J Neural Transm (1997) 104:299-305 _Journal of_ Neural Transmission 9 Springer-Verlag 1997 Printed in Austria Inositol has behavioral effects with adaptation after chronic administration H. Cohen, M. Kotler, Z. Kaplan, M. A. Matar, O. Kofman, and R. H. Belmaker Ministry of Health Mental Health Center, Faculty of Health Sciences, Ben Gurion University of the Negev, Beersheva, Israel Accepted October 25, 1996 Summary. Inositol is a simple dietary polyol that serves as a precursor in important second messenger systems. Inositol in pharmacological doses has been reported recently to be therapeutic in depression, panic disorder and obsessive compulsive disorder. We hereby report effects of inositol in the elevated plus maze model of anxiety. These results should allow development of new inositol analogs that could expand psychoactive drug development possibilities via second messenger manipulation. Keywords: Inositol, PI cycle, anxiety, animal model. Introduction Inositol is a simple polyol precursor of phosphatidylinositol (PI). PI is a key juncture of intracellular second messenger generation in response to several important brain neurotransmitters (Baraban et al., 1989). The enzyme which generates PI from inositol (and cytidine monophosphate phosphatidic acid (CMP-PA)) has been reported to be unsaturated at physiological inositol concentrations (Ghalayini et al., 1985). Lithium (Li) reduces brain inositol by inhibiting inositol-monophosphatase, the enzyme required for regeneration of inositol from inositol-triphosphate (IP3) degradation products or from glucose. The role of this Li-induced reduction of inositol in lithium's mecha- nism of action is controversial (Jope et al., 1994). Some groups have found that Li-induced reduction of inositol does not affect PI turnover, whereas others have reported effects of inositol to reverse lithium's effects on behavior (Kofman et al., 1993a). The dose of inositol necessary to reverse lithium effects in animals, in vitro or in vivo, is high (Again et al., 1994; Kofman et al., 1993). Effects of inositol on human behavior were first studied by Levine et al. (1995a) who found antidepressant effects of 12gm daily inositol over four weeks in a double-blind controlled trial. Benjamin etal. (1995) reported anti-