Group II metabotropic glutamate receptors (mGluR2/3) are suggested to modulate anxiety, arousal, and stress including autonomic control. However, no study has investigated mGluR2/3-related effects on baseline autonomic activity and reactivity to emotional challenge in humans as yet. Using a double-blind, randomized placebo-controlled, cross-over study design, we investigated the influence of a 1-week treatment with the mGluR2/3 agonist LY544344, prodrug of LY354740, on autonomic reactivity to a cholecystokinin tetrapeptide (CCK-4) panic challenge in eight healthy young men. The main outcome measures were time and frequency domain heart rate variability parameters during baseline, CCK-4 challenge, and recovery. There was no evidence for LY544344-mediated effects on baseline and CCK-4 challenge vagal activity, but a significantly lower recovery low frequency (%) and low frequency/high frequency ratio in the LY544344 group, suggesting enhanced autonomic recovery. This pilot study provides first human data indicating that mGluR2/3 agonism is involved in autonomic responsiveness, suggesting an important role of mGluR2/3 in central autonomic regulation.