Effects of the metabotropic glutamate type II receptor agonist LY544344 on panic anxiety induced by cholecystokinin tetrapeptide in healthy volunteers

Objective: Preclinical studies have repeatedly shown an anxiolytic-like action of type II metabotropic glutamate receptor agonists, such as LY544344 and LY354740. We tested whether LY544344, a prodrug of LY354740, would 1) reduce cholecystokinin tetrapeptide (CCK–4)-induced panic anxiety and 2) reduce CCK–4 activated stress hormone secretion in normal man.

Methods: Twelve healthy male volunteers were treated with LY544344 (80mg bid po) or placebo for one week each in a double blind, randomized crossover design, with a two-week washout between treatment periods. On day 8 of each treatment period, CCK–4 challenges (50µg iv bolus) were performed at 11: 00. Panic and anxiety were assessed by panic questionnaires and visual analog scales for anxiety and tension. Adrenocorticotropic hormone (ACTH) and cortisol levels were measured from 10: 30 until 13: 00.

Results: Analysis of variance did not show an overall significant main effect for treatment. However, in the 10 subjects who had a lower CCK–4 elicited ACTH release following LY544344 vs. placebo treatment, significantly fewer CCK–4-induced panic symptoms and significantly lower anxiety ratings were detected.

Conclusions: Our preliminary results suggest that additional studies with a larger number of study subjects are needed to further clarify the potential of the metabotropic glutamate type II receptor agonist LY544344 as a new anxiolytic or anti-panic drug in man.