Hyperpolarization-Activated Cation Current (Ih) Is an Ethanol Target in Midbrain Dopamine Neurons of Mice

Ethanol stimulates the firing activity of midbrain dopamine (DA) neurons, leading to enhanced dopaminergic transmission in the mesolimbic system. This effect is thought to underlie the behavioral reinforcement of alcohol intake. Ethanol has been shown to directly enhance the intrinsic pacemaker activity of DA neurons, yet the cellular mechanism mediating this excitation remains poorly understood. The hyperpolarization-activated cation current, Ih, is known to contribute to the pacemaker firing of DA neurons. To determine the role of Ih in ethanol excitation of DA neurons, we performed patch-clamp recordings in acutely prepared mouse midbrain slices. Superfusion of ethanol increased the spontaneous firing frequency of DA neurons in a reversible fashion. Treatment with ZD7288, a blocker of Ih, irreversibly depressed basal firing frequency and significantly attenuated the stimulatory effect of ethanol on firing. Furthermore, ethanol reversibly augmented Ih amplitude and accelerated its activation kinetics. This effect of ethanol was accompanied by a shift in the voltage dependence of Ih activation to more depolarized potentials and an increase in the maximum Ih conductance. Cyclic AMP mediated the depolarizing shift in Ih activation but not the increase in the maximum conductance. Finally, repeated ethanol treatment in vivo induced downregulation of Ih density in DA neurons and an accompanying reduction in the magnitude of ethanol stimulation of firing. These results suggest an important role of Ih in the reinforcing actions of ethanol and in the neuroadaptations underlying escalation of alcohol consumption associated with alcoholism.

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Calcium dynamics control K-ATP channel-mediated bursting in substantia nigra dopamine neurons: a combined experimental and modeling study

Journal of Neurophysiology ◽

10.1152/jn.00351.2017 ◽

2018 ◽

Vol 119 (1) ◽

pp. 84-95 ◽

Cited By ~ 11

Author(s):

Christopher Knowlton ◽

Sylvie Kutterer ◽

Jochen Roeper ◽

Carmen C. Canavier

Keyword(s):

Substantia Nigra ◽

Activity Patterns ◽

Receptor Activation ◽

Burst Firing ◽

Dopamine Neurons ◽

Open Probability ◽

Midbrain Dopamine

Burst firing in medial substantia nigra (mSN) dopamine (DA) neurons has been selectively linked to novelty-induced exploration behavior in mice. Burst firing in mSN DA neurons, in contrast to lateral SN DA neurons, requires functional ATP-sensitive potassium (K-ATP) channels both in vitro and in vivo. However, the precise role of K-ATP channels in promoting burst firing is unknown. We show experimentally that L-type calcium channel activity in mSN DA neurons enhances open probability of K-ATP channels. We then generate a mathematical model to study the role of Ca2+ dynamics driving K-ATP channel function in mSN DA neurons during bursting. In our model, Ca2+ influx leads to local accumulation of ADP due to Ca-ATPase activity, which in turn activates K-ATP channels. If K-ATP channel activation reaches levels sufficient to terminate spiking, rhythmic bursting occurs. The model explains the experimental observation that, in vitro, coapplication of NMDA and a selective K-ATP channel opener, NN414, is required to elicit bursting as follows. Simulated NMDA receptor activation increases the firing rate and the rate of Ca2+ influx, which increases the activation of K-ATP. The model suggests that additional sources of hyperpolarization, such as GABAergic synaptic input, are recruited in vivo for burst termination or rebound burst discharge. The model predicts that NN414 increases the sensitivity of the K-ATP channel to ADP, promoting burst firing in vitro, and that that high levels of Ca2+ buffering, as might be expected in the calbindin-positive SN DA neuron subpopulation, promote rhythmic bursting pattern, consistent with experimental observations in vivo. NEW & NOTEWORTHY Recently identified distinct subpopulations of midbrain dopamine neurons exhibit differences in their two primary activity patterns in vivo: tonic (single spike) firing and phasic bursting. This study elucidates the biophysical basis of bursts specific to dopamine neurons in the medial substantia nigra, enabled by ATP-sensitive K+ channels and necessary for novelty-induced exploration. A better understanding of how dopaminergic signaling differs between subpopulations may lead to therapeutic strategies selectively targeted to specific subpopulations.

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Neuroprotective Potential of a Small Molecule RET Agonist in Cultured Dopamine Neurons and Hemiparkinsonian Rats

Journal of Parkinson s Disease ◽

10.3233/jpd-202400 ◽

2021 ◽

pp. 1-24

Author(s):

Juho-Matti Renko ◽

Arun Kumar Mahato ◽

Tanel Visnapuu ◽

Konsta Valkonen ◽

Mati Karelson ◽

...

Keyword(s):

Mapk Signaling ◽

Dopamine Neurons ◽

Dopamine Depletion ◽

Wild Type ◽

Disease Modifying Therapy ◽

Immortalized Cells ◽

Midbrain Dopamine ◽

6 Hydroxydopamine

Background: Parkinson’s disease (PD) is a progressive neurological disorder where loss of dopamine neurons in the substantia nigra and dopamine depletion in the striatum cause characteristic motor symptoms. Currently, no treatment is able to halt the progression of PD. Glial cell line-derived neurotrophic factor (GDNF) rescues degenerating dopamine neurons both in vitro and in animal models of PD. When tested in PD patients, however, the outcomes from intracranial GDNF infusion paradigms have been inconclusive, mainly due to poor pharmacokinetic properties. Objective: We have developed drug-like small molecules, named BT compounds that activate signaling through GDNF’s receptor, the transmembrane receptor tyrosine kinase RET, both in vitro and in vivo and are able to penetrate through the blood-brain barrier. Here we evaluated the properties of BT44, a second generation RET agonist, in immortalized cells, dopamine neurons and rat 6-hydroxydopamine model of PD. Methods: We used biochemical, immunohistochemical and behavioral methods to evaluate the effects of BT44 on dopamine system in vitro and in vivo. Results: BT44 selectively activated RET and intracellular pro-survival AKT and MAPK signaling pathways in immortalized cells. In primary midbrain dopamine neurons cultured in serum-deprived conditions, BT44 promoted the survival of the neurons derived from wild-type, but not from RET knockout mice. BT44 also protected cultured wild-type dopamine neurons from MPP +-induced toxicity. In a rat 6-hydroxydopamine model of PD, BT44 reduced motor imbalance and could have protected dopaminergic fibers in the striatum. Conclusion: BT44 holds potential for further development into a novel, possibly disease-modifying therapy for PD.

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Midbrain dopaminergic innervation of the hippocampus is sufficient to modulate formation of aversive memories

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2111069118 ◽

2021 ◽

Vol 118 (40) ◽

pp. e2111069118

Author(s):

Theodoros Tsetsenis ◽

Julia K. Badyna ◽

Julianne A. Wilson ◽

Xiaowen Zhang ◽

Elizabeth N. Krizman ◽

...

Keyword(s):

Dopaminergic Neurons ◽

Dorsal Hippocampus ◽

Memory Formation ◽

Dopamine Neurons ◽

Substantia Nigra Pars Compacta ◽

Aversive Learning ◽

Contextual Fear ◽

Dopaminergic Transmission ◽

Midbrain Dopaminergic Neurons ◽

Midbrain Dopamine

Aversive memories are important for survival, and dopaminergic signaling in the hippocampus has been implicated in aversive learning. However, the source and mode of action of hippocampal dopamine remain controversial. Here, we utilize anterograde and retrograde viral tracing methods to label midbrain dopaminergic projections to the dorsal hippocampus. We identify a population of midbrain dopaminergic neurons near the border of the substantia nigra pars compacta and the lateral ventral tegmental area that sends direct projections to the dorsal hippocampus. Using optogenetic manipulations and mutant mice to control dopamine transmission in the hippocampus, we show that midbrain dopamine potently modulates aversive memory formation during encoding of contextual fear. Moreover, we demonstrate that dopaminergic transmission in the dorsal CA1 is required for the acquisition of contextual fear memories, and that this acquisition is sustained in the absence of catecholamine release from noradrenergic terminals. Our findings identify a cluster of midbrain dopamine neurons that innervate the hippocampus and show that the midbrain dopamine neuromodulation in the dorsal hippocampus is sufficient to maintain aversive memory formation.

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Queer Currents, Steady Rhythms, and Drunken DA Neurons. Focus on “Hyperpolarization-Activated Cation Current (Ih) Is an Ethanol Target in Midbrain Dopamine Neurons of Mice”

Journal of Neurophysiology ◽

10.1152/jn.00957.2005 ◽

2006 ◽

Vol 95 (2) ◽

pp. 585-586 ◽

Cited By ~ 7

Author(s):

Carl R. Lupica ◽

Mark S. Brodie

Keyword(s):

Dopamine Neurons ◽

Cation Current ◽

Midbrain Dopamine ◽

Midbrain Dopamine Neurons

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Opposing effects of APP/PS1 and TrkB.T1 genotypes on midbrain dopamine neurons and stimulated dopamine release in vivo

Brain Research ◽

10.1016/j.brainres.2015.07.006 ◽

2015 ◽

Vol 1622 ◽

pp. 452-465 ◽

Cited By ~ 1

Author(s):

E. Kärkkäinen ◽

L. Yavich ◽

P.O. Miettinen ◽

H. Tanila

Keyword(s):

Dopamine Release ◽

Dopamine Neurons ◽

Midbrain Dopamine ◽

Opposing Effects ◽

Midbrain Dopamine Neurons

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In vivo functional diversity of midbrain dopamine neurons within identified axonal projections

eLife ◽

10.7554/elife.48408 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 10

Author(s):

Navid Farassat ◽

Kauê Machado Costa ◽

Strahinja Stojanovic ◽

Stefan Albert ◽

Lora Kovacheva ◽

...

Keyword(s):

Functional Diversity ◽

Multiple Scales ◽

Dopamine Neurons ◽

Unit Recording ◽

Axonal Projections ◽

Intact Brain ◽

Functional Topography ◽

Midbrain Dopamine

Functional diversity of midbrain dopamine (DA) neurons ranges across multiple scales, from differences in intrinsic properties and connectivity to selective task engagement in behaving animals. Distinct in vitro biophysical features of DA neurons have been associated with different axonal projection targets. However, it is unknown how this translates to different firing patterns of projection-defined DA subpopulations in the intact brain. We combined retrograde tracing with single-unit recording and labelling in mouse brain to create an in vivo functional topography of the midbrain DA system. We identified differences in burst firing among DA neurons projecting to dorsolateral striatum. Bursting also differentiated DA neurons in the medial substantia nigra (SN) projecting either to dorsal or ventral striatum. We found differences in mean firing rates and pause durations among ventral tegmental area (VTA) DA neurons projecting to lateral or medial shell of nucleus accumbens. Our data establishes a high-resolution functional in vivo landscape of midbrain DA neurons.

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