Endocannabinoids activate transient receptor potential vanilloid 1 receptors to reduce hyperdopaminergia-related hyperactivity: therapeutic implications.
BACKGROUND
Knockout (KO) mice invalidated for the dopamine transporter (DAT) constitute a powerful animal model of neurobiological alterations associated with hyperdopaminergia relevant to schizophrenia and attention-deficit/hyperactivity disorder (ADHD).


METHODS
Because of continuously increasing evidence for a neuromodulatory role of endocannabinoids in dopamine-related pathophysiological responses, we assessed endocannabinoid signaling in DAT KO mice and evaluated the ability of endocannabinoid ligands to normalize behavioral deficits, namely spontaneous hyperlocomotion in these mice.


RESULTS
In DAT KO mice, we found markedly reduced anandamide levels, specifically in striatum, the dopamine nerve terminal region. Furthermore, three distinct indirect endocannabinoid agonists, the selective anandamide reuptake inhibitors AM404 and VDM11 and the fatty acid amidohydrolase inhibitor AA5HT, attenuated spontaneous hyperlocomotion in DAT KO mice. The hypolocomotor effects of AM404, VDM11, and AA5HT were significantly attenuated by co-administration of the transient receptor potential vanilloid 1 (TRPV1) antagonist capsazepine but not the selective cannabinoid type 1 (CB1)receptor antagonist AM251. Interestingly, TRPV1 binding was increased in the striatum of DAT KO mice, while CB1 receptor binding was unaffected.


CONCLUSIONS
These data indicate a dysregulated striatal endocannabinoid neurotransmission associated with hyperdopaminergic state. Restoring endocannabinoid homeostasis in active synapses might constitute an alternative therapeutic strategy for disorders associated with hyperdopaminergia. In this process, TRPV1 receptors seem to play a key role and represent a novel promising pharmacological target.
Tzavara
Eleni T
ET
INSERM U-513, Neurobiology and Psychiatry, Université de Médecine, Créteil, France.
Li
Dominic L
DL
Moutsimilli
Larissa
L
Bisogno
Tiziana
T
Di Marzo
Vincenzo
V
Phebus
Lee A
LA
Nomikos
George G
GG
Giros
Bruno
B
D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology; D001289:Attention Deficit Disorder with Hyperactivity / Q000503:physiopathology*; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology* / Q000502:physiology*; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D063388:Endocannabinoids; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D050916:TRPV Cation Channels / Q000187:drug effects / Q000502:physiology*; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D002211:Capsaicin; D004298:Dopamine; D050483:Dopamine Plasma Membrane Transport Proteins; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D012701:Serotonin; D050916:TRPV Cation Channels; D000099252:Fatty Acid Amide Hydrolases; C462953:N-(2-methyl-3-hydroxyphenyl)-5,8,11,14-eicosatetraenamide; C493921:TRPV1 protein, mouse; C114007:arachidonoylserotonin; C071423:capsazepine; C078814:anandamide; C107594:N-(4-hydroxyphenyl)arachidonylamide