. This exploratory study shows that MRS is capable of detecting neuronal activation following functional stimulation of a targeted brain area.