Abstract
The cellular mechanisms regulating dopamine (DA) release in the striatum have attracted much interest in recent years. By in vitro amperometric recordings in mouse striatal slices, we show that a brief (5 min) exposure to the metabotropic glutamate receptor agonist DHPG (50 μM) induces a profound depression of synaptic DA release, lasting over 1 h from DHPG washout. This long-term depression is sensitive to glycine, which preferentially inhibits local cholinergic interneurons, as well as to drugs acting on nicotinic acetylcholine receptors and to the pharmacological depletion of released acetylcholine. The same DHPG treatment induces a parallel long-lasting enhancement in the tonic firing of presumed striatal cholinergic interneurons, measured with multi-electrode array recordings. When DHPG is bilaterally infused in vivo in the mouse striatum, treated mice display an anxiety-like behavior. Our results demonstrate that metabotropic glutamate receptors stimulation gives rise to a prolonged depression of the striatal dopaminergic transmission, through a sustained enhancement of released acetylcholine, due to the parallel long-lasting potentiation of striatal cholinergic interneurons firing. This plastic interplay between dopamine, acetylcholine, and glutamate in the dorsal striatum may be involved in anxiety-like behavior typical of several neuropsychiatric disorders.
Highlights
Dopamine (DA) is a catecholamine playing a crucial role in a variety of human and animal behaviors, spanning from control in the precision of movements to higher cognitive functions, including learning, memory, decision making, and seeking behavior associated to reward (Groenewegen, 2003; Nelson and Kreitzer, 2014; Schultz, 2016; Westbrook et al, 2021)
In the presence of DHPG (50 μM), a sharp reduction of evoked DA release was observed (35.98 ± 3.60% of control), that only partially recovered at DHPG washout, attaining (59.72 ± 4.59% of control, n = 23 slices from nine animals) after 60 min (Figure 1), giving rise to a DHPG-induced long-term depression of the DAergic transmission (DA-LTD)
According to post hoc analysis with Bonferroni’s test, we found that DA release may undergo a sustained depression (DA-LTD) was not significantly different from that induced with no added drugs, in the presence of 1 μM sulpiride
Summary
Dopamine (DA) is a catecholamine playing a crucial role in a variety of human and animal behaviors, spanning from control in the precision of movements to higher cognitive functions, including learning, memory, decision making, and seeking behavior associated to reward (Groenewegen, 2003; Nelson and Kreitzer, 2014; Schultz, 2016; Westbrook et al, 2021). It is mostly through the striatum that the DAergic transmission exerts its fundamental role in motor control and in cognitive behavior as well as in neuropsychiatric symptoms (Weintraub et al, 2005; Tritsch and Sabatini, 2012; Thobois et al, 2017) With these premises, it is not surprising that much experimental effort has been put in recent years in trying to uncover all the subtle cellular and molecular mechanisms participating in the modulation of striatal DA release, through the convergence of intrinsic and extrinsic synaptic circuitries within the striatum (Zhang and Sulzer, 2004; Cachope and Cheer, 2014; Sulzer et al, 2016). NAChRs facilitate DA release, a narrow window of extracellular ACh appears to be required, as depression of DA release can be achieved under higher ACh release, possibly due to nAChRs desensitization (Zhou et al, 2001; Wang et al, 2014)
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