scholarly journals Axonal mechanisms mediating γ-aminobutyric acid receptor type A (GABA-A) inhibition of striatal dopamine release

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Paul F Kramer ◽  
Emily L Twedell ◽  
Jung Hoon Shin ◽  
Renshu Zhang ◽  
Zayd M Khaliq
Keyword(s):  
Dopamine Release ◽  
Branching Processes ◽  
Striatal Dopamine ◽  
Gaba A ◽  
Cholinergic Interneurons ◽  
Adult Mice ◽  
Receptor Modulation ◽  
Channel Inactivation ◽  
Mechanism Of Inhibition ◽  
Striatal Dopamine Release

Axons of dopaminergic neurons innervate the striatum where they contribute to movement and reinforcement learning. Past work has shown that striatal GABA tonically inhibits dopamine release, but whether GABA-A receptors directly modulate transmission or act indirectly through circuit elements is unresolved. Here, we use whole-cell and perforated-patch recordings to test for GABA-A receptors on the main dopaminergic neuron axons and branching processes within the striatum of adult mice. Application of GABA depolarized axons, but also decreased the amplitude of axonal spikes, limited propagation and reduced striatal dopamine release. The mechanism of inhibition involved sodium channel inactivation and shunting. Lastly, we show the positive allosteric modulator diazepam enhanced GABA-A currents on dopaminergic axons and directly inhibited release, but also likely acts by reducing excitation from cholinergic interneurons. Thus, we reveal the mechanisms of GABA-A receptor modulation of dopamine release and provide new insights into the actions of benzodiazepines within the striatum.

scholarly journals Axonal mechanisms mediating GABA-A receptor inhibition of striatal dopamine release

2020 ◽  
Author(s):  
Paul F. Kramer ◽  
Emily L. Twedell ◽  
Jung Hoon Shin ◽  
Renshu Zhang ◽  
Zayd M. Khaliq
Keyword(s):  
Dopaminergic Neuron ◽  
Dopamine Release ◽  
Branching Processes ◽  
Striatal Dopamine ◽  
Gaba A ◽  
Cholinergic Interneurons ◽  
Receptor Modulation ◽  
Mechanism Of Inhibition ◽  
Midbrain Dopaminergic Neurons ◽  
Striatal Dopamine Release

AbstractAxons of midbrain dopaminergic neurons innervate the striatum where they contribute to movement and reinforcement learning. Past work has shown that striatal GABA tonically inhibits dopamine release, but whether GABA-A receptors directly modulate transmission or act indirectly through circuit elements is unresolved. Here, we use whole-cell and perforated-patch recordings to test for GABA-A receptors on the main dopaminergic neuron axons and branching processes within striatum. Application of GABA depolarized axons, but also decreased the amplitude of axonal spikes, limited propagation and reduced striatal dopamine release. The mechanism of inhibition involved sodium channel inactivation and shunting. Lastly, we show that the positive allosteric modulator diazepam enhanced GABA-A currents on dopaminergic neuron axons and directly inhibited release, but also likely acts by reducing excitatory drive from cholinergic interneurons. Thus, we reveal the mechanisms of GABA-A receptor modulation of dopamine release and provide new insight into the actions of benzodiazepines within the striatum.

scholarly journals Cell-intrinsic effects of TorsinA(ΔE) disrupt dopamine release in a mouse model of DYT1-TOR1A dystonia

2020 ◽  
Author(s):  
Anthony M. Downs ◽  
Xueliang Fan ◽  
Radhika Kadakia ◽  
Yuping Donsante ◽  
H.A. Jinnah ◽  
...  
Keyword(s):  
Dopamine Release ◽  
Ex Vivo ◽  
Dopamine Neurons ◽  
Striatal Dopamine ◽  
Cholinergic Interneurons ◽  
Base Pair Deletion ◽  
Presynaptic Mechanisms ◽  
Conditional Expression ◽  
Striatal Dopamine Release

ABSTRACTDYT1-TOR1A dystonia is an inherited dystonia caused by a three base-pair deletion in the TOR1A gene (TOR1AΔE). Although the mechanisms underlying the dystonic movements are largely unknown, abnormalities in striatal dopamine and acetylcholine neurotransmission are consistently implicated whereby dopamine release is reduced while cholinergic tone is increased. Because striatal cholinergic neurotransmission mediates dopamine release, it is not known if the dopamine release deficit is mediated indirectly by abnormal acetylcholine neurotransmission or if Tor1a(ΔE) acts directly within dopaminergic neurons to attenuate release. To dissect the microcircuit that governs the deficit in dopamine release, we conditionally expressed Tor1a(ΔE) in either dopamine neurons or cholinergic interneurons in mice and assessed striatal dopamine release using ex vivo fast scan cyclic voltammetry or dopamine efflux using in vivo microdialysis. Conditional expression of Tor1a(ΔE) in cholinergic neurons did not affect striatal dopamine release. In contrast, conditional expression of Tor1a(ΔE) in dopamine neurons reduced dopamine release to 50% of normal, which is comparable to the deficit in Tor1a+/ΔE knockin mice that express the mutation ubiquitously. Despite the deficit in dopamine release, we found that the Tor1a(ΔE) mutation does not cause obvious nerve terminal dysfunction as other presynaptic mechanisms, including electrical excitability, vesicle recycling/refilling, Ca2+ signaling, D2 dopamine autoreceptor function and GABAB receptor function, are intact. Although the mechanistic link between Tor1a(ΔE) and dopamine release is unclear, these results clearly demonstrate that the defect in dopamine release is caused by the action of the Tor1a(ΔE) mutation within dopamine neurons.

scholarly journals Insulin enhances striatal dopamine release by activating cholinergic interneurons and thereby signals reward

2015 ◽  
Vol 6 (1) ◽  
Author(s):  
Melissa A. Stouffer ◽  
Catherine A. Woods ◽  
Jyoti C. Patel ◽  
Christian R. Lee ◽  
Paul Witkovsky ◽  
...  
Keyword(s):  
Dopamine Release ◽  
Striatal Dopamine ◽  
Cholinergic Interneurons ◽  
Striatal Dopamine Release

scholarly journals Striatal Dopamine Release Is Triggered by Synchronized Activity in Cholinergic Interneurons

Neuron ◽  
2012 ◽  
Vol 75 (1) ◽  
pp. 58-64 ◽  
Author(s):  
Sarah Threlfell ◽  
Tatjana Lalic ◽  
Nicola J. Platt ◽  
Katie A. Jennings ◽  
Karl Deisseroth ◽  
...  
Keyword(s):  
Dopamine Release ◽  
Striatal Dopamine ◽  
Cholinergic Interneurons ◽  
Striatal Dopamine Release

Nitrogen at Raised Pressure Interacts with the GABAAReceptor to Produce Its Narcotic Pharmacological Effect in the Rat

2001 ◽  
Vol 95 (4) ◽  
pp. 921-927 ◽  
Author(s):  
Hélène N. David ◽  
Norbert Balon ◽  
Jean-Claude Rostain ◽  
Jacques H. Abraini
Keyword(s):  
Locomotor Activity ◽  
Dopamine Release ◽  
Nitrogen Pressure ◽  
Inert Gases ◽  
Striatal Dopamine ◽  
Gamma Aminobutyric Acid ◽  
Gaba A ◽  
Striatal Dopamine Release ◽  
Sedative Action ◽  
Increased Pressure

Background Strong evidence supports the concept that conventional anesthetics, including inhalational agents and inert gases, such as xenon and nitrous oxide, interact directly with ion channel neurotransmitter receptors. However, there is no evidence that nitrogen, which only exhibits narcotic potency at increased pressure, may act by a similar mechanism. Methods We compared the inhibitory and sedative effects of gamma-aminobutyric acid (GABA) and nitrogen pressure on locomotor activity and striatal dopamine release in freely moving rats and investigated the pharmacologic properties of the GABA-induced and nitrogen pressure-induced narcotic action using the highly selective competitive GABA(A) receptor antagonist bicuculine. Results Intracerebroventricular GABA infusion up to 60 micromol or exposure to nitrogen pressure up to 3 MPa decreased to a similar extent striatal dopamine release (r2= 0.899, df = 4, P < 0.01) and locomotor activity (r2 = 0.996, df = 28, P < 0.001). However, both agents only showed small effects on striatal dopamine release, reducing dopamine currents by only 12-13% at sedative concentrations. Pretreatment with bicuculline at 0.5, 1, and 2.5 pmol reduced the sedative action of GABA on locomotor activity by 10, 20, and 41%, respectively. Bicuculline in the nanomole range at 1, 2.5, and 5 nmol but not in the picomole range reduced the sedative action of nitrogen pressure by 5, 37, and 73%, respectively. Schild plot analysis is consistent with the fact that bicuculline is a competitive antagonist of both GABA and nitrogen at pressure. Conclusions These results suggest (1) that the presynaptic effects of both GABA and nitrogen pressure on striatal dopamine transmission are modest and not mainly involved in their sedative action and (2) that nitrogen at increased pressure may interact directly with the GABA(A) receptor. However, because the antagonistic effect of bicuculline on nitrogen sedation only occurred at much higher bicuculline concentrations than seen with GABA, it is suggested that nitrogen does not compete for the same site as GABA.

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