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 /␦ selective opioid [Met 5 ]enkephalin (1 M) 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.

Ultrafast neuronal imaging of dopamine dynamics with designed genetically encoded sensors

“…S8D, E and G), the fluorescence response suggested a 10–30 μM DA release (Fig. 2I), which is 1–2 orders of magnitude higher than previously reported in ventral striatum using fast-scan cyclic voltammetry (FSCV) (25) and is similar to that reported by measuring DRD2 activation (26). Addition of saturating amphetamine (10 μM, in the presence of 400 μM sulpiride) increased tonic dopamine to 3.3 μM (fig.…”

Alterations in the intrinsic properties of striatal cholinergic interneurons after dopamine lesion and chronic L-DOPA

“…Critically, we were able to titrate the concentrations of antagonists to resemble the degree of channel inhibition caused by DA depletion and chronic L-DOPA treatment. Consistent with previous studies, a saturating concentration of apamin caused ChIs to transition into burst firing mode, characterized by increased firing frequency within bursts, long pauses between bursts and decreased average firing frequency (data not shown and (Bennett et al, 2000;Yorgason et al, 2017)). However, when SK channels were only partially inhibited using an IC50 concentration of apamin, the average firing rate of ChIs was increased without an increase in burstiness, closely mimicking changes observed in the ChIs from L-DOPA treated mice.…”

Methamphetamine Induces Dopamine Release in the Nucleus Accumbens Through a Sigma Receptor-Mediated Pathway

“…However, the mechanisms behind ROS-induced increases in DA release are unclear and may involve multiple effects on DA terminals. Furthermore, it is questionable that this effect involves VMAT2 impairment and resultant vesicular depletion, as the VMAT2 inhibitor reserpine only appears to decrease evoked DA release (Yorgason et al, 2017;Gantz et al, 2013). METH-induced ROS formation includes nonenzymatic formation of nitric oxide (Friend et al, 2014).…”