title: Cannabinoids enhance subsecond dopamine release in the nucleus accumbens of awake rats.
abstract: Dopaminergic neurotransmission has been highly implicated in the reinforcing properties of many substances of abuse, including marijuana. Cannabinoids activate ventral tegmental area dopaminergic neurons, the main ascending projections of the mesocorticolimbic dopamine system, and change their spiking pattern by increasing the number of impulses in a burst and elevating the frequency of bursts. Although they also increase time-averaged striatal dopamine levels for extended periods of time, little is known about the temporal structure of this change. To elucidate this, fast-scan cyclic voltammetry was used to monitor extracellular dopamine in the nucleus accumbens of freely moving rats with subsecond timescale resolution. Intravenous administration of the central cannabinoid (CB1) receptor agonist, R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-6-yl]-(1-naphthalenyl) methanone mesylate, dose-dependently produced catalepsy, decreased locomotion, and reduced the amplitude of electrically evoked dopamine release while markedly increasing the frequency of detected (nonstimulated) dopamine concentration transients. The CB1 receptor antagonist [N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide] reversed and prevented all agonist-induced effects but did not show effects on dopamine release when injected alone. These data demonstrate that doses of a cannabinoid agonist known to increase burst firing produce ongoing fluctuations in extracellular dopamine on a previously unrecognized temporal scale in the nucleus accumbens.
authors.affiliation: Department of Chemistry, The University of North Carolina, Chapel Hill, North Carolina 27599-3290, USA.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Cheer
authors.forename: Kate M
authors.initials: KM
authors.lastname: Wassum
authors.forename: Michael L A V
authors.initials: ML
authors.lastname: Heien
authors.forename: Paul E M
authors.initials: PE
authors.lastname: Phillips
authors.forename: R Mark
authors.initials: RM
authors.lastname: Wightman
mesh_terms: D000818:Animals; D048588:Benzoxazines; D002186:Cannabinoids / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004563:Electrochemistry; D004567:Electrodes, Implanted; D008297:Male; D008474:Medial Forebrain Bundle / Q000502:physiology; D009025:Morpholines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009281:Naphthalenes / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism*; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D000077285:Rimonabant; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D014851:Wakefulness / Q000502:physiology*
chemical_list: D048588:Benzoxazines; D002186:Cannabinoids; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D000077285:Rimonabant; D004298:Dopamine