Hypothalamic glutamate levels following serotonergic stimulation: a pilot study using 7-Tesla magnetic resonance spectroscopy in healthy volunteers.
OBJECTIVE
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 (7T) 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 7day wash-out period. After administration of the oral 5-HTP function test, ACTH and cortisol were measured over 4h and MRS scans at 7T were performed every 30min over 3h 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 180min but induced a significant decrease of Glx at 60min on post-hoc analysis. 5-HTP-induced significant ACTH release reaching an E(max) of 60.2ng/L at 80min followed by cortisol with an E(max) of 246.4ng/mL at 110min.


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.
Centre for Human Drug Research, Leiden, The Netherlands. gjacobs@chdr.nl
G E
GE
Jacobs
J van
Jv
der Grond
W M
WM
Teeuwisse
T J C
TJ
Langeveld
J
J
van Pelt
J C M
JC
Verhagen
M L
ML
de Kam
A F
AF
Cohen
F G
FG
Zitman
J M A
JM
van Gerven
D006916:5-Hydroxytryptophan / Q000494:pharmacology*; D000324:Adrenocorticotropic Hormone / Q000097:blood; D000328:Adult; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D002230:Carbidopa / Q000494:pharmacology; D002794:Choline / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology; D004311:Double-Blind Method; D018698:Glutamic Acid / Q000187:drug effects*; D005973:Glutamine / Q000378:metabolism; D017829:Granisetron / Q000494:pharmacology; D006801:Humans; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010865:Pilot Projects; D018490:Serotonin Agents / Q000494:pharmacology*; D013997:Time Factors; D055815:Young Adult
D006916:5-Hydroxytryptophan; D000324:Adrenocorticotropic Hormone; D001224:Aspartic Acid; D002230:Carbidopa; D002794:Choline; D015259:Dopamine Agents; D018698:Glutamic Acid; D005973:Glutamine; D017829:Granisetron; D018490:Serotonin Agents; C000179:N-acetylaspartate