Cortical Control of Striatal Dopamine Transmission via Striatal Cholinergic Interneurons

Abstract

Corticostriatal regulation of striatal dopamine (DA) transmission has long been postulated, but ionotropic glutamate receptors have not been localized directly to DA axons. Striatal cholinergic interneurons (ChIs) are emerging as major players in striatal function, and can govern DA transmission by activating nicotinic receptors (nAChRs) on DA axons. Cortical inputs to ChIs have historically been perceived as sparse, but recent evidence indicates that they strongly activate ChIs. We explored whether activation of M1/M2 corticostriatal inputs can consequently gate DA transmission, via ChIs. We reveal that optogenetic activation of channelrhodopsin-expressing corticostriatal axons can drive striatal DA release detected with fast-scan cyclic voltammetry and requires activation of nAChRs on DA axons and AMPA receptors on ChIs that promote short-latency action potentials. By contrast, DA release driven by optogenetic activation of intralaminar thalamostriatal inputs involves additional activation of NMDA receptors on ChIs and action potential generation over longer timescales. Therefore, cortical and thalamic glutamate inputs can modulate DA transmission by regulating ChIs as gatekeepers, through ionotropic glutamate receptors. The different use of AMPA and NMDA receptors by cortical versus thalamic inputs might lead to distinct input integration strategies by ChIs and distinct modulation of the function of DA and striatum.

Chronic ethanol exposure increases inhibition of optically targeted phasic dopamine release in the nucleus accumbens core and medial shell ex vivo

“…While VTA glutamatergic projections may be included in the stimulation field, dopamine terminal fields do not receive direct glutamatergic input (Sulzer et al 2016; Rice et al 2011). Further, optogenetically targeted dopamine release is insensitive to blockade of nicotinic acetylcholine receptors and GABA B receptors (GABA A receptors are not expressed on dopamine terminals) in ex vivo preparations (Melchior et al 2015), which suggests that non-dopaminergic projections from VTA are not cross-modulating dopamine terminals, either directly or indirectly through cholinergic interneurons (Kosillo et al 2016) in this model.…”

N-Methyl-d-aspartate Modulation of Nucleus Accumbens Dopamine Release by Metabotropic Glutamate Receptors: Fast Cyclic Voltammetry Studies in Rat Brain Slices in Vitro

“…A second possibility is that the effect is mediated through cholinergic systems, since ionotropic glutamate receptor activation has been shown to modulate dopamine release in dorsal striatum via cholinergic mechanisms 10,23,24,25 . A third possibility is that mGluR may regulate this effect, since group 2 and 3 mGluR have been reported to be present on dopaminergic terminals in NAc, and activation has been shown decrease accumbal dopamine release through presynaptic mechanisms 26 .…”

“…Three possible indirect routes for this action were considered; via GABAergic systems, given the abundance of GABAergic medium spiny neurones and interneurons in NAc, via cholinergic mechanisms, on the basis of the evidence showing cholinergic modulation of dopamine release in the striatum 10,13,23,24,25 or through mGluR-mediated mechanisms, since mGluR group 2 and 3 receptors are widely distributed in striatal areas, have been shown to be inhibitory, and they decrease dopamine release, probably through presynaptic receptors located on dopamine terminals 29,30 .…”

“…The effects were blocked by the NMDA-R antagonist AP-5, indicating a specific, NMDA-R mediated mechanism, but not by picrotoxin, indicating that an intermediary action via GABA-A receptors is unlikely. Cholinergic systems are known to modulate of striatal dopamine release, through both nicotinic and muscarinic mechanisms 13,23,24,25 . In the present study we found that the α4β2 nicotinic antagonist, DHβE, attenuated the NNDA-R evoked suppression of stimulated dopamine release.…”

Striatal Local Circuitry: A New Framework for Lateral Inhibition

“…While anatomical evidence for axo-axonal synapses in the striatum is still lagging behind, functional data indicates that presynaptic heteroreceptors can be activated quickly and reliable upon neurotransmitter release from other terminals (Cachope et al, 2012; Kosillo et al, 2016; Threlfell et al, 2012; Shin et al, in revisions ). A recent example of an axo-axonal connection that was functionally identified in the striatum is between CINs and dopamine (DA) fibers.…”