scholarly journals Dopaminylation of histone H3 in ventral tegmental area regulates cocaine seeking

Science ◽  
2020 ◽  
Vol 368 (6487) ◽  
pp. 197-201 ◽  
Author(s):  
Ashley E. Lepack ◽  
Craig T. Werner ◽  
Andrew F. Stewart ◽  
Sasha L. Fulton ◽  
Ping Zhong ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ventral Tegmental Area ◽  
Critical Role ◽  
Histone H3 ◽  
Dopamine Neurons ◽  
Cocaine Seeking ◽  
Seeking Behavior ◽  
Ventral Tegmental ◽  
Midbrain Dopamine ◽  
Transcriptional Plasticity

Vulnerability to relapse during periods of attempted abstinence from cocaine use is hypothesized to result from the rewiring of brain reward circuitries, particularly ventral tegmental area (VTA) dopamine neurons. How cocaine exposures act on midbrain dopamine neurons to precipitate addiction-relevant changes in gene expression is unclear. We found that histone H3 glutamine 5 dopaminylation (H3Q5dop) plays a critical role in cocaine-induced transcriptional plasticity in the midbrain. Rats undergoing withdrawal from cocaine showed an accumulation of H3Q5dop in the VTA. By reducing H3Q5dop in the VTA during withdrawal, we reversed cocaine-mediated gene expression changes, attenuated dopamine release in the nucleus accumbens, and reduced cocaine-seeking behavior. These findings establish a neurotransmission-independent role for nuclear dopamine in relapse-related transcriptional plasticity in the VTA.

scholarly journals NR4A Gene Expression Is Dynamically Regulated in the Ventral Tegmental Area Dopamine Neurons and Is Related to Expression of Dopamine Neurotransmission Genes

2011 ◽  
Vol 46 (3) ◽  
pp. 545-553 ◽  
Author(s):  
Jeffrey B. Eells ◽  
Josiah Wilcots ◽  
Scott Sisk ◽  
Shirley X. Guo-Ross
Keyword(s):  
Gene Expression ◽  
Ventral Tegmental Area ◽  
Dopamine Neurons ◽  
Ventral Tegmental

Differential Modulation by Nicotine of Substantia Nigra Versus Ventral Tegmental Area Dopamine Neurons

2007 ◽  
Vol 98 (6) ◽  
pp. 3388-3396 ◽  
Author(s):  
J. Russel Keath ◽  
Michael P. Iacoviello ◽  
Lindy E. Barrett ◽  
Huibert D. Mansvelder ◽  
Daniel S. McGehee
Keyword(s):  
Substantia Nigra ◽  
Ventral Tegmental Area ◽  
Dorsal Striatum ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Synaptic Modulation ◽  
Afferent Projections ◽  
Ventral Tegmental ◽  
Midbrain Dopamine ◽  
Da Release

Midbrain dopamine (DA) neurons are found in two nuclei, the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA). The SNc dopaminergic projections to the dorsal striatum are involved in voluntary movement and habit learning, whereas the VTA projections to the ventral striatum contribute to reward and motivation. Nicotine induces profound DA release from VTA dopamine neurons but substantially less from the SNc. Nicotinic acetylcholine receptor (nAChR) expression differs between these nuclei, but it is unknown whether there are differences in nAChR expression on the afferent projections to these nuclei. Here we have compared the nicotinic modulation of excitatory and inhibitory synaptic inputs to VTA and SNc dopamine neurons. Although nicotine enhances both the excitatory and inhibitory drive to SNc DA cells with response magnitudes similar to those seen in the VTA, the prevalence of these responses in SNc is much lower. We also found that a mixture of nAChR subtypes underlies the synaptic modulation in SNc, further distinguishing this nucleus from the VTA, where α7 nAChRs enhance glutamate inputs and non-α7 receptors enhance GABA inputs. Finally, we compared the nicotine sensitivity of DA neurons in these two nuclei and found larger response magnitudes in VTA relative to SNc. Thus the observed differences in nicotine-induced DA release from VTA and SNc are likely due to differences in nAChR expression on the afferent inputs as well as on the DA neurons themselves. This may explain why nicotine has a greater effect on behaviors associated with the VTA than the SNc.

scholarly journals Functional evidence for a direct excitatory projection from the lateral habenula to the ventral tegmental area in the rat

2016 ◽  
Vol 116 (3) ◽  
pp. 1161-1174 ◽  
Author(s):  
P. Leon Brown ◽  
Paul D. Shepard
Keyword(s):  
Ventral Tegmental Area ◽  
Dopamine Neurons ◽  
Lateral Habenula ◽  
Aversive Stimuli ◽  
Rat Pups ◽  
Tegmental Nucleus ◽  
Fasciculus Retroflexus ◽  
Ventral Tegmental ◽  
Midbrain Dopamine ◽  
Midbrain Dopamine Neurons

The lateral habenula, a phylogenetically conserved epithalamic structure, is activated by aversive stimuli and reward omission. Excitatory efferents from the lateral habenula predominately inhibit midbrain dopamine neuronal firing through a disynaptic, feedforward inhibitory mechanism involving the rostromedial tegmental nucleus. However, the lateral habenula also directly targets dopamine neurons within the ventral tegmental area, suggesting that opposing actions may result from increased lateral habenula activity. In the present study, we tested the effect of habenular efferent stimulation on dopamine and nondopamine neurons in the ventral tegmental area of Sprague-Dawley rats using a parasagittal brain slice preparation. Single pulse stimulation of the fasciculus retroflexus excited 48% of dopamine neurons and 51% of nondopamine neurons in the ventral tegmental area of rat pups. These proportions were not altered by excision of the rostromedial tegmental nucleus and were evident in both cortical- and striatal-projecting dopamine neurons. Glutamate receptor antagonists blocked this excitation, and fasciculus retroflexus stimulation elicited evoked excitatory postsynaptic potentials with a nearly constant onset latency, indicative of a monosynaptic, glutamatergic connection. Comparison of responses in rat pups and young adults showed no significant difference in the proportion of neurons excited by fasciculus retroflexus stimulation. Our data indicate that the well-known, indirect inhibitory effect of lateral habenula activation on midbrain dopamine neurons is complemented by a significant, direct excitatory effect. This pathway may contribute to the role of midbrain dopamine neurons in processing aversive stimuli and salience.

scholarly journals Inactivation of NMDA Receptors in the Ventral Tegmental Area during Cocaine Self-Administration Prevents GluA1 Upregulation but with Paradoxical Increases in Cocaine-Seeking Behavior

2017 ◽  
Vol 38 (3) ◽  
pp. 575-585 ◽  
Author(s):  
Daniel Guzman ◽  
Maria B. Carreira ◽  
Allyson K. Friedman ◽  
Megumi Adachi ◽  
Rachael L. Neve ◽  
...  
Keyword(s):  
Nmda Receptors ◽  
Ventral Tegmental Area ◽  
Self Administration ◽  
Cocaine Seeking ◽  
Seeking Behavior ◽  
Ventral Tegmental

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

eLife ◽  
2018 ◽  
Vol 7 ◽  
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.

Cannabidiol prevents priming- and stress-induced reinstatement of the conditioned place preference induced by cocaine in mice

2021 ◽  
pp. 026988112096595
Author(s):  
Claudia Calpe-López ◽  
Ani Gasparyan ◽  
Francisco Navarrete ◽  
Jorge Manzanares ◽  
Jose Miñarro ◽  
...  
Keyword(s):  
Gene Expression ◽  
Ventral Tegmental Area ◽  
Conditioned Place Preference ◽  
Cannabis Sativa ◽  
Social Defeat ◽  
Place Preference ◽  
Cocaine Seeking ◽  
Ventral Tegmental ◽  
Relative Gene ◽  
Reinstatement Test

Background: Cocaine dependence is an important problem without any effective pharmacological treatment. Some preclinical studies have suggested that cannabidiol (CBD), a component of the Cannabis sativa plant, could be useful for the treatment of cocaine use disorders. Aims: This work aims to evaluate the ability of CBD to reduce priming- and stress-induced reinstatement of the conditioned place preference (CPP) induced by cocaine. Methods: Young adult CD-1 male mice were allocated to 10 groups ( n = 12/group), conditioned with cocaine (10 mg/kg) and exposed to extinction of CPP (two sessions per week). When extinction was achieved, each group received the corresponding treatment before the reinstatement test. In experiment 1, six groups were used: vehicle+saline (Veh+Sal), 5 mg/kg cocaine alone (Veh+Coc) or with CBD 30 or 60 mg/kg (CBD30+Coc, CBD60+Coc) and CBD alone (CBD30+Sal, CBD60+Sal). In experiment 2, four groups were used: exploration (Veh+Expl), social defeat (Veh+SD) and social defeat with CBD (CBD30+SD and CBD60+SD). Furthermore, the relative gene expression of the dopamine transporter (DAT) in the ventral tegmental area was measured. Results: All mice acquired cocaine CPP and extinguished it after three or four weeks. Only the groups treated with cocaine priming (Veh+Coc) or exposed to social defeat (Veh+SD) showed reinstatement of CPP. Interestingly, CBD itself did not induce reinstatement and blocked the reinstating effects of cocaine priming and social defeat. Furthermore, cocaine priming increased DAT gene expression in the ventral tegmental area and CBD completely reversed this effect. Conclusion: These results suggest that CBD could reduce reinstatement to cocaine seeking after a period of abstinence.

scholarly journals Midbrain dopamine neurons encode internal effort signal

2020 ◽  
Author(s):  
Dong V Wang
Keyword(s):  
Ventral Tegmental Area ◽  
Dopamine Neurons ◽  
Ventral Tegmental ◽  
Midbrain Dopamine ◽  
Midbrain Dopamine Neurons

AbstractMidbrain dopamine neurons of the ventral tegmental area (VTA) play a central role in both positive and negative motivation. As motivation and effort are intrinsically connected, we asked how the VTA dopamine neurons may also process internally driven effort signal. We designed two novel jumping tasks, the reward- and escape-motivated jumps, and revealed that the VTA dopamine neurons exhibit an effort-correlated activation during both jumping behaviors.

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