Experimental parkinsonism alters anandamide precursor synthesis, and functional deficits are improved by AM404: a modulator of endocannabinoid function.
Modulation of the endocannabinoid system might be useful in treating Parkinson's disease. Here, we show that systemic administration of N-(4-hydroxyphenyl)-arachidonamide (AM404), a cannabinoid modulator that enhances anandamide (AEA) availability in the biophase, exerts antiparkinsonian effects in 6-hydroxydopamine-lesioned rats. Local injections of AM404 into denervated striata reduced parkinsonian motor asymmetries, these effects being associated with the reduction of D2 dopamine receptor function together with a positive modulation of 5-HT(1B) serotonin receptor function. Stimulation of striatal 5-HT(1B) receptors alone was observed to ameliorate parkinsonian deficits, supporting the fact that AM404 exerts antiparkinsonian effects likely through stimulation of striatal 5-HT(1B) serotonin receptor function. Hence, modulation of cannabinoid function leading to enhancement of AEA in the biophase might be of therapeutic value in the control of symptoms of Parkinson's disease. On the other hand, reduced levels of N-acyl-transferase (AEA precursor synthesizing enzyme), without changes in fatty acid amidohydrolase (AEA degradative enzyme), were detected in denervated striata in comparison with intact striata. This finding reveals the presence of a homeostatic striatal mechanism emerging after dopaminergic denervation likely tending to enhance low dopamine tone.