title: Nitric oxide donors enhance the frequency dependence of dopamine release in nucleus accumbens.
abstract: Dopamine (DA) neurotransmission in the nucleus accumbens (NAc) is critically involved in normal as well as maladaptive motivated behaviors including drug addiction. Whether the striatal neuromodulator nitric oxide (NO) influences DA release in NAc is unknown. We investigated whether exogenous NO modulates DA transmission in NAc core and how this interaction varies depending on the frequency of presynaptic activation. We detected DA with cyclic voltammetry at carbon-fiber microelectrodes in mouse NAc in slices following stimuli spanning a full range of DA neuron firing frequencies (1-100 Hz). NO donors 3-morpholinosydnonimine hydrochloride (SIN-1) or z-1-[N-(3-ammoniopropyl)-N-(n-propyl)amino]diazen-1-ium-1,2-diolate (PAPA/NONOate) enhanced DA release with increasing stimulus frequency. This NO-mediated enhancement of frequency sensitivity of DA release was not prevented by inhibition of soluble guanylyl cyclase (sGC), DA transporters, or large conductance Ca(2+)-activated K(+) channels, and did not require glutamatergic or GABAergic input. However, experiments to identify whether frequency-dependent NO effects were mediated via changes in powerful acetylcholine-DA interactions revealed multiple components to NO modulation of DA release. In the presence of a nicotinic receptor antagonist (dihydro-β-erythroidine), NO donors increased DA release in a frequency-independent manner. These data suggest that NO in the NAc can modulate DA release through multiple GC-independent neuronal mechanisms whose net outcome varies depending on the activity in DA neurons and accumbal cholinergic interneurons. In the presence of accumbal acetylcholine, NO promotes the sensitivity of DA release to presynaptic activation, but with reduced acetylcholine input, NO will promote DA release in an activity-independent manner through a direct action on dopaminergic terminals.
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK [2] Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK [3] Department of Pharmacology, University of Oxford, Oxford, UK. henrike.hartung@pharm.ox.ac.uk
authors.forename: Henrike
authors.initials: H
authors.lastname: Hartung
authors.forename: Sarah
authors.initials: S
authors.lastname: Threlfell
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Cragg
mesh_terms: D000109:Acetylcholine / Q000502:physiology; D000818:Animals; D004298:Dopamine / Q000378:metabolism*; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018733:Nicotinic Antagonists / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D018733:Nicotinic Antagonists; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D000109:Acetylcholine; D004298:Dopamine