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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 the GABAB receptor antagonist CGP54626 and the GABAA receptor antagonist PTX on the frequency of sEPSCs of VTA-DA neurons in rats.(A) Effect of the GABAB receptor antagonist CGP54626 on the frequency of sEPSCs in VTA-DA neurons. Left panel: typical current traces of sEPSCs before and after CGP54626 (2 μM). Middle panel: typical time course of the frequency of sEPSCs in DA neurons before and after CGP54626 (2 μM). Right panel: average frequency of sEPSCs before and after CGP54626 (2 μM) (n = 6 cells from four rats, p < 0.05, compared to control before CGP54626). (B) Effect of the GABAA receptor antagonist PTX on the frequency of sEPSCs in VTA-DA neurons. Left panel: typical current traces of sEPSCs before and after PTX (100 μM). Middle panel: typical time course of the frequency of sEPSCs before and after PTX (100 μM). Right panel: average frequency of sEPSCs before and after PTX (100 μM) (n = 6 cells from four rats, p = 0.29). Data are shown as the mean ±s.e.m. *p < 0.05.DOI:http://dx.doi.org/10.7554/eLife.09275.010
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fig8: Effect of the GABAB receptor antagonist CGP54626 and the GABAA receptor antagonist PTX on the frequency of sEPSCs of VTA-DA neurons in rats.(A) Effect of the GABAB receptor antagonist CGP54626 on the frequency of sEPSCs in VTA-DA neurons. Left panel: typical current traces of sEPSCs before and after CGP54626 (2 μM). Middle panel: typical time course of the frequency of sEPSCs in DA neurons before and after CGP54626 (2 μM). Right panel: average frequency of sEPSCs before and after CGP54626 (2 μM) (n = 6 cells from four rats, p < 0.05, compared to control before CGP54626). (B) Effect of the GABAA receptor antagonist PTX on the frequency of sEPSCs in VTA-DA neurons. Left panel: typical current traces of sEPSCs before and after PTX (100 μM). Middle panel: typical time course of the frequency of sEPSCs before and after PTX (100 μM). Right panel: average frequency of sEPSCs before and after PTX (100 μM) (n = 6 cells from four rats, p = 0.29). Data are shown as the mean ±s.e.m. *p < 0.05.DOI:http://dx.doi.org/10.7554/eLife.09275.010

Mentions: In addition, to determine whether there is basal GABAergic inhibitory control through GABAB receptors on presynaptic glutamate release in VTA-DA neurons, we observed the effect of the GABAB receptor antagonist CGP54626 on the frequency of sEPSCs in rats. The results showed that after the application of CGP54626, the frequency of sEPSCs significantly increased (Figure 8A). The average frequency of sEPSCs was 3.6 ± 0.3 Hz before and 4.5 ± 0.3 Hz for 10–15 min after CGP54626 application (2 µM) (n = 6 cells from four rats, paired t test, p < 0.05, compared to control before CGP54626, right panel of Figure 8A). However, the GABAA receptor antagonist PTX had no significant effect on the frequency of sEPSCs (Figure 8B). The average frequency of sEPSCs was 5.8 ± 1.0 Hz before and 5.7 ± 0.9 Hz for 10–15 min after PTX (100 µM) application (n = 6 cells from four rats, paired t test, p > 0.05, compared to control before PTX, right panel of Figure 8B). This is consistent with the above result showing that GABA-mediated inhibition of presynaptic glutamate release in VTA-DA neurons is via GABAB receptors rather than GABAA receptors.10.7554/eLife.09275.010Figure 8.Effect of the GABAB receptor antagonist CGP54626 and the GABAA receptor antagonist PTX on the frequency of sEPSCs of VTA-DA neurons 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)

Effect of the GABAB receptor antagonist CGP54626 and the GABAA receptor antagonist PTX on the frequency of sEPSCs of VTA-DA neurons in rats.(A) Effect of the GABAB receptor antagonist CGP54626 on the frequency of sEPSCs in VTA-DA neurons. Left panel: typical current traces of sEPSCs before and after CGP54626 (2 μM). Middle panel: typical time course of the frequency of sEPSCs in DA neurons before and after CGP54626 (2 μM). Right panel: average frequency of sEPSCs before and after CGP54626 (2 μM) (n = 6 cells from four rats, p < 0.05, compared to control before CGP54626). (B) Effect of the GABAA receptor antagonist PTX on the frequency of sEPSCs in VTA-DA neurons. Left panel: typical current traces of sEPSCs before and after PTX (100 μM). Middle panel: typical time course of the frequency of sEPSCs before and after PTX (100 μM). Right panel: average frequency of sEPSCs before and after PTX (100 μM) (n = 6 cells from four rats, p = 0.29). Data are shown as the mean ±s.e.m. *p < 0.05.DOI:http://dx.doi.org/10.7554/eLife.09275.010
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4538365&req=5

fig8: Effect of the GABAB receptor antagonist CGP54626 and the GABAA receptor antagonist PTX on the frequency of sEPSCs of VTA-DA neurons in rats.(A) Effect of the GABAB receptor antagonist CGP54626 on the frequency of sEPSCs in VTA-DA neurons. Left panel: typical current traces of sEPSCs before and after CGP54626 (2 μM). Middle panel: typical time course of the frequency of sEPSCs in DA neurons before and after CGP54626 (2 μM). Right panel: average frequency of sEPSCs before and after CGP54626 (2 μM) (n = 6 cells from four rats, p < 0.05, compared to control before CGP54626). (B) Effect of the GABAA receptor antagonist PTX on the frequency of sEPSCs in VTA-DA neurons. Left panel: typical current traces of sEPSCs before and after PTX (100 μM). Middle panel: typical time course of the frequency of sEPSCs before and after PTX (100 μM). Right panel: average frequency of sEPSCs before and after PTX (100 μM) (n = 6 cells from four rats, p = 0.29). Data are shown as the mean ±s.e.m. *p < 0.05.DOI:http://dx.doi.org/10.7554/eLife.09275.010
Mentions: In addition, to determine whether there is basal GABAergic inhibitory control through GABAB receptors on presynaptic glutamate release in VTA-DA neurons, we observed the effect of the GABAB receptor antagonist CGP54626 on the frequency of sEPSCs in rats. The results showed that after the application of CGP54626, the frequency of sEPSCs significantly increased (Figure 8A). The average frequency of sEPSCs was 3.6 ± 0.3 Hz before and 4.5 ± 0.3 Hz for 10–15 min after CGP54626 application (2 µM) (n = 6 cells from four rats, paired t test, p < 0.05, compared to control before CGP54626, right panel of Figure 8A). However, the GABAA receptor antagonist PTX had no significant effect on the frequency of sEPSCs (Figure 8B). The average frequency of sEPSCs was 5.8 ± 1.0 Hz before and 5.7 ± 0.9 Hz for 10–15 min after PTX (100 µM) application (n = 6 cells from four rats, paired t test, p > 0.05, compared to control before PTX, right panel of Figure 8B). This is consistent with the above result showing that GABA-mediated inhibition of presynaptic glutamate release in VTA-DA neurons is via GABAB receptors rather than GABAA receptors.10.7554/eLife.09275.010Figure 8.Effect of the GABAB receptor antagonist CGP54626 and the GABAA receptor antagonist PTX on the frequency of sEPSCs of VTA-DA neurons 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