anandamide and Dyskinesia--Drug-Induced

L-DOPA-induced dyskinesia (LID) is a frequent complication of chronic L-DOPA therapy in the clinical treatment of Parkinson's disease (PD). The pathogenesis of LID involves complex molecular mechanisms in the striatum. Metabolomics can shed light on striatal metabolic alterations in LID. In the present study, we compared metabolomics profiles of striatum tissue from Parkinsonian rats with or without dyskinetic symptoms after chronic L-DOPA administration. A liquid chromatography-mass spectrometry based global metabolomics method combined with multivariate statistical analyses were used to detect candidate metabolites associated with LID. 36 dysregulated metabolites in the striatum of LID rats, including anandamide, 2-arachidonoylglycerol, adenosine, glutamate and sphingosine1-phosphate were identified. Furthermore, IMPaLA metabolite set analysis software was used to identify differentially regulated metabolic pathways. The results showed that the metabolic pathways of "Retrograde endocannabinoid signaling", "Phospholipase D signaling pathway", "Glycerophospholipid metabolism" and "Sphingolipid signaling", etc. were dysregulated in LID rats compared to non-LID controls. Moreover, integrated pathway analysis based on results from the present metabolomics and our previous gene expression data in LID rats further demonstrates that aberrant "Retrograde endocannabinoid signaling" pathway might be involved in the development of LID. The present results provide a new profile for the understanding of the pathological mechanism of LID.

Topics: Animals; Antiparkinson Agents; Apomorphine; Arachidonic Acids; Biomarkers; Cannabinoid Receptor Agonists; Corpus Striatum; Disease Models, Animal; Dopamine Agonists; Dyskinesia, Drug-Induced; Endocannabinoids; Glycerides; Levodopa; Male; Metabolome; Metabolomics; Motor Activity; Oxidopamine; Parkinsonian Disorders; Polyunsaturated Alkamides; Rats, Sprague-Dawley

Topics: Animals; Anti-Dyskinesia Agents; Arachidonic Acids; Brain; Cannabidiol; Capsaicin; Cyclooxygenase 2; Dyskinesia, Drug-Induced; Endocannabinoids; Extracellular Signal-Regulated MAP Kinases; Histones; Levodopa; Male; Mice, Inbred C57BL; NF-kappa B; Oxidopamine; Parkinsonian Disorders; Polyunsaturated Alkamides; PPAR gamma; Receptor, Cannabinoid, CB1; TRPV Cation Channels; Tyrosine 3-Monooxygenase

Antipsychotics may cause tardive dyskinesia in humans and orofacial dyskinesia in rodents. Although the dopaminergic system has been implicated in these movement disorders, which involve the basal ganglia, their underlying pathomechanisms remain unclear. CB1 cannabinoid receptors are highly expressed in the basal ganglia, and a potential role for endocannabinoids in the control of basal ganglia-related movement disorders has been proposed. Therefore, this study investigated whether CB1 receptors are involved in haloperidol-induced orofacial dyskinesia in rats. Adult male rats were treated for four weeks with haloperidol decanoate (38mg/kg, intramuscularly - i.m.). The effect of anandamide (6nmol, intracerebroventricularly - i.c.v.) and/or the CB1 receptor antagonist SR141716A (30μg, i.c.v.) on haloperidol-induced vacuous chewing movements (VCMs) was assessed 28days after the start of the haloperidol treatment. Anandamide reversed haloperidol-induced VCMs; SR141716A (30μg, i.c.v.) did not alter haloperidol-induced VCM per se but prevented the effect of anandamide on VCM in rats. These results suggest that CB1 receptors may prevent haloperidol-induced VCMs in rats, implicating CB1 receptor-mediated cannabinoid signaling in orofacial dyskinesia.

Topics: Animals; Antipsychotic Agents; Arachidonic Acids; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Disease Models, Animal; Dose-Response Relationship, Drug; Dyskinesia, Drug-Induced; Endocannabinoids; Haloperidol; Male; Mastication; Movement; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats, Wistar; Receptor, Cannabinoid, CB1; Rimonabant; Treatment Outcome

Levodopa is the most commonly prescribed drug for Parkinson's disease (PD). Although levodopa improves PD symptoms in the initial stages of the disease, its long-term use is limited by the development of side effects, including abnormal involuntary movements (dyskinesias) and psychiatric complications. The endocannabinoid system is emerging as an important modulator of basal ganglia functions and its pharmacologic manipulation represents a promising therapy to alleviate levodopa-induced dyskinesias. Rats with 6-OHDA lesions that are chronically treated with levodopa develop increasingly severe axial, limb, locomotor and oro-facial abnormal involuntary movements (AIMs). Administration of the cannabinoid agonist WIN 55,212-2 attenuated levodopa-induced axial, limb and oral AIMs dose-dependently via a CB(1)-mediated mechanism, whereas it had no effect on locomotive AIMs. By contrast, systemic administration of URB597, a potent FAAH inhibitor, did not affect AIMs scoring despite its ability to increase anandamide concentration throughout the basal ganglia. Unlike WIN, anandamide can also bind and activate transient receptor potential vanilloid type-1 (TRPV1) receptors, which have been implicated in the modulation of dopamine transmission in the basal ganglia. Interestingly, URB597 significantly decreased all AIMs subtypes only if co-administered with the TRPV1 antagonist capsazepine. Our data indicate that pharmacological blockade of TRPV1 receptors unmasks the anti-dyskinetic effects of FAAH inhibitors and that CB(1) and TRPV1 receptors play opposite roles in levodopa-induced dyskinesias.

Topics: Amidohydrolases; Animals; Antiparkinson Agents; Arachidonic Acids; Basal Ganglia; Benzamides; Benzoxazines; Cannabinoids; Capsaicin; Carbamates; Drug Therapy, Combination; Dyskinesia, Drug-Induced; Endocannabinoids; Levodopa; Male; Morpholines; Naphthalenes; Oxidopamine; Parkinson Disease, Secondary; Polyunsaturated Alkamides; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; TRPV Cation Channels

Endocannabinoids and cannabinoid CB1 receptors play a role in the control of movement by modulating GABA, glutamate, and other neurotransmitters throughout the basal ganglia. Roles for abnormalities in endocannabinoid signaling in Parkinson's disease (PD) and the major side effect of current treatments, levodopa-induced dyskinesia (LID), have been suggested by rodent studies. Here we show that signaling by endocannabinoids contributes to the pathophysiology of parkinsonism and LID in MPTP-lesioned, non-human primate models of Parkinson's disease. In MPTP-lesioned marmosets previously treated with levodopa to establish LID, attenuation of CB1 signaling by systemic administration of rimonabant (1 and 3 mg/kg) had anti-parkinsonian actions, equivalent to a 71% increase in motor activity at 3 mg/kg. Rimonabant did not elicit dyskinesia. Co-administration of levodopa (8 mg/kg) and rimonabant (1 and 3 mg/kg) resulted in significantly less dyskinesia than levodopa alone, without significantly affecting the anti-parkinsonian action of levodopa. These data suggest that enhanced endocannabinoid signaling may be involved in the pathophysiology of both parkinsonism and LID. To define potential mechanisms by which such a role might be mediated, we determined the levels of the endocannabinoids anandamide and 2-arachidonyl glycerol (2-AG) throughout the basal ganglia in normal and three groups of MPTP-lesioned cynomolgus monkeys (untreated; acutely treated with L-DOPA, non-dyskinetic; long-term treated, with levodopa-induced dyskinesia). In the untreated, MPTP-lesioned primate, parkinsonism was associated with increases in both 2-AG (+88%) and anandamide (+49%) in the striatum, and of 2-AG (+97%) in the substantia nigra, changes that are consistent with the previously suggested role for endocannabinoids in mechanisms attempting to compensate for loss of dopamine in untreated parkinsonism. Increased levels of anandamide (+34%) in the external globus pallidus of MPTP-lesioned animals were normalized by levodopa treatment and may contribute to the generation of parkinsonian symptoms. However, no clear alteration in endocannabinoid levels could be correlated with the expression of LID. These data highlight the potential roles played by endocannabinoids and CB1 in PD and LID and suggest the need for further research to pursue the multiple therapeutic opportunities for manipulating this system in movement disorders.

Topics: Animals; Arachidonic Acids; Callithrix; Cannabinoid Receptor Modulators; Dyskinesia, Drug-Induced; Endocannabinoids; Female; gamma-Aminobutyric Acid; Glycerides; Levodopa; Male; MPTP Poisoning; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Receptor, Cannabinoid, CB1; Rimonabant