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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 selective presynaptic GABAB receptor antagonist CGP36216 on spontaneous firing and the influence of the selective presynaptic GABAB receptor antagonist CGP36216 on the effect of morphine on spontaneous firing of VTA-DA neurons in rats.(A) Effect of the selective presynaptic GABAB receptor antagonist CGP36216 on spontaneous firing in VTA-DA neurons. Left panel: representative spontaneous firing traces before and after CGP36216 (100 μM). Middle panel: time course of spontaneous firing before and after CGP36216 (100 μM) (n = 6 cells from four rats). Right panel: average frequency of spontaneous firing before and after CGP36216 (100 μM) (n = 6 cells from four rats, p < 0.05, compared to control before CGP36216). (B) Influence of the selective presynaptic GABAB receptor antagonist CGP36216 on the effect of morphine on spontaneous firing in VTA-DA neurons. Left panel: representative spontaneous firing traces before and after morphine (10 μM) in the presence of CGP36216 (100 μM). Middle panel: time course of spontaneous firing before and after morphine (10 μM) in the presence of CGP36216 (100 μM) (n = 6 cells from four rats). Right panel: average frequency of spontaneous firing before and after morphine (10 μM) in the presence of CGP36216 (100 μM) (n = 6 cells from four rats, p = 0.35, compared to CGP36216 before morphine). Data are shown as the mean ±s.e.m. *p < 0.05.DOI:http://dx.doi.org/10.7554/eLife.09275.012
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fig10: Effect of the selective presynaptic GABAB receptor antagonist CGP36216 on spontaneous firing and the influence of the selective presynaptic GABAB receptor antagonist CGP36216 on the effect of morphine on spontaneous firing of VTA-DA neurons in rats.(A) Effect of the selective presynaptic GABAB receptor antagonist CGP36216 on spontaneous firing in VTA-DA neurons. Left panel: representative spontaneous firing traces before and after CGP36216 (100 μM). Middle panel: time course of spontaneous firing before and after CGP36216 (100 μM) (n = 6 cells from four rats). Right panel: average frequency of spontaneous firing before and after CGP36216 (100 μM) (n = 6 cells from four rats, p < 0.05, compared to control before CGP36216). (B) Influence of the selective presynaptic GABAB receptor antagonist CGP36216 on the effect of morphine on spontaneous firing in VTA-DA neurons. Left panel: representative spontaneous firing traces before and after morphine (10 μM) in the presence of CGP36216 (100 μM). Middle panel: time course of spontaneous firing before and after morphine (10 μM) in the presence of CGP36216 (100 μM) (n = 6 cells from four rats). Right panel: average frequency of spontaneous firing before and after morphine (10 μM) in the presence of CGP36216 (100 μM) (n = 6 cells from four rats, p = 0.35, compared to CGP36216 before morphine). Data are shown as the mean ±s.e.m. *p < 0.05.DOI:http://dx.doi.org/10.7554/eLife.09275.012

Mentions: We studied the influence of the selective presynaptic GABAB receptor antagonist CGP36216 on the effect of morphine on the frequency of spontaneous firing of VTA-DA neurons in rats. First, we observed the effect of CGP36216 on the frequency of spontaneous firing in VTA-DA neurons. The results showed that CGP36216 (100 µM) could increase the frequency of spontaneous firing in VTA-DA neurons (Figure 10A). The average frequency of spontaneous firing increased from 1.8 ± 0.3 Hz before to 2.1 ± 0.3 Hz after CGP36216 application (n = 6 cells from four rats, paired t test, p < 0.05, compared to control before CGP36216, right panel of Figure 10A). Then, we observed the influence of CGP36216 on the effect of morphine on the frequency of spontaneous firing in VTA-DA neurons. As shown by raw spontaneous firing traces (left panel of Figure 10B) and the time course of spontaneous firing (middle panel of Figure 10B) in VTA-DA neurons, the effect of morphine (10 µM) disappeared in the presence of CGP36216 (100 µM). The average frequency of spontaneous firing in VTA-DA neurons was 1.3 ± 0.2 Hz before and 1.2 ± 0.2 Hz for 10–15 min after morphine application in the presence of CGP36216 (n = 6 cells from four rats, paired t test, p > 0.05, compared to CGP36216 before morphine, right panel of Figure 10B).10.7554/eLife.09275.012Figure 10.Effect of the selective presynaptic GABAB receptor antagonist CGP36216 on spontaneous firing and the influence of the selective presynaptic GABAB receptor antagonist CGP36216 on the effect of morphine on spontaneous firing 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 selective presynaptic GABAB receptor antagonist CGP36216 on spontaneous firing and the influence of the selective presynaptic GABAB receptor antagonist CGP36216 on the effect of morphine on spontaneous firing of VTA-DA neurons in rats.(A) Effect of the selective presynaptic GABAB receptor antagonist CGP36216 on spontaneous firing in VTA-DA neurons. Left panel: representative spontaneous firing traces before and after CGP36216 (100 μM). Middle panel: time course of spontaneous firing before and after CGP36216 (100 μM) (n = 6 cells from four rats). Right panel: average frequency of spontaneous firing before and after CGP36216 (100 μM) (n = 6 cells from four rats, p < 0.05, compared to control before CGP36216). (B) Influence of the selective presynaptic GABAB receptor antagonist CGP36216 on the effect of morphine on spontaneous firing in VTA-DA neurons. Left panel: representative spontaneous firing traces before and after morphine (10 μM) in the presence of CGP36216 (100 μM). Middle panel: time course of spontaneous firing before and after morphine (10 μM) in the presence of CGP36216 (100 μM) (n = 6 cells from four rats). Right panel: average frequency of spontaneous firing before and after morphine (10 μM) in the presence of CGP36216 (100 μM) (n = 6 cells from four rats, p = 0.35, compared to CGP36216 before morphine). Data are shown as the mean ±s.e.m. *p < 0.05.DOI:http://dx.doi.org/10.7554/eLife.09275.012
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fig10: Effect of the selective presynaptic GABAB receptor antagonist CGP36216 on spontaneous firing and the influence of the selective presynaptic GABAB receptor antagonist CGP36216 on the effect of morphine on spontaneous firing of VTA-DA neurons in rats.(A) Effect of the selective presynaptic GABAB receptor antagonist CGP36216 on spontaneous firing in VTA-DA neurons. Left panel: representative spontaneous firing traces before and after CGP36216 (100 μM). Middle panel: time course of spontaneous firing before and after CGP36216 (100 μM) (n = 6 cells from four rats). Right panel: average frequency of spontaneous firing before and after CGP36216 (100 μM) (n = 6 cells from four rats, p < 0.05, compared to control before CGP36216). (B) Influence of the selective presynaptic GABAB receptor antagonist CGP36216 on the effect of morphine on spontaneous firing in VTA-DA neurons. Left panel: representative spontaneous firing traces before and after morphine (10 μM) in the presence of CGP36216 (100 μM). Middle panel: time course of spontaneous firing before and after morphine (10 μM) in the presence of CGP36216 (100 μM) (n = 6 cells from four rats). Right panel: average frequency of spontaneous firing before and after morphine (10 μM) in the presence of CGP36216 (100 μM) (n = 6 cells from four rats, p = 0.35, compared to CGP36216 before morphine). Data are shown as the mean ±s.e.m. *p < 0.05.DOI:http://dx.doi.org/10.7554/eLife.09275.012
Mentions: We studied the influence of the selective presynaptic GABAB receptor antagonist CGP36216 on the effect of morphine on the frequency of spontaneous firing of VTA-DA neurons in rats. First, we observed the effect of CGP36216 on the frequency of spontaneous firing in VTA-DA neurons. The results showed that CGP36216 (100 µM) could increase the frequency of spontaneous firing in VTA-DA neurons (Figure 10A). The average frequency of spontaneous firing increased from 1.8 ± 0.3 Hz before to 2.1 ± 0.3 Hz after CGP36216 application (n = 6 cells from four rats, paired t test, p < 0.05, compared to control before CGP36216, right panel of Figure 10A). Then, we observed the influence of CGP36216 on the effect of morphine on the frequency of spontaneous firing in VTA-DA neurons. As shown by raw spontaneous firing traces (left panel of Figure 10B) and the time course of spontaneous firing (middle panel of Figure 10B) in VTA-DA neurons, the effect of morphine (10 µM) disappeared in the presence of CGP36216 (100 µM). The average frequency of spontaneous firing in VTA-DA neurons was 1.3 ± 0.2 Hz before and 1.2 ± 0.2 Hz for 10–15 min after morphine application in the presence of CGP36216 (n = 6 cells from four rats, paired t test, p > 0.05, compared to CGP36216 before morphine, right panel of Figure 10B).10.7554/eLife.09275.012Figure 10.Effect of the selective presynaptic GABAB receptor antagonist CGP36216 on spontaneous firing and the influence of the selective presynaptic GABAB receptor antagonist CGP36216 on the effect of morphine on spontaneous firing 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