title: D2 receptor-mediated inhibition of dopamine release in the rat striatum in vitro is modulated by CB1 receptors: studies using fast cyclic voltammetry.
abstract: Cannabinoid CB(1) receptors are highly expressed in the striatum where they are known to be co-localized with dopamine D(2) receptors. There is now strong evidence that cannabinoids modulate dopamine release in the brain. Using fast cyclic voltammetry, single pulse stimulation (0.1 ms; 10 V) was applied every 5 min and peak dopamine release was measured with a carbon fibre microelectrode. Application of the D(2) receptor agonist, quinpirole, inhibited single pulse dopamine overflow in a concentration-dependent manner (IC(50): 3.25 x 10(-8) M). The CB(1) receptor agonist WIN55212-2 (WIN; 1 microM) had no effect on single pulse dopamine release (93.9 +/- 6.6% at 60 min, n = 5) but attenuated the inhibitory effect of quinpirole (30 nM; quinpirole 39.0 +/- 4.2% vs. quinpirole + WIN, 48.2 +/- 3.7%, n = 5, p < 0.05). This affect was antagonized by the CB(1) receptor antagonist [N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] (AM-251, 1 microM). Dopamine release evoked by four pulses delivered at 1 Hz (4P1Hz) and 10 pulses delivered at 5 Hz (10P5Hz) was significantly inhibited by WIN [72.3 +/- 7.9% control (peak 4 to 1 ratio measurement) and 66.9 +/- 3.8% control (area under the curve measurement), respectively, p < 0.05; n = 6 for both]. Prior perfusion of WIN significantly attenuated the effects of quinpirole on multiple pulse-evoked dopamine release (4P1Hz: quinpirole, 28.4 +/- 4.8% vs. WIN + quinpirole, 52.3 +/- 1.2%; 10P5Hz: quinpirole, 29.5 +/- 1.3% vs. WIN + quinpirole, 59.4 +/-7.1%; p < 0.05 for both; n = 6). These effects were also antagonized by AM-251 (1 microM). This is the first report demonstrating a functional, antagonistic interaction between CB(1) receptors and D(2) autoreceptors in regulating rat striatal dopamine release.
authors.affiliation: UCD School of Biomolecular and Biomedical Science, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Carmel
authors.initials: C
authors.lastname: O'Neill
authors.forename: Alex
authors.initials: A
authors.lastname: Evers-Donnelly
authors.forename: David
authors.initials: D
authors.lastname: Nicholson
authors.forename: Kathy M
authors.initials: KM
authors.lastname: O'Boyle
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Connor
mesh_terms: D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D004563:Electrochemistry; D066298:In Vitro Techniques; D008024:Ligands; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000502:physiology*
chemical_list: D048588:Benzoxazines; D018491:Dopamine Agonists; D008024:Ligands; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D017448:Receptors, Dopamine D2; D019257:Quinpirole; C103505:AM 251; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D004298:Dopamine