Prior stimulation of the endocannabinoid system prevents methamphetamine-induced dopaminergic neurotoxicity in the striatum through activation of CB2 receptors.
Methamphetamine toxicity is associated with cell death and loss of dopamine neuron terminals in the striatum similar to what is found in some neurodegenerative diseases. Conversely, the endocannabinoid system (ECS) has been suggested to be neuroprotective in the brain, and new pharmacological tools have been developed to increase their endogenous tone. In this study, we evaluated whether ECS stimulation could reduce the neurotoxicity of high doses of methamphetamine on the dopamine system. We found that methamphetamine alters the levels of the major endocannabinoids, anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) in the striatum, suggesting that the ECS participates in the brain responses to methamphetamine. Δ(9)-tetrahydrocannabinol (THC), a cannabis-derived agonist of both CB1 and CB2 cannabinoid receptors, or inhibitors of the main enzymes responsible for the degradation of AEA and 2-AG (URB597 and JZL184, respectively), blunted the decrease in striatal protein levels of tyrosine hydroxylase induced by methamphetamine. In addition, antagonists of CB2, but not of CB1, blocked the preventive effects of URB597 and JZL184, suggesting that only the former receptor subtype is engaged in neuroprotection exerted by ECS stimulation. Finally, we found that methamphetamine increases striatal levels of the cytokine tumor necrosis factor alpha, an effect that was blocked by ECS stimulation. Altogether, our results indicate that stimulation of ECS prior to the administration of an overdose of methamphetamine considerably reduces the neurotoxicity of the drug through CB2 receptor activation and highlight a protective function for the ECS against the toxicity induced by drugs and other external insults to the brain. This article is part of the Special Issue entitled 'CNS Stimulants'.
INSERM, U1084, Experimental and Clinical Neurosciences Laboratory, Neurobiology and Neuropharmacology of Addiction, F-86022 Poitiers, France; University of Poitiers, U1084, F-86022 Poitiers, France.
Joëlle
J
Nader
Faculty of Veterinary Medicine, University of Teramo, Teramo, Italy.
Cinzia
C
Rapino
INSERM, U1084, Experimental and Clinical Neurosciences Laboratory, Neurobiology and Neuropharmacology of Addiction, F-86022 Poitiers, France; University of Poitiers, U1084, F-86022 Poitiers, France.
Benjamin
B
Gennequin
University of Poitiers, U1084, F-86022 Poitiers, France; Pharmacology Department, Poitiers University Hospital, Poitiers, France.
Francois
F
Chavant
INSERM, U1084, Experimental and Clinical Neurosciences Laboratory, Neurobiology and Neuropharmacology of Addiction, F-86022 Poitiers, France; University of Poitiers, U1084, F-86022 Poitiers, France.
Maureen
M
Francheteau
Center for Drug Discovery, Department of Pharmaceutical Sciences, and Chemistry and Chemical Biology, Northeastern University, Boston, USA.
Alexandros
A
Makriyannis
Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino "Carlo Bo", Urbino, Italy.
Andrea
A
Duranti
Center of Integrated Research, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy; European Center for Brain Research/IRCCS Santa Lucia Foundation, Via del Fosso di Fiorano 35, 00146 Rome, Italy. Electronic address: m.maccarrone@unicampus.it.
Mauro
M
Maccarrone
INSERM, U1084, Experimental and Clinical Neurosciences Laboratory, Neurobiology and Neuropharmacology of Addiction, F-86022 Poitiers, France; University of Poitiers, U1084, F-86022 Poitiers, France.
Marcello
M
Solinas
INSERM, U1084, Experimental and Clinical Neurosciences Laboratory, Neurobiology and Neuropharmacology of Addiction, F-86022 Poitiers, France; University of Poitiers, U1084, F-86022 Poitiers, France. Electronic address: nathalie.thiriet@univ-poitiers.fr.
Nathalie
N
Thiriet
D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001549:Benzamides / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000633:toxicity*; D013759:Dronabinol / Q000494:pharmacology; D063388:Endocannabinoids / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005989:Glycerides / Q000378:metabolism; D008297:Male; D008694:Methamphetamine / Q000633:toxicity*; D008810:Mice, Inbred C57BL; D017072:Neostriatum / Q000187:drug effects* / Q000378:metabolism; D020258:Neurotoxicity Syndromes / Q000378:metabolism / Q000517:prevention & control*; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D011897:Random Allocation; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D001095:Arachidonic Acids; D001549:Benzamides; D052117:Benzodioxoles; D063385:Cannabinoid Receptor Modulators; D002219:Carbamates; D000697:Central Nervous System Stimulants; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005989:Glycerides; C534333:JZL 184; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D014409:Tumor Necrosis Factor-alpha; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; D008694:Methamphetamine; D013759:Dronabinol; C094503:glyceryl 2-arachidonate; D014446:Tyrosine 3-Monooxygenase; C078814:anandamide
Endocannabinoids; Methamphetamine; Neuroinflammation; Neuroprotection; Neurotoxicity; THC