Hippocampal α5-GABAA receptors modulate dopamine neuron activity in the rat ventral tegmental area

Dopamine is an essential neurotransmitter that plays an important role in a number of different physiological processes and disorders. There is substantial evidence that the neuropeptide neurotensin interacts with the mesolimbic dopamine system and can regulate dopamine neuron activity. In these studies we have used whole cell patch-clamp electrophysiology in brain slices from mice to examine how neurotensin regulates dopamine neuron activity by examining the effect of neurotensin on the inhibitory postsynaptic current generated by somatodendritic dopamine release (D2R IPSC) in ventral tegmental area (VTA) dopamine neurons. Neurotensin inhibited the D2R IPSC and activated an inward current in VTA dopamine neurons that appeared to be at least partially mediated by activation of a transient receptor potential C-type channel. Neither the inward current nor the inhibition of the D2R IPSC was affected by blocking PKC or calcium release from intracellular stores, and the inhibition of the D2R IPSC was greater with neurotensin compared with activation of other Gq-coupled receptors. Interestingly, the effects of neurotensin were not specific to D2R signaling as neurotensin also inhibited GABAB inhibitory postsynaptic currents in VTA dopamine neurons. Finally, the effects of neurotensin were significantly larger when intracellular Ca2+ was strongly buffered, suggesting that reduced intracellular calcium facilitates these effects. Overall these results suggest that neurotensin may inhibit the D2R and GABAB IPSCs downstream of receptor activation, potentially through regulation of G protein-coupled inwardly rectifying potassium channels. These studies provide an important advance in our understanding of dopamine neuron activity and how it is controlled by neurotensin.

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HCN2 channels in the ventral tegmental area regulate behavioral responses to chronic stress

eLife ◽

10.7554/elife.32420 ◽

2018 ◽

Vol 7 ◽

Cited By ~ 20

Author(s):

Peng Zhong ◽

Casey R Vickstrom ◽

Xiaojie Liu ◽

Ying Hu ◽

Laikang Yu ◽

...

Keyword(s):

Ventral Tegmental Area ◽

Chronic Stress ◽

Ex Vivo ◽

Critical Role ◽

Dopamine Neuron ◽

Dopamine Neurons ◽

Neuron Activity ◽

Hcn Channels ◽

Neuron Firing ◽

Ventral Tegmental

Dopamine neurons in the ventral tegmental area (VTA) are powerful regulators of depression-related behavior. Dopamine neuron activity is altered in chronic stress-based models of depression, but the underlying mechanisms remain incompletely understood. Here, we show that mice subject to chronic mild unpredictable stress (CMS) exhibit anxiety- and depressive-like behavior, which was associated with decreased VTA dopamine neuron firing in vivo and ex vivo. Dopamine neuron firing is governed by voltage-gated ion channels, in particular hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Following CMS, HCN-mediated currents were decreased in nucleus accumbens-projecting VTA dopamine neurons. Furthermore, shRNA-mediated HCN2 knockdown in the VTA was sufficient to recapitulate CMS-induced depressive- and anxiety-like behavior in stress-naïve mice, whereas VTA HCN2 overexpression largely prevented CMS-induced behavioral deficits. Together, these results reveal a critical role for HCN2 in regulating VTA dopamine neuronal activity and depressive-related behaviors.

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Long-lasting synaptic regulation of dopamine neurons by astrocytes in the Ventral Tegmental Area

10.21203/rs.3.rs-301561/v1 ◽

2021 ◽

Author(s):

Linda Requie ◽

Marta Gómez-Gonzalo ◽

Francesca Managò ◽

Mauro Congiu ◽

Marcello Melone ◽

...

Keyword(s):

Ventral Tegmental Area ◽

Metabotropic Glutamate Receptor ◽

Receptor Activation ◽

Dopamine Neuron ◽

Dopamine Neurons ◽

Neuron Activity ◽

Astrocytic Process ◽

Metabotropic Glutamate ◽

Ventral Tegmental

Abstract The plasticity of glutamatergic transmission in the Ventral Tegmental Area (VTA) represents a fundamental mechanism in the modulation of dopamine neuron burst firing and the phasic dopamine release at VTA target regions. These processes encode basic behavioral responses, including locomotor activity, learning and motivated-behaviors. Here we describe a hitherto unidentified mechanism of long-lasting potentiation of glutamatergic synapses on DA neurons. We found that VTA astrocytes respond to dopamine neuron bursts with Ca2+ elevations that require activation of endocannabinoid CB1 and dopamine D2 receptors colocalized at the same astrocytic process. Astrocytes, in turn, release glutamate that, through presynaptic metabotropic glutamate receptor activation coupled with neuronal nitric oxide production, induces long-lasting potentiation of excitatory synapses on adjacent dopamine neurons. Consistent with this finding, selective activation of VTA astrocytes increases dopamine neuron bursts in vivo and induces locomotor hyperactivity. Astrocytes play, therefore, a key role in the modulation of VTA dopamine neuron activity.

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