Extrapyramidal and neuroendocrine effects of AM404, an inhibitor of the carrier-mediated transport of anandamide

A selective inhibitor of the carrier-mediated transport of endogenous canna binoids, N-(4-hydroxyphenyl)-arachidonylethanolamide (AM404), has been rece ntly synthesized and proposed as a useful tool for studying the physiologic al effects of endogenous cannabinoids and as a potential therapeutic agent in a variety of diseases. In the present study, we have examined the effect s of this compound in two important brain processes in which a role for ana ndamide and other endogenous cannabinoids has been claimed: neuroendocrine regulation and extrapyramidal motor activity. A single and well-characteriz ed dose of AM404, which presumably resulted in a significant elevation of t he levels of endogenous cannabinoids, produced a marked decrease in plasma prolactin (PRL) levels, with no changes in luteinizing hormone (LH) levels. This decrease in PRL levels was accompanied by an increase in the activity of tyrosine hydroxylase (TH) in the medial basal hypothalamus. Both decrea sed PRL secretion and increased hypothalamic TH activity have been reported to occur after the administration of anandamide. Administration of AM404 a lso produced a marked motor inhibition in the open-field test, as also repo rted for anandamide, with a decrease in ambulatory and exploratory activiti es and an increase in the time spent in inactivity. This was accompanied by a decrease in the activity of TH in the substantia nigra, an effect also p reviously observed for anandamide.