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The Journal of Neuroscience, May 1, 2000, 20(9):3401-3407

Reversal of Dopamine D₂ Receptor Responses by an Anandamide Transport Inhibitor

Massimiliano Beltramo¹, Fernando Rodríguez de Fonseca², Miguel Navarro², Antonio Calignano⁴, Miguel Angel Gorriti², Gerasimos Grammatikopoulos⁵, Adolfo G. Sadile⁵, Andrea Giuffrida³, and Daniele Piomelli¹

¹ The Neurosciences Institute, San Diego, CA 92121, ² Department of Psychobiology, Complutense University, Madrid, Spain 28233, ³ Department of Pharmacology, University of Naples, Italy, 80131, ⁴ Laboratory of Neurophysiology, Behavior and Neural Networks, II University of Naples, Italy, 80138, and ⁵ Department of Pharmacology, University of California, Irvine, California 92697-4625

We characterized the pharmacological properties of the anandamide transport inhibitor N-(4-hydroxyphenyl)-arachidonamide (AM404) in rats and investigated the effects of this drug on behavioral responses associated with activation of dopamine D₂ family receptors. Rat brain slices accumulated [³H]anandamide via a high-affinity transport mechanism that was blocked by AM404. When administered alone in vivo, AM404 caused a mild and slow-developing hypokinesia that was significant 60 min after intracerebroventricular injection of the drug and was reversed by the CB1 cannabinoid receptor antagonist SR141716A. AM404 produced no significant catalepsy or analgesia, two typical effects of direct-acting cannabinoid agonists. However, AM404 prevented the stereotypic yawning produced by systemic administration of a low dose of apomorphine, an effect that was dose-dependent and blocked by SR141716A. Furthermore, AM404 reduced the stimulation of motor behaviors elicited by the selective D₂ family receptor agonist quinpirole. Finally, AM404 reduced hyperactivity in juvenile spontaneously hypertensive rats, a putative model of attention deficit hyperactivity disorder. The results support a primary role of the endocannabinoid system in the regulation of psychomotor activity and point to anandamide transport as a potential target for neuropsychiatric medicines.

Key words: AM404; anandamide transport; cannabinoid receptors; dopamine receptors; spontaneously hypertensive rats; Wistar-Kyoto rats

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Copyright © 2000 Society for Neuroscience  0270-6474/00/2093401-07$05.00/0

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