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Morphine disinhibits glutamatergic input to VTA dopamine neurons and promotes dopamine neuron excitation.

Chen M, Zhao Y, Yang H, Luan W, Song J, Cui D, Dong Y, Lai B, Ma L, Zheng P - Elife (2015)

Bottom Line: However, it is not known whether morphine has an additional strengthening effect on excitatory input.We also studied the contribution of the morphine-induced disinhibitory effect on the presynaptic glutamate release to the overall excitatory effect of morphine on VTA-DA neurons and related behavior.Our results suggest that the disinhibitory action of morphine on presynaptic glutamate release might be the main mechanism for morphine-induced increase in VTA-DA neuron firing and related behaviors.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences and Institutes of Brain Science, Fudan Univeristy, Shanghai, China.

ABSTRACT
One reported mechanism for morphine activation of dopamine (DA) neurons of the ventral tegmental area (VTA) is the disinhibition model of VTA-DA neurons. Morphine inhibits GABA inhibitory neurons, which shifts the balance between inhibitory and excitatory input to VTA-DA neurons in favor of excitation and then leads to VTA-DA neuron excitation. However, it is not known whether morphine has an additional strengthening effect on excitatory input. Our results suggest that glutamatergic input to VTA-DA neurons is inhibited by GABAergic interneurons via GABAB receptors and that morphine promotes presynaptic glutamate release by removing this inhibition. We also studied the contribution of the morphine-induced disinhibitory effect on the presynaptic glutamate release to the overall excitatory effect of morphine on VTA-DA neurons and related behavior. Our results suggest that the disinhibitory action of morphine on presynaptic glutamate release might be the main mechanism for morphine-induced increase in VTA-DA neuron firing and related behaviors.

No MeSH data available.


Related in: MedlinePlus

The presence of GABAB receptors in the presynaptic glutamatergic terminals of the ventral tegmental area (VTA) in rats.(A) GABAB receptor expression in the synaptosomes from the VTA. A representative Western blot shows GABAB receptor expression in the synaptosomes from the VTA. (B) GABAB receptor expression in the VTA shown using the triple-immunofluorescence method. Panel 1: GABAB receptor immunolabeling (green-colored) in the VTA. Panel 2: VGLUT2-labeled axon terminals (red-colored) in the VTA. Panel 3: DA neuron labeled with TH (blue-colored) in the VTA. Panel 4: Merged image (yellow-colored) of GABAB receptors and VGLUT2 in the VTA. The insets marked with small white rectangles in panels 1–4 are magnified views. Scale bars: 5 µm (in panels 1–4); 1 µm (in the insets in panels 1–4).DOI:http://dx.doi.org/10.7554/eLife.09275.009
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fig7: The presence of GABAB receptors in the presynaptic glutamatergic terminals of the ventral tegmental area (VTA) in rats.(A) GABAB receptor expression in the synaptosomes from the VTA. A representative Western blot shows GABAB receptor expression in the synaptosomes from the VTA. (B) GABAB receptor expression in the VTA shown using the triple-immunofluorescence method. Panel 1: GABAB receptor immunolabeling (green-colored) in the VTA. Panel 2: VGLUT2-labeled axon terminals (red-colored) in the VTA. Panel 3: DA neuron labeled with TH (blue-colored) in the VTA. Panel 4: Merged image (yellow-colored) of GABAB receptors and VGLUT2 in the VTA. The insets marked with small white rectangles in panels 1–4 are magnified views. Scale bars: 5 µm (in panels 1–4); 1 µm (in the insets in panels 1–4).DOI:http://dx.doi.org/10.7554/eLife.09275.009

Mentions: We examined the expression of GABAB receptors in the presynaptic terminals of the VTA in rats. Western blotting indicated that GABAB receptors were present in synaptosomes from the VTA (Figure 7A). Immunohistochemistry results for GABAB receptors, VGLUT2 (a glutamatergic terminal marker) and TH (a DA neuron marker) showed that GABAB receptors (green color, panel 1 of Figure 7B), VGLUT2 (red color, panel 2 of Figure 7B) and TH-positive neurons (blue color, panel 3 of Figure 7B) were present in VTA slices and the coexpression of GABAB receptors and VGLUT2 (yellow color, panel 4 of Figure 7B) indicated that GABAB receptors were present in glutamatergic terminals of the VTA in rats. Moreover, this coexpression was close to TH-positive neurons (panel 4 of Figure 7B).10.7554/eLife.09275.009Figure 7.The presence of GABAB receptors in the presynaptic glutamatergic terminals of the ventral tegmental area (VTA) in rats.


Morphine disinhibits glutamatergic input to VTA dopamine neurons and promotes dopamine neuron excitation.

Chen M, Zhao Y, Yang H, Luan W, Song J, Cui D, Dong Y, Lai B, Ma L, Zheng P - Elife (2015)

The presence of GABAB receptors in the presynaptic glutamatergic terminals of the ventral tegmental area (VTA) in rats.(A) GABAB receptor expression in the synaptosomes from the VTA. A representative Western blot shows GABAB receptor expression in the synaptosomes from the VTA. (B) GABAB receptor expression in the VTA shown using the triple-immunofluorescence method. Panel 1: GABAB receptor immunolabeling (green-colored) in the VTA. Panel 2: VGLUT2-labeled axon terminals (red-colored) in the VTA. Panel 3: DA neuron labeled with TH (blue-colored) in the VTA. Panel 4: Merged image (yellow-colored) of GABAB receptors and VGLUT2 in the VTA. The insets marked with small white rectangles in panels 1–4 are magnified views. Scale bars: 5 µm (in panels 1–4); 1 µm (in the insets in panels 1–4).DOI:http://dx.doi.org/10.7554/eLife.09275.009
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Related In: Results  -  Collection

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fig7: The presence of GABAB receptors in the presynaptic glutamatergic terminals of the ventral tegmental area (VTA) in rats.(A) GABAB receptor expression in the synaptosomes from the VTA. A representative Western blot shows GABAB receptor expression in the synaptosomes from the VTA. (B) GABAB receptor expression in the VTA shown using the triple-immunofluorescence method. Panel 1: GABAB receptor immunolabeling (green-colored) in the VTA. Panel 2: VGLUT2-labeled axon terminals (red-colored) in the VTA. Panel 3: DA neuron labeled with TH (blue-colored) in the VTA. Panel 4: Merged image (yellow-colored) of GABAB receptors and VGLUT2 in the VTA. The insets marked with small white rectangles in panels 1–4 are magnified views. Scale bars: 5 µm (in panels 1–4); 1 µm (in the insets in panels 1–4).DOI:http://dx.doi.org/10.7554/eLife.09275.009
Mentions: We examined the expression of GABAB receptors in the presynaptic terminals of the VTA in rats. Western blotting indicated that GABAB receptors were present in synaptosomes from the VTA (Figure 7A). Immunohistochemistry results for GABAB receptors, VGLUT2 (a glutamatergic terminal marker) and TH (a DA neuron marker) showed that GABAB receptors (green color, panel 1 of Figure 7B), VGLUT2 (red color, panel 2 of Figure 7B) and TH-positive neurons (blue color, panel 3 of Figure 7B) were present in VTA slices and the coexpression of GABAB receptors and VGLUT2 (yellow color, panel 4 of Figure 7B) indicated that GABAB receptors were present in glutamatergic terminals of the VTA in rats. Moreover, this coexpression was close to TH-positive neurons (panel 4 of Figure 7B).10.7554/eLife.09275.009Figure 7.The presence of GABAB receptors in the presynaptic glutamatergic terminals of the ventral tegmental area (VTA) in rats.

Bottom Line: However, it is not known whether morphine has an additional strengthening effect on excitatory input.We also studied the contribution of the morphine-induced disinhibitory effect on the presynaptic glutamate release to the overall excitatory effect of morphine on VTA-DA neurons and related behavior.Our results suggest that the disinhibitory action of morphine on presynaptic glutamate release might be the main mechanism for morphine-induced increase in VTA-DA neuron firing and related behaviors.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Medical Neurobiology, Collaborative Innovation Center for Brain Science, School of Basic Medical Sciences and Institutes of Brain Science, Fudan Univeristy, Shanghai, China.

ABSTRACT
One reported mechanism for morphine activation of dopamine (DA) neurons of the ventral tegmental area (VTA) is the disinhibition model of VTA-DA neurons. Morphine inhibits GABA inhibitory neurons, which shifts the balance between inhibitory and excitatory input to VTA-DA neurons in favor of excitation and then leads to VTA-DA neuron excitation. However, it is not known whether morphine has an additional strengthening effect on excitatory input. Our results suggest that glutamatergic input to VTA-DA neurons is inhibited by GABAergic interneurons via GABAB receptors and that morphine promotes presynaptic glutamate release by removing this inhibition. We also studied the contribution of the morphine-induced disinhibitory effect on the presynaptic glutamate release to the overall excitatory effect of morphine on VTA-DA neurons and related behavior. Our results suggest that the disinhibitory action of morphine on presynaptic glutamate release might be the main mechanism for morphine-induced increase in VTA-DA neuron firing and related behaviors.

No MeSH data available.


Related in: MedlinePlus