Ethanol Inhibition of M-Current and Ethanol-Induced Direct Excitation of Ventral Tegmental Area Dopamine Neurons

Ethanol-induced excitation of ventral tegmental area dopamine (DA VTA) neurons is thought to be critical for the reinforcing effects of ethanol. Although ligand-gated ion channels are known to be the targets of ethanol, ethanol modulation of voltage-dependent ion channels of central neurons has not been well studied. We have demonstrated that ethanol excites DA VTA neurons by the reduction of sustained K+ currents and recently reported that M-current ( IM) regulates action potential generation through fast and slow afterhyperpolarization phases. In the present study we thus examined whether ethanol inhibition of IM contributes to the excitation of DA VTA neurons using nystatin-perforated patch current- and voltage-clamp recordings. Ethanol (20–120 mM) reduced IM in a concentration-dependent manner and increased the spontaneous firing frequency of DA VTA neurons. Ethanol-induced increase in spontaneous firing frequency correlated positively with ethanol inhibition of IM with a slope value of 1.3. Specific IM inhibition by XE991 (0.3–10 μM) increased spontaneous firing frequency which correlated positively with IM inhibition with a slope value of 0.5. In the presence of 10 μM XE991, a concentration that produced maximal inhibition of IM, ethanol still increased the spontaneous firing frequency of DA VTA neurons in a concentration-dependent manner. Thus we conclude that, although ethanol causes inhibition of IM and this results in some increase in the firing frequency of DA VTA neurons, another effect of ethanol is primarily responsible for the ethanol-induced increase in firing rate in these neurons.

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Serotonin Reduces the Hyperpolarization-Activated Current (Ih) in Ventral Tegmental Area Dopamine Neurons: Involvement of 5-HT2 Receptors and Protein Kinase C

Journal of Neurophysiology ◽

10.1152/jn.00281.2003 ◽

2003 ◽

Vol 90 (5) ◽

pp. 3201-3212 ◽

Cited By ~ 53

Author(s):

Zhaoping Liu ◽

E. Bradshaw Bunney ◽

Sarah B. Appel ◽

Mark S. Brodie

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Ventral Tegmental Area ◽

Kinase Inhibitor ◽

Brain Slices ◽

Dopamine Neurons ◽

Dependent Manner ◽

Cationic Current ◽

Kinase C ◽

Ventral Tegmental

Dopaminergic neurons of the ventral tegmental area (VTA) have been implicated in the rewarding properties of drugs of abuse and in the etiology of schizophrenia; serotonin modulation of these neurons may play a role in these phenomena. Whole cell patch-in-the-slice recording in rat brain slices was used to investigate modulation of the hyperpolarization-activated cationic current Ih by serotonin in these neurons. Serotonin (50-500 μM) reduced the amplitude of Ih in a concentration-dependent manner; this effect was reversible after prolonged washout of serotonin. This effect was mimicked by the 5-HT2 agonist α-methylserotonin (25 μM) and reversed by the 5-HT2 antagonist ketanserin (25 μM). Serotonin reduced the maximal Ih current and conductance (measured at -130 mV) and caused a negative shift in the voltage dependence of Ih activation. The serotonin-induced reduction in Ih amplitude was antagonized by intracellular administration of the nonspecific protein kinase inhibitor H-7 (75 μM) and the selective protein kinase C inhibitor chelerythrine (25 μM). The protein kinase C activator phorbol 12, 13 diacetate (PDA, 2 μM) reduced Ih amplitude; when PDA and serotonin were applied together, the effect on Ih was less than additive. These data support the conclusion that serotonin reduces Ih in dopaminergic VTA neurons by acting at serotonin 5-HT2 receptors, which activate protein kinase C. This reduction of Ih may be physiologically important, as the selective inhibitor of Ih, ZD7288, significantly increased dopamine inhibition of firing rate of dopaminergic VTA neurons, an effect that we previously demonstrated with serotonin.

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Ventral Tegmental Area GABA, glutamate, and glutamate-GABA neurons are heterogenous in their electrophysiological and pharmacological properties

10.1101/2020.07.22.216093 ◽

2020 ◽

Author(s):

Jorge Miranda-Barrientos ◽

Ian Chambers ◽

Smriti Mongia ◽

Bing Liu ◽

Hui-Ling Wang ◽

...

Keyword(s):

Ventral Tegmental Area ◽

Viral Vectors ◽

Ex Vivo ◽

Glutamate Transporter ◽

Receptor Activation ◽

Firing Frequency ◽

Dopamine Neurons ◽

Gaba Neurons ◽

Double Transgenic Mouse ◽

Ventral Tegmental

AbstractThe ventral tegmental area (VTA) contains dopamine neurons intermixed with GABA-releasing (expressing vesicular GABA transporter, VGaT), glutamate-releasing (expressing vesicular glutamate transporter, VGluT2), and co-releasing (co-expressing VGaT and VGluT2) neurons. By delivering INTRSECT viral vectors into VTA of double vglut2-Cre/vgat-Flp transgenic mice, we targeted specific VTA cell populations for ex vivo recordings. We found that VGluT2+ VGaT− and VGluT2+ VGaT+ neurons on average had relatively hyperpolarized resting membrane voltage, greater rheobase, and lower spontaneous firing frequency compared to VGluT2− VGaT+ neurons, suggesting that VTA glutamate-releasing and glutamate-GABA co-releasing neurons require stronger excitatory drive to fire than GABA-releasing neurons. In addition, we detected expression of Oprm1mRNA (encoding μ opioid receptors, MOR) in VGluT2+ VGaT− and VGluT2− VGaT+ neurons, and their hyperpolarization by the MOR agonist DAMGO. Collectively, we demonstrate the utility of the double transgenic mouse to access VTA glutamate, glutamate-GABA and GABA neurons, and show some electrophysiological heterogeneity among them.Impact StatementSome physiological properties of VTA glutamate-releasing and glutamate-GABA co-releasing neurons are distinct from those of VTA GABA-releasing neurons. μ-opioid receptor activation hyperpolarizes some VTA glutamate-releasing and some GABA-releasing neurons.

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Ventral Tegmental Area Microinjected-SKF38393 Increases Regular Chow Intake in 18 Hours Food-Deprived Rats

Basic and Clinical Neuroscience Journal ◽

10.32598/bcn.11.6.2226.1 ◽

2020 ◽

Vol 11 (6) ◽

pp. 773-780

Author(s):

Farzaneh Saebi Rad ◽

◽

Abbas Haghparast ◽

Afsaneh Eliassi ◽

◽

...

Keyword(s):

Food Intake ◽

Ventral Tegmental Area ◽

Dopamine Receptors ◽

Glutamate Release ◽

D1 Receptor ◽

Dopamine Neurons ◽

Dependent Manner ◽

Regulatory Pathways ◽

Serotonergic Receptors ◽

Ventral Tegmental

Introduction: Ventral Tegmental Area (VTA) dopamine neurons play an important role in reward mechanisms of food intake, and VTA dopamine receptors exist on the terminal of glutamatergic and GABAergic neurons and regulate Gamma-Aminobutyric Acid (GABA) and glutamate release. To our knowledge, no evidence indicates any role for VTA D1 dopamine receptors in regular chow intake. Methods: In this paper, different dose of SKF38393, a D1 receptor agonist, was microinjected in VTA of 18-h food deprived-conscious rats and food intake was measured. Results: Our results revealed that VTAmicroinjected SKF383993 increased regular chow intake in a dose-dependent manner. The SKF3833 stimulatory effect persisted over 2 h post-injection. The results showed that the SKF38393, at doses less than 5 μg, did not affect locomotor activities. Conclusion: VTA D1-like and/or serotonergic receptors may be involved in regulatory pathways. the current study suggests that VTA D1-like and/or serotonergic receptors not only affects food reward but is also involved in regulatory mechanisms of regular feeding.

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Characterization of M-Current in Ventral Tegmental Area Dopamine Neurons

Journal of Neurophysiology ◽

10.1152/jn.00574.2005 ◽

2006 ◽

Vol 96 (2) ◽

pp. 535-543 ◽

Cited By ~ 45

Author(s):

Susumu Koyama ◽

Sarah B. Appel

Keyword(s):

Action Potential ◽

Ventral Tegmental Area ◽

Neuronal Excitability ◽

Drugs Of Abuse ◽

Dopamine Neurons ◽

M Current ◽

Potential Shape ◽

Voltage Dependent ◽

Dependent Inhibition ◽

Ventral Tegmental

M-current ( IM) is a voltage-gated potassium current (KCNQ type) that affects neuronal excitability and is modulated by some drugs of abuse. Ventral tegmental area (VTA) dopamine (DA) neurons are important for the reinforcing effects of drugs of abuse. Therefore we studied IM in acutely dissociated rat DA VTA neurons with nystatin-perforated patch recording. The standard deactivation protocol was used to measure IM during voltage-clamp recording with hyperpolarizing voltage steps to −65 mV (in 10-mV increments) from a holding potential of −25 mV. IM amplitude was voltage dependent and maximal current amplitude was detected at −45 mV. The deactivation time constant of IM was voltage dependent and became shorter at more negative voltages. The IM/KCNQ antagonist XE991 (0.3–30 μM) caused a concentration-dependent reduction in IM amplitude with an IC50 of 0.71 μM. Tetraethylammonium (TEA, 0.3–10 mM) caused a concentration-dependent inhibition of IM with an IC50 of 1.56 mM. In current-clamp recordings, all DA VTA neurons were spontaneously active. Analysis of evoked action potential shape indicated that XE991 (1–10 μM) reduced the fast and slow components of the spike afterhyperpolarization (AHP) without affecting the middle component of the AHP. Action potential amplitude, duration, and threshold were not affected by XE991. In addition, 10 μM XE991 significantly shortened the interspike intervals in evoked spike trains. In conclusion, IM is active near threshold in DA VTA neurons, is blocked by XE991 (10 μM) and TEA (10 mM), may contribute to the shape of the AHP, and may decrease excitability of these neurons.

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