title: Cholinergic Interneurons Underlie Spontaneous Dopamine Release in Nucleus Accumbens.
abstract: The release of dopamine from terminals in the NAc is regulated by a number of factors, including voltage-gated ion channels, D2-autoreceptors, and nAChRs. Cholinergic interneurons (CINs) drive dopamine release through activation of nAChRs on dopamine terminals. Using cyclic voltammetry in mouse brain slices, nAChR-dependent spontaneous dopamine transients and the mechanisms underlying the origin were examined in the NAc. Spontaneous events were infrequent (0.3 per minute), but the rate and amplitude were increased after blocking Kv channels with 4-aminopyridine. Although the firing frequency of CINs was increased by blocking glutamate reuptake with TBOA and the Sk blocker apamin, only 4-aminopyridine increased the frequency of dopamine transients. In contrast, inhibition of CIN firing with the μ/δ selective opioid [Met5]enkephalin (1 μm) decreased spontaneous dopamine transients. Cocaine increased the rate and amplitude of dopamine transients, suggesting that the activity of the dopamine transporter limits the detection of these events. In the presence of cocaine, the rate of spontaneous dopamine transients was further increased after blocking D2-autoreceptors. Blockade of muscarinic receptors had no effect on evoked dopamine release, suggesting that feedback inhibition of acetylcholine release was not involved. Thus, although spontaneous dopamine transients are reliant on nAChRs, the frequency was not strictly governed by the activity of CINs. The increase in frequency of spontaneous dopamine transients induced by cocaine was not due to an increase in cholinergic tone and is likely a product of an increase in detection resulting from decreased dopamine reuptake.SIGNIFICANCE STATEMENTThe actions of dopamine in the NAc are thought to be responsible for endogenous reward and the reinforcing properties of drugs of abuse, such as psychostimulants. The present work examines the mechanisms underlying nAChR-induced spontaneous dopamine release. This study demonstrates that spontaneous dopamine release is (1) dependent of the activation of nicotinic receptors, (2) independent on the spontaneous activity of cholinergic interneurons, and (3) that cocaine increased the detection of dopamine transients by prolonging the presence and increasing the diffusion of dopamine in the extracellular space. The release of acetylcholine is therefore responsible for spontaneous dopamine transients, and cocaine augments dopamine tone without altering activity of cholinergic interneurons.
authors.affiliation: Vollum Institute, Oregon Health & Science University, Portland, Oregon 97239.
authors.forename: Jordan T
authors.identifier: 0000-0002-5687-0676
authors.initials: JT
authors.lastname: Yorgason
authors.affiliation: Vollum Institute, Oregon Health & Science University, Portland, Oregon 97239.
authors.forename: Douglas M
authors.identifier: 0000-0002-1800-649X
authors.initials: DM
authors.lastname: Zeppenfeld
authors.affiliation: Vollum Institute, Oregon Health & Science University, Portland, Oregon 97239 williamj@ohsu.edu.
authors.forename: John T
authors.identifier: 0000-0002-0647-6144
authors.initials: JT
authors.lastname: Williams
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000109:Acetylcholine / Q000378:metabolism* / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000704:Analysis of Variance; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D001224:Aspartic Acid / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology; D004558:Electric Stimulation; D004744:Enkephalin, Methionine / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D007395:Interneurons / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009714:Nucleus Accumbens / Q000166:cytology*; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology
chemical_list: D018765:Dopamine Uptake Inhibitors; D026902:Potassium Channel Blockers; C120673:benzyloxyaspartate; D001030:Apamin; D001224:Aspartic Acid; D004744:Enkephalin, Methionine; D015761:4-Aminopyridine; D003042:Cocaine; D000109:Acetylcholine; D004298:Dopamine
keywords: D2; cocaine; nicotinic; opioid; striatum; voltametry