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

• Published in: Life sciences (1973) Vol. 65; no. 3; pp. 327 - 336
• Main Authors: González, S., Romero, J., de Miguel, R., Lastres-Becker, I., Villanua, M.A., Makriyannis, A., Ramos, J.A., Fernández-Ruiz, J.J.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 1999
• Subjects: 3,4-Dihydroxyphenylacetic Acid - metabolism; AM404; anandamide; Animals; Arachidonic Acids - metabolism; Arachidonic Acids - therapeutic use; basal ganglia; Basal Ganglia - drug effects; Basal Ganglia - metabolism; Biological Transport, Active; cannabinoids; Carrier Proteins - metabolism; carrier-mediated transport; Chromatography, High Pressure Liquid; dopamine; Dopamine - metabolism; Electrochemistry; Endocannabinoids; Extrapyramidal Tracts - drug effects; Extrapyramidal Tracts - metabolism; GABA; gamma-Aminobutyric Acid - metabolism; Glutamate Decarboxylase - metabolism; Hypothalamo-Hypophyseal System - drug effects; Hypothalamo-Hypophyseal System - metabolism; hypothalamus/anterior pituitary axis; Luteinizing Hormone - blood; Male; motor activity; N-(4-Hydroxyphenyl)-arachidonylethanolamide; Neurosecretory Systems - drug effects; Pituitary-Adrenal System - drug effects; Pituitary-Adrenal System - metabolism; Polyunsaturated Alkamides; PRL secretion; Prolactin - blood; Rats; Rats, Wistar; Tyrosine 3-Monooxygenase - metabolism; hypothalamus/anterior pituitary axis; basal ganglia; PRL secretion; GABA; cannabinoids; carrier-mediated transport; AM404; anandamide; dopamine; motor activity
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/S0024-3205(99)00251-9

A selective inhibitor of the carrier-mediated transport of endogenous cannabinoids, N-(4-hydroxyphenyl)-arachidonylethanolamide (AM404), has been recently synthesized and proposed as a useful tool for studying the physiological effects of endogenous cannabinoids and as a potential therapeutic agent in a variety of diseases. In the present study, we have examined the effects of this compound in two important brain processes in which a role for anandamide and other endogenous cannabinoids has been claimed: neuroendocrine regulation and extrapyramidal motor activity. A single and well-characterized dose of AM404, which presumably resulted in a significant elevation of the 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 decreased PRL secretion and increased hypothalamic TH activity have been reported to occur after the administration of anandamide. Administration of AM404 also produced a marked motor inhibition in the open-field test, as also reported for anandamide, with a decrease in ambulatory and exploratory activities 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 previously observed for anandamide.