Muscarinic regulation of dopamine and glutamate transmission in the nucleus accumbens

Abstract

Cholinergic transmission in the striatum functions as a key modulator of dopamine (DA) transmission and synaptic plasticity, both of which are required for reward and motor learning. Acetylcholine (ACh) can elicit striatal DA release through activation of nicotinic ACh receptors (nAChRs) on DA axonal projections. However, it remains controversial how muscarinic ACh receptors (mAChRs) modulate striatal DA release, with studies reporting both potentiation and depression of striatal DA transmission by mAChR agonists. This study investigates the mAChR-mediated regulation of release from three types of midbrain neurons that project to striatum: DA, DA/glutamate, and glutamate neurons. We found that M5 mAChRs potentiate DA and glutamate release only from DA and DA/glutamate projections from the midbrain. We also show that M2/M4 mAChRs depress the nAChR-dependent mechanism of DA release in the striatum. These results suggest that M5 receptors on DA neuron terminals enhance DA release, whereas M2/M4 autoreceptors on cholinergic terminals inhibit ACh release and subsequent nAChR-dependent DA release. Our findings clarify the mechanisms of mAChR-dependent modulation of DA and glutamate transmission in the striatum.

Nucleus Accumbens Acetylcholine Receptors Modulate Dopamine and Motivation

“…Recently however, activity at M 5 mAChRs on dopamine terminals has been shown to enhance striatal dopamine (Shin et al, 2015). The current result, demonstrating a blunting of cue-and rewardevoked dopamine release by nonselectively blocking NAc mAChR activity, could be achieved by either mechanism, and future work is needed to determine precisely how these different classes of NAc mAChRs influence behaviorallyrelevant dopamine signaling.…”

“…Under some conditions, inactivation of these nAChRs can actually augment the release of dopamine generated by high-frequency stimulation (simulating burst firing) (Rice and Cragg, 2004). Activating mAChR autoreceptors on striatal cholinergic interneurons, which can decrease acetylcholine tone at nAChRs on dopamine terminals, can also augment terminal dopamine release to high-frequency stimulation (Shin et al, 2015;Threlfell et al, 2010). Not only is it well established that reward-predictive cues trigger burst firing in dopamine cells (Schultz, 2001), but there is growing evidence that the resulting dopamine release in the NAc mediates cue-motivated instrumental behavior (Lex and Hauber, 2008;Ostlund et al, 2014b;Peciña and Berridge, 2013).…”

“…Nicotinic acetylcholine receptors (nAChR) on striatal dopamine terminals (Jones et al, 2001) are known to be particularly relevant to the regulation of striatal dopamine signaling (Cachope et al, 2012;Exley et al, 2008a;Threlfell et al, 2012). Muscarinic acetylcholine receptor (mAChR) activity also contributes to dopamine modulation both via regulation of endogenous activity at nAChRs on dopamine terminals (Threlfell et al, 2010) and through activation of mAChRs on dopamine terminals (Foster et al, 2014;Shin et al, 2015).…”

The deletion of M4 muscarinic receptors increases motor activity in females in the dark phase

“…Given the current understanding of M 4 modulation of dopamine signaling and evidence from M 4 KO mice, the impaired cholinergic control of dopamine signaling either directly in the striatum (Cachope & Cheer, 2014; Shin, Adrover, Wess, & Alvarez, 2015), or, in a more complex manner, involving polysynaptic circuits (Tzavara et al., 2004), can be suggested as the underlying mechanism affecting the motor activity and biorhythm in M 4 KO mice. M 4 MR are particularly abundant in striatum, where they modulate dopamine transmission.…”

“…In the recent past, the role of MR in local control of dopamine release in the nucleus accumbens, the ventral striatum, has been clarified. M 2/4 MR have been shown to decrease the dopamine release triggered by stimulation of nicotinic receptors located at dopaminergic terminals via autoinhibition of ACh release (Shin et al., 2015). In the striatum, M 4 serve as the main autoinhibitory receptors (Zhang et al., 2002).…”