title: The endocannabinoid 2-arachidonoylglycerol mediates D1 and D2 receptor cooperative enhancement of rat nucleus accumbens core neuron firing.
abstract: Many motivated and addiction-related behaviors are sustained by activity of both dopamine D1- and D2-type receptors (D1Rs and D2Rs) as well as CB1 receptors (CB1Rs) in the nucleus accumbens (NAc). Here, we use in vitro whole-cell patch-clamp electrophysiology to describe an endocannabinoid (eCB)-dopamine receptor interaction in adult rat NAc core neurons. D1R and D2R agonists in combination enhanced firing, with no effect of a D1R or D2R agonist alone. This D1R+D2R-mediated firing increase required CB1Rs, since it was prevented by the CB1R antagonists AM251 and Rimonabant. The D1R+D2R firing increase also required phospholipase C (PLC), the major synthesis pathway for the eCB 2-arachidonoylglycerol (2-AG) and one of several pathways for anandamide. Further, inhibition of 2-AG hydrolysis with the monoglyceride lipase (MGL) inhibitor JZL184 allowed subthreshold levels of D1R+D2R receptor agonists to enhance firing, while inhibition of anandamide hydrolysis with the fatty acid amide hydrolase (FAAH) inhibitors URB597 or AM3506 did not. Filling the postsynaptic neuron with 2-AG enabled subthreshold D1R+D2R agonists to increase firing, and the 2AG+D1R+D2R increase in firing was prevented by a CB1R antagonist. Also, the metabotropic glutamate receptor 5 (mGluR5) blocker MPEP prevented the ability of JZL184 to promote subthreshold D1R+D2R enhancement of firing, while the 2-AG+D1R+D2R increase in firing was not prevented by the mGluR5 blocker, suggesting that mGluR5s acted upstream of 2-AG production. Thus, our results taken together are consistent with the hypothesis that NAc core eCBs mediate dopamine receptor (DAR) enhancement of firing, perhaps providing a cellular mechanism underlying the central role of NAc core D1Rs, D2Rs, CB1Rs, and mGluR5s during many drug-seeking behaviors.
authors.affiliation: Ernest Gallo Clinic and Research Center, University of California, San Francisco, Department of Neurology, 5858 Horton Street, Suite 200, Emeryville, CA 94608, USA.
authors.forename: T
authors.initials: T
authors.lastname: Seif
authors.forename: A
authors.initials: A
authors.lastname: Makriyannis
authors.forename: G
authors.initials: G
authors.lastname: Kunos
authors.forename: A
authors.initials: A
authors.lastname: Bonci
authors.forename: F W
authors.initials: FW
authors.lastname: Hopf
mesh_terms: D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000704:Analysis of Variance; D000818:Animals; D015259:Dopamine Agents / Q000494:pharmacology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005989:Glycerides / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009714:Nucleus Accumbens / Q000166:cytology*; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors; D064529:Receptor, Metabotropic Glutamate 5; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D000077285:Rimonabant; D013997:Time Factors; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D015259:Dopamine Agents; D004791:Enzyme Inhibitors; D005989:Glycerides; C578937:Grm5 protein, rat; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D064529:Receptor, Metabotropic Glutamate 5; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D018094:Receptors, Metabotropic Glutamate; C103505:AM 251; D010738:Type C Phospholipases; C026433:1-arachidonyl monoglyceride; D000077285:Rimonabant