Increased dopamine D2 receptor activity in the striatum alters the firing pattern of dopamine neurons in the ventral tegmental area

There is strong evidence that the core deficits of schizophrenia result from dysfunction of the dopamine (DA) system, but details of this dysfunction remain unclear. We previously reported a model of transgenic mice that selectively and reversibly overexpress DA D2 receptors (D2Rs) in the striatum (D2R-OE mice). D2R-OE mice display deficits in cognition and motivation that are strikingly similar to the deficits in cognition and motivation observed in patients with schizophrenia. Here, we show that in vivo, both the firing rate (tonic activity) and burst firing (phasic activity) of identified midbrain DA neurons are impaired in the ventral tegmental area (VTA), but not in the substantia nigra (SN), of D2R-OE mice. Normalizing striatal D2R activity by switching off the transgene in adulthood recovered the reduction in tonic activity of VTA DA neurons, which is concordant with the rescue in motivation that we previously reported in our model. On the other hand, the reduction in burst activity was not rescued, which may be reflected in the observed persistence of cognitive deficits in D2R-OE mice. We have identified a potential molecular mechanism for the altered activity of DA VTA neurons in D2R-OE mice: a reduction in the expression of distinct NMDA receptor subunits selectively in identified mesolimbic DA VTA, but not nigrostriatal DA SN, neurons. These results suggest that functional deficits relevant for schizophrenia symptoms may involve differential regulation of selective DA pathways.

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N-methyl-d-aspartic acid biphasically regulates the biochemical and electrophysiological response of A10 dopamine neurons in the ventral tegmental area: in vivo microdialysis and in vitro electrophysiological studies

Brain Research ◽

10.1016/0006-8993(94)90780-3 ◽

1994 ◽

Vol 666 (2) ◽

pp. 255-262 ◽

Cited By ~ 44

Author(s):

Ting Wang ◽

William T. O'Connor ◽

Urban Ungerstedt ◽

Edward D. French

Keyword(s):

Ventral Tegmental Area ◽

Aspartic Acid ◽

In Vivo Microdialysis ◽

Dopamine Neurons ◽

Electrophysiological Response ◽

Electrophysiological Studies ◽

Ventral Tegmental

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Slow Oscillatory Firing: A Major Firing Pattern of Dopamine Neurons in the Ventral Tegmental Area

Journal of Neurophysiology ◽

10.1152/jn.00317.2005 ◽

2005 ◽

Vol 94 (5) ◽

pp. 3516-3522 ◽

Cited By ~ 30

Author(s):

Wei-Xing Shi

Keyword(s):

Ventral Tegmental Area ◽

Single Unit ◽

Firing Pattern ◽

Receptor Activation ◽

Dopamine Neurons ◽

Interspike Intervals ◽

Firing Activity ◽

Unit Recording ◽

Ventral Tegmental

Using spectral analysis and in vivo single-unit recording in rats, the present study revealed a pronounced slow oscillation (SO) in the firing activity of about half the dopamine (DA) neurons recorded in the ventral tegmental area. DA neurons in this group tended to fire repetitive spike clusters, making them appear to be rhythmic bursting cells. However, only some of these burst-like events met the traditional “80/160 ms” burst criteria entirely. The observation that the SO could be found in nonbursting DA cells, occurred at frequencies different from those of bursts, and persisted after bursts were digitally removed from spike trains further supports the suggestion that the SO is different from the traditionally defined bursting. Interspike intervals (ISIs) had been thought to be bimodally distributed in bursting DA neurons. This study found that some nonbursting DA cells also had a bimodal ISI distribution and a significant number of bursting cells did not. In the majority of cells where less than half the spikes occurred in bursts, a bimodal ISI distribution was highly predictive of the presence of the SO. Results further showed that the generation of the SO required forebrain inputs to DA neurons but not the adrenergic α1 receptor activation responsible for psychostimulant-induced increases in the SO. Taken together, these results suggest that the SO is distinct from the traditionally defined bursting and represents a major firing pattern of DA neurons in the ventral tegmental area.

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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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Increased desensitization of dopamine D2 receptor-mediated response in the ventral tegmental area in the absence of adenosine A2A receptors

Neuroscience ◽

10.1016/j.neuroscience.2011.05.068 ◽

2011 ◽

Vol 190 ◽

pp. 103-111 ◽

Cited By ~ 4

Author(s):

R. Al-Hasani ◽

J.D. Foster ◽

A. Metaxas ◽

C. Ledent ◽

S.M.O. Hourani ◽

...

Keyword(s):

Ventral Tegmental Area ◽

Dopamine D2 Receptor ◽

D2 Receptor ◽

Adenosine A2a Receptors ◽

A2a Receptors ◽

Dopamine D2 ◽

Ventral Tegmental ◽

Adenosine A2a

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Cocaine-induced adaptation of dopamine D2S, but not D2L autoreceptors

eLife ◽

10.7554/elife.31924 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 4

Author(s):

Brooks G Robinson ◽

Alec F Condon ◽

Daniela Radl ◽

Emiliana Borrelli ◽

John T Williams ◽

...

Keyword(s):

Neuronal Excitability ◽

Dopamine D2 Receptor ◽

Splice Variants ◽

D2 Receptor ◽

Receptor Expression ◽

Dopamine Neurons ◽

Cocaine Exposure ◽

Drug Induced ◽

Viral Receptor

The dopamine D2 receptor has two splice variants, D2S (Short) and D2L (Long). In dopamine neurons, both variants can act as autoreceptors to regulate neuronal excitability and dopamine release, but the roles of each variant are incompletely characterized. In a previous study we used viral receptor expression in D2 receptor knockout mice to show distinct effects of calcium signaling on D2S and D2L autoreceptor function (Gantz et al., 2015). However, the cocaine-induced plasticity of D2 receptor desensitization observed in wild type mice was not recapitulated with this method of receptor expression. Here we use mice with genetic knockouts of either the D2S or D2L variant to investigate cocaine-induced plasticity in D2 receptor signaling. Following a single in vivo cocaine exposure, the desensitization of D2 receptors from neurons expressing only the D2S variant was reduced. This did not occur in D2L-expressing neurons, indicating differential drug-induced plasticity between the variants.

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