Protective activation of the endocannabinoid system during ischemia in dopamine neurons.
Endocannabinoids act as neuroprotective molecules promptly released in response to pathological stimuli. Hence, they may represent one component of protection and/or repair mechanisms mobilized by dopamine (DA) neurons under ischemia. Here, we show that the endocannabinoid 2-arachidonoyl-glycerol (2-AG) plays a key role in protecting DA neurons from ischemia-induced altered spontaneous activity both in vitro and in vivo. Accordingly, neuroprotection can be elicited through moderate cannabinoid receptor type-1 (CB1) activation. Conversely, blockade of endocannabinoid actions through CB1 receptor antagonism worsens the outcome of transient ischemia on DA neuronal activity. These findings indicate that 2-AG mediates neuroprotective actions by delaying damage and/or restoring function of DA cells through activation of presynaptic CB1 receptors. Lastly, they point to CB1 receptors as valuable targets in protection of DA neurons against ischemic injury and emphasize the need for a better understanding of endocannabinoid actions in the fine control of DA transmission.
Melis
Miriam
M
Centre of Excellence Neurobiology of Addiction, University of Cagliari, Italy. myriam@unica.it
Pillolla
Giuliano
G
Bisogno
Tiziana
T
Minassi
Alberto
A
Petrosino
Stefania
S
Perra
Simona
S
Muntoni
Anna Lisa
AL
Lutz
Beat
B
Gessa
Gian Luigi
GL
Marsicano
Giovanni
G
Di Marzo
Vincenzo
V
Pistis
Marco
M
D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D048588:Benzoxazines; D002545:Brain Ischemia / Q000503:physiopathology*; D063385:Cannabinoid Receptor Modulators / Q000502:physiology*; D004298:Dopamine / Q000502:physiology*; D004594:Electrophysiology; D063388:Endocannabinoids; D005989:Glycerides / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009474:Neurons / Q000502:physiology*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists; D000077285:Rimonabant; D015398:Signal Transduction / Q000502:physiology; D017557:Ventral Tegmental Area / Q000166:cytology / Q000503:physiopathology; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001095:Arachidonic Acids; D048588:Benzoxazines; D063385:Cannabinoid Receptor Modulators; D004298:Dopamine; D063388:Endocannabinoids; D005989:Glycerides; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D000077285:Rimonabant; D000099252:Fatty Acid Amide Hydrolases; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C094503:glyceryl 2-arachidonate; C109925:AM 281