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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

Effect of GABA on the frequency of sEPSCs and the influence of GABAB receptor antagonist CGP54626 on the effect of GABA on the frequency of sEPSCs in VTA-DA neurons of mice.(A) Effect of GABA on the frequency of sEPSCs in VTA-DA neurons. Left panel: Typical current traces of sEPSC before and after GABA (10 μM). Middle panel: Time course of the frequency of sEPSCs before and after GABA (10 μM). Right panel: Average frequency of sEPSCs before and after GABA (10 μM) (n = 6, P < 0.05, compared to control before GABA). (B) Influence of GABAB receptor antagonist CGP54626 on the effect of GABA. Left panel: Typical current traces of sEPSC before and after GABA (10 μM) in the presence of CGP54626 (2 μM). Middle panel: Time course of the frequency of sEPSCs before and after GABA (10 μM) in the presence of CGP54626 (2 μM). Right panel: Average frequency of sEPSCs before and after GABA (10 μM) in the presence of CGP54626 (2 μM) (n = 6, P > 0.05, compared to CGP54626 before GABA).DOI:http://dx.doi.org/10.7554/eLife.09275.017
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fig13: Effect of GABA on the frequency of sEPSCs and the influence of GABAB receptor antagonist CGP54626 on the effect of GABA on the frequency of sEPSCs in VTA-DA neurons of mice.(A) Effect of GABA on the frequency of sEPSCs in VTA-DA neurons. Left panel: Typical current traces of sEPSC before and after GABA (10 μM). Middle panel: Time course of the frequency of sEPSCs before and after GABA (10 μM). Right panel: Average frequency of sEPSCs before and after GABA (10 μM) (n = 6, P < 0.05, compared to control before GABA). (B) Influence of GABAB receptor antagonist CGP54626 on the effect of GABA. Left panel: Typical current traces of sEPSC before and after GABA (10 μM) in the presence of CGP54626 (2 μM). Middle panel: Time course of the frequency of sEPSCs before and after GABA (10 μM) in the presence of CGP54626 (2 μM). Right panel: Average frequency of sEPSCs before and after GABA (10 μM) in the presence of CGP54626 (2 μM) (n = 6, P > 0.05, compared to CGP54626 before GABA).DOI:http://dx.doi.org/10.7554/eLife.09275.017

Mentions: From raw current traces (left panel of Author response image 1A) and time course of sEPSCs (middle panel of Author response image 1A), we could see that GABA (10 μM) apparently decreased the frequency of sEPSCs. The average frequency of sEPSCs decreased from 3.4 ± 0.2 Hz before to 2.1 ± 0.2 Hz during 10-15 min after GABA (n = 6, paired t test, P < 0.05, compared to control before GABA, right panel of Author response Image 1A). In the presence of GABAB receptor antagonist CGP54626, the effect of GABA on the frequency of sEPSCs disappeared (Author response image 1B). The average frequency of sEPSCs was 3.6 ± 0.4 Hz before to 3.4 ± 0.4 Hz during 10-15 min after GABA in the presence of CGP54626 (2 µM) (n = 6, paired t test, P > 0.05, compared to CGP54626 before GABA, right panel of Author response image 1B).10.7554/eLife.09275.017Author response image 1.Effect of GABA on the frequency of sEPSCs and the influence of GABAB receptor antagonist CGP54626 on the effect of GABA on the frequency of sEPSCs in VTA-DA neurons of mice.


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)

Effect of GABA on the frequency of sEPSCs and the influence of GABAB receptor antagonist CGP54626 on the effect of GABA on the frequency of sEPSCs in VTA-DA neurons of mice.(A) Effect of GABA on the frequency of sEPSCs in VTA-DA neurons. Left panel: Typical current traces of sEPSC before and after GABA (10 μM). Middle panel: Time course of the frequency of sEPSCs before and after GABA (10 μM). Right panel: Average frequency of sEPSCs before and after GABA (10 μM) (n = 6, P < 0.05, compared to control before GABA). (B) Influence of GABAB receptor antagonist CGP54626 on the effect of GABA. Left panel: Typical current traces of sEPSC before and after GABA (10 μM) in the presence of CGP54626 (2 μM). Middle panel: Time course of the frequency of sEPSCs before and after GABA (10 μM) in the presence of CGP54626 (2 μM). Right panel: Average frequency of sEPSCs before and after GABA (10 μM) in the presence of CGP54626 (2 μM) (n = 6, P > 0.05, compared to CGP54626 before GABA).DOI:http://dx.doi.org/10.7554/eLife.09275.017
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Related In: Results  -  Collection

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fig13: Effect of GABA on the frequency of sEPSCs and the influence of GABAB receptor antagonist CGP54626 on the effect of GABA on the frequency of sEPSCs in VTA-DA neurons of mice.(A) Effect of GABA on the frequency of sEPSCs in VTA-DA neurons. Left panel: Typical current traces of sEPSC before and after GABA (10 μM). Middle panel: Time course of the frequency of sEPSCs before and after GABA (10 μM). Right panel: Average frequency of sEPSCs before and after GABA (10 μM) (n = 6, P < 0.05, compared to control before GABA). (B) Influence of GABAB receptor antagonist CGP54626 on the effect of GABA. Left panel: Typical current traces of sEPSC before and after GABA (10 μM) in the presence of CGP54626 (2 μM). Middle panel: Time course of the frequency of sEPSCs before and after GABA (10 μM) in the presence of CGP54626 (2 μM). Right panel: Average frequency of sEPSCs before and after GABA (10 μM) in the presence of CGP54626 (2 μM) (n = 6, P > 0.05, compared to CGP54626 before GABA).DOI:http://dx.doi.org/10.7554/eLife.09275.017
Mentions: From raw current traces (left panel of Author response image 1A) and time course of sEPSCs (middle panel of Author response image 1A), we could see that GABA (10 μM) apparently decreased the frequency of sEPSCs. The average frequency of sEPSCs decreased from 3.4 ± 0.2 Hz before to 2.1 ± 0.2 Hz during 10-15 min after GABA (n = 6, paired t test, P < 0.05, compared to control before GABA, right panel of Author response Image 1A). In the presence of GABAB receptor antagonist CGP54626, the effect of GABA on the frequency of sEPSCs disappeared (Author response image 1B). The average frequency of sEPSCs was 3.6 ± 0.4 Hz before to 3.4 ± 0.4 Hz during 10-15 min after GABA in the presence of CGP54626 (2 µM) (n = 6, paired t test, P > 0.05, compared to CGP54626 before GABA, right panel of Author response image 1B).10.7554/eLife.09275.017Author response image 1.Effect of GABA on the frequency of sEPSCs and the influence of GABAB receptor antagonist CGP54626 on the effect of GABA on the frequency of sEPSCs in VTA-DA neurons of mice.

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