Transient receptor potential vanilloid 1 channels control acetylcholine/2-arachidonoylglicerol coupling in the striatum.
The neurotransmitter acetylcholine (Ach) controls both excitatory and inhibitory synaptic transmission in the striatum. Here, we investigated the involvement of the endocannabinoid system in Ach-mediated inhibition of striatal GABA transmission, and the potential role of transient receptor potential vanilloid 1 (TRPV1) channels in the control of Ach-endocannabinoid coupling. We found that inhibition of Ach degradation and direct pharmacological stimulation of muscarinic M1 receptors reduced striatal inhibitory postsynaptic currents (IPSCs) through the stimulation of 2-arachidonoylglicerol (2AG) synthesis and the activation of cannabinoid CB1 receptors. The effects of M1 receptor activation on IPSCs were occlusive with those of metabotropic glutamate receptor 5 stimulation, and were prevented in the presence of capsaicin, agonist of TRPV1 channels. Elevation of anandamide (AEA) tone with URB597, a blocker of fatty acid amide hydrolase, mimicked the effects of capsaicin, indicating that endogenous AEA acts as an endovanilloid substance in the control of M1-dependent 2AG-mediated synaptic effects in the striatum. Accordingly, both capsaicin and URB597 effects were absent in mice lacking TRPV1 channels. Pharmacological interventions targeting AEA metabolism and TRPV1 channels might be considered alternative therapeutic routes in disorders of striatal cholinergic or endocannabinoid neurotransmission.
Musella
A
A
Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata, Rome, Italy.
De Chiara
V
V
Rossi
S
S
Cavasinni
F
F
Castelli
M
M
Cantarella
C
C
Mataluni
G
G
Bernardi
G
G
Centonze
D
D
D000109:Acetylcholine / Q000378:metabolism*; D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism*; D001549:Benzamides / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002211:Capsaicin / Q000494:pharmacology; D002219:Carbamates / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005989:Glycerides / Q000378:metabolism*; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018721:Muscarinic Agonists / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology; D009924:Organ Culture Techniques; D053284:Polyunsaturated Alkamides / Q000378:metabolism; D064529:Receptor, Metabotropic Glutamate 5; D043643:Receptor, Muscarinic M1 / Q000819:agonists / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists / Q000378:metabolism; D018689:Sensory System Agents / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D050916:TRPV Cation Channels / Q000187:drug effects / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D000099252:Fatty Acid Amide Hydrolases
D000109:Acetylcholine; D000581:Amidohydrolases; D001095:Arachidonic Acids; D001549:Benzamides; D063385:Cannabinoid Receptor Modulators; D002211:Capsaicin; D002219:Carbamates; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005989:Glycerides; D018721:Muscarinic Agonists; D053284:Polyunsaturated Alkamides; D064529:Receptor, Metabotropic Glutamate 5; D043643:Receptor, Muscarinic M1; D018094:Receptors, Metabotropic Glutamate; D018689:Sensory System Agents; D050916:TRPV Cation Channels; D005680:gamma-Aminobutyric Acid; D000099252:Fatty Acid Amide Hydrolases; C493921:TRPV1 protein, mouse; C500528:cyclohexyl carbamic acid 3'-carbamoylbiphenyl-3-yl ester; C094503:glyceryl 2-arachidonate; C078814:anandamide