Project Summary

Donmienne D. M. Leung, Ph.D. (Young Investigator 2005) of The Scripps Research Institute, proposes studying the biosynthetic enzymes in the brain’s endocannabinoid system, which, Dr. Leung hypothesizes, may be out of balance in schizophrenia. Fatty acid amides (FAAs) represent an emerging family of endogenous brain signaling lipids that modulate several neuroreceptors, including the cannabinoid receptor, and are implicated in many neurophysiological processes, including pain, sleep, anxiety and memory. Fatty acid amide hydrolase (FAAH) is the key regulator of endocannabinoid signaling and modulates different behavioral responses. FAAH inhibitors can augment brain levels of anandamide in rodents and produce analgesia and benzodiazepine-like anti-anxiety effects in vivo, making FAAH a possible target for pain and depression treatment. While FAAH has been characterized, the enzyme(s) involved in the fatty acid amide biosynthesis, in particular anandamide, are mostly uncharacterized. Cannabis consumption is high among schizophrenics and abuse of the substance may trigger psychotic symptom relapse. Elevated FAA concentrations and higher densities of cannabinoid receptors in the dorsolateral prefrontal cortex have been observed in schizophrenics compared to controls, suggesting a link between the endocannabinoid system and schizophrenia. Also, many clinical characteristics of schizophrenia, such as high pain tolerance, may be explained by endocannabinoid system dysregulation. Dr. Leung plans to characterize the enzymes in the endocannabionoid pathway and study the effect of alteration in their behavior in schizophrenia.

Program Area: MULTIPLE FOCUS AREAS\Mood Disorders/Schizophrenia

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