title: A critical interaction between dopamine D2 receptors and endocannabinoids mediates the effects of cocaine on striatal gabaergic Transmission.
abstract: Compelling evidence indicates that endocannabinoids are implicated in drug addiction. In the present study, we have addressed the interaction between cocaine and endocannabinoid system by means of neurochemical and neurophysiological experiments in rat brain slices. Using gas chromatography-electron impact mass spectrometry, we have found that cocaine increased the levels of the endocannabinoid anandamide in the striatum, a brain area primarily involved in the compulsive drug-seeking and drug-taking behaviors typical of addiction. This effect was attenuated by pharmacological inhibition of D2-like receptors but not D1-like receptors, and it was mimicked by D2-like but not D1-like receptor stimulation. The cocaine-induced increase in anandamide concentrations was attributable to both stimulation of its synthesis and inhibition of its degradation, as suggested by the ability of cocaine and quinpirole, a D2-like receptor agonist, to enhance the activity of NAPE-phospholipase D and to inhibit fatty acid amide hydrolase. By means of electrophysiological recordings from single striatal neurons, we have then observed that the ability of cocaine to inhibit, via D2-like receptors, GABA transmission was partially prevented following blockade of cannabinoid receptors, suggesting that endocannabinoids may act as downstream effectors in the action of cocaine in the striatum. Understanding the molecular and physiological effects of drugs of abuse in the brain is essential for the development of effective strategies against addiction.
authors.affiliation: Clinica Neurologica, Dipartimento di Neuroscienze, Università Tor Vergata & IRCCS Fondazione Santa Lucia, Rome, Italy.
authors.forename: Diego
authors.initials: D
authors.lastname: Centonze
authors.forename: Natalia
authors.initials: N
authors.lastname: Battista
authors.forename: Silvia
authors.initials: S
authors.lastname: Rossi
authors.forename: Nicola B
authors.initials: NB
authors.lastname: Mercuri
authors.forename: Alessandro
authors.initials: A
authors.lastname: Finazzi-Agrò
authors.forename: Giorgio
authors.initials: G
authors.lastname: Bernardi
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
authors.forename: Mauro
authors.initials: M
authors.lastname: Maccarrone
mesh_terms: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000493:pharmacokinetics / Q000494:pharmacology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology; D003042:Cocaine / Q000494:pharmacology*; D003511:Cyclohexanols / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004594:Electrophysiology; D063388:Endocannabinoids; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D017072:Neostriatum / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D053284:Polyunsaturated Alkamides; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000187:drug effects / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects*; D013574:Synaptosomes / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000502:physiology*; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D000581:Amidohydrolases; D001095:Arachidonic Acids; D003042:Cocaine; D003511:Cyclohexanols; D018491:Dopamine Agonists; D013759:Dronabinol; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D019257:Quinpirole; D043884:Receptor, Cannabinoid, CB1; D017448:Receptors, Dopamine D2; D005680:gamma-Aminobutyric Acid; D000099252:Fatty Acid Amide Hydrolases; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; C062018:HU 211; C078814:anandamide