Anxiolytic effects of a novel group II metabotropic glutamate receptor agonist (LY354740) in the fear-potentiated startle paradigm in humans
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LY354740, a structural analogue of glutamate that shows specificity at the mGluR2/3 receptor, has anxiolytic effects in animal models.
This study investigated the anxiolytic effects of LY354740 in humans using the fear-potentiated startle reflex methodology.
Subjects were given either placebo (n=16), 20 mg LY354740 (n=15), or 200 mg LY354740 (n=13). The fear-potentiated startle tests examined startle potentiation to shock anticipation and to darkness.
Consistent with previous results, startle was increased by threat of shock and by darkness. LY354740 did not affect baseline startle. Correspondingly, subjects did not report LY354740 to be sedative. LY354740 significantly reduced the increase in startle magnitude during shock anticipation, but not during darkness. Subjective reports of state anxiety and negative affectivity during the fear-potentiated startle tests were also reduced in a dose-dependent manner by LY354740.
These results suggest that LY354740 has an anxiolytic profile in humans without being sedative.
KeywordsGlutamate LY354740 Fear Anxiolytic Fear-potentiated startle Darkness
The authors acknowledge Lilly Research Laboratories for their financial assistance and for providing LY354740. The work was conducted at Yale University School of Medicine, Department of Psychiatry, New Haven, Conn., USA.
- Dantzer R (1977) Behavioral effects of benzodiazepines: a review. Biobehav Rev 1:71–86Google Scholar
- Davis M, Astrachan DI (1978) Conditioned fear and startle magnitude: effects of different footshock or backshock intensities used during training. J Exp Psychol [Anim Behav Proc] 4:95–103Google Scholar
- Grillon C, Sinha R, O'Malley SS (1994) Effects of ethanol on the acoustic startle reflex in humans. Psychopharmacology 114:167–171Google Scholar
- Grillon C, Ameli R, Goddard A, Woods S, Davis M (1997b) Baseline and fear-potentiated startle in panic disorder patients. Biol Psychiatry 35:431–439Google Scholar
- Kahneman D (1999) Objective hapiness. In: Kahneman D, Diener E, Schwarz N (eds) Well-being: the foundations of hedonic psychology. Russell Sage Foundation, New York, N.Y., pp 3–25Google Scholar
- Kumari V, Cotter P, Corr PJ, Gray JA, Checkley SA (1993) Effect of clonidine on the human acoustic startle reflex. Psychopharmacology 123:353–360Google Scholar
- Landis C, Hunt WA (1939) The startle pattern. Farrar and Rinehart, New YorkGoogle Scholar
- Lang PJ, Bradley MM, Cuthbert BN (1990) Emotion, attention, and the startle reflex. Psychol Rev 97:1–19Google Scholar
- Levine LR, Gaydos B, Sheehan D, et al. (2001) The mGlu2/3 receptor agonist, LY354740, reduces panic anxiety induced by CO2 challenge in patients diagnosed with panic disorder. Neuropharmacology 43:294Google Scholar
- Spielberger CD (1983) Manual for the state-trait anxiety inventory. Consulting Psychologist Press, Palo Alto, Calif.Google Scholar
- Walker DL, Davis M (2000) Quantifying fear-potentiated startle: a comparison of absolute versus percent increase scoring methods. Soc Neurosci Abstr 26:482Google Scholar
- Walker DL, Davis M (2002a) Light-enhanced startle: further pharmacological and behavioral characterization. Psychopharmacology 159:304–310Google Scholar
- Walker DL, Rattiner L, Davis M (2002) Group II metabotropic glutamate receptor within the amygdala regulate anxiety in rats as assessed with fear-potentiated startle. Behav Neurosci 116:1075–1083Google Scholar
- Watson D, Clark LA, Tellegen A (1988) Development and validation of brief measures of positive and negative affect: the PANAS scales. J Person Soc Psychol 54:1063–1070Google Scholar