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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

Influence of the GABAA receptor antagonist PTX and the GABAB receptor antagonist CGP54626 on the effect of exogenous application of GABA as well as the influence of the GABAB receptor antagonist CGP54626 on 470 nm light-induced inhibition of the frequency of sEPSCs in VTA-DA neurons.(A) Influence of the GABAA receptor antagonist PTX on the effect of exogenous application of GABA of VTA-DA neurons in rats. Left panel: typical current traces of sEPSC before and after GABA (10 μM) in the presence of PTX (100 μM). Middle panel: typical time course of the frequency of sEPSCs before and after GABA (10 μM) in the presence of PTX (100 μM). Right panel: average frequency of sEPSCs before and after GABA (10 μM) in the presence of PTX (100 μM) (n = 6 cells from four rats, p < 0.05, compared to PTX before GABA). (B) Influence of the GABAB receptor antagonist CGP54626 on the effect of exogenous application of GABA of VTA-DA neurons in rats. Left panel: typical current traces of sEPSC before and after GABA (10 μM) in the presence of CGP54626 (2 μM). Middle panel: typical 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 cells from four rats, p = 0.87). (C) Influence of the GABAB receptor antagonist CGP54626 on 470 nm light-induced inhibition of the frequency of sEPSCs of VTA-DA neurons in mice. Left panel: typical current traces of sEPSCs before and after blue light (470 nm) stimulation in the presence of CGP54626 (2 μM). Middle panel: typical time course of the frequency of sEPSCs before and after blue light (470 nm) stimulation in the presence of CGP54626 (2 μM). Right panel: average frequency of sEPSCs before and after blue light (470 nm) stimulation in the presence of CGP54626 (2 μM) (n = 6 cells from five mice, p = 0.21). Data are shown as the mean ±s.e.m. *p < 0.05.DOI:http://dx.doi.org/10.7554/eLife.09275.008
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fig6: Influence of the GABAA receptor antagonist PTX and the GABAB receptor antagonist CGP54626 on the effect of exogenous application of GABA as well as the influence of the GABAB receptor antagonist CGP54626 on 470 nm light-induced inhibition of the frequency of sEPSCs in VTA-DA neurons.(A) Influence of the GABAA receptor antagonist PTX on the effect of exogenous application of GABA of VTA-DA neurons in rats. Left panel: typical current traces of sEPSC before and after GABA (10 μM) in the presence of PTX (100 μM). Middle panel: typical time course of the frequency of sEPSCs before and after GABA (10 μM) in the presence of PTX (100 μM). Right panel: average frequency of sEPSCs before and after GABA (10 μM) in the presence of PTX (100 μM) (n = 6 cells from four rats, p < 0.05, compared to PTX before GABA). (B) Influence of the GABAB receptor antagonist CGP54626 on the effect of exogenous application of GABA of VTA-DA neurons in rats. Left panel: typical current traces of sEPSC before and after GABA (10 μM) in the presence of CGP54626 (2 μM). Middle panel: typical 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 cells from four rats, p = 0.87). (C) Influence of the GABAB receptor antagonist CGP54626 on 470 nm light-induced inhibition of the frequency of sEPSCs of VTA-DA neurons in mice. Left panel: typical current traces of sEPSCs before and after blue light (470 nm) stimulation in the presence of CGP54626 (2 μM). Middle panel: typical time course of the frequency of sEPSCs before and after blue light (470 nm) stimulation in the presence of CGP54626 (2 μM). Right panel: average frequency of sEPSCs before and after blue light (470 nm) stimulation in the presence of CGP54626 (2 μM) (n = 6 cells from five mice, p = 0.21). Data are shown as the mean ±s.e.m. *p < 0.05.DOI:http://dx.doi.org/10.7554/eLife.09275.008

Mentions: We also studied which kinds of GABA receptors (GABAA or GABAB receptors) mediated the decreasing effect of GABA on presynaptic glutamate release in VTA-DA neurons by examining the influence of the GABAA or GABAB receptor antagonist on the effect of GABA on the frequency of sEPSCs in rats. The results showed that the GABAA receptor antagonist PTX (100 µM) had no significant influence on the effect of GABA (Figure 6A). The average frequency of sEPSCs still decreased from 4.0 ± 0.3 Hz before to 3.0 ± 0.2 Hz for 10–15 min after GABA application in the presence of PTX (n = 6 cells from four rats, paired t test, p < 0.05, compared to PTX before GABA, right panel of Figure 6A). The percentage of GABA-produced response in the presence of PTX (−25.8 ± 3.8%) was not statistically significant (n = 6, independent t test, p > 0.05) compared to that without PTX (−29.2 ± 6.0%). However, in the presence of the GABAB receptor antagonist CGP54626, the effect of GABA on the frequency of sEPSCs disappeared (Figure 6B). The average frequency of sEPSCs was 3.8 ± 0.4 Hz before and 3.8 ± 0.4 Hz for 10–15 min after GABA application in the presence of CGP54626 (2 µM) (n = 6 cells from four rats, paired t test, p > 0.05, compared to CGP54626 before GABA, right panel of Figure 6B). These results suggest that it is GABAB receptors, rather than GABAA receptors, that mediate the decreasing effect of GABA on presynaptic glutamate release in VTA-DA neurons.10.7554/eLife.09275.008Figure 6.Influence of the GABAA receptor antagonist PTX and the GABAB receptor antagonist CGP54626 on the effect of exogenous application of GABA as well as the influence of the GABAB receptor antagonist CGP54626 on 470 nm light-induced inhibition of the frequency of sEPSCs in VTA-DA neurons.


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)

Influence of the GABAA receptor antagonist PTX and the GABAB receptor antagonist CGP54626 on the effect of exogenous application of GABA as well as the influence of the GABAB receptor antagonist CGP54626 on 470 nm light-induced inhibition of the frequency of sEPSCs in VTA-DA neurons.(A) Influence of the GABAA receptor antagonist PTX on the effect of exogenous application of GABA of VTA-DA neurons in rats. Left panel: typical current traces of sEPSC before and after GABA (10 μM) in the presence of PTX (100 μM). Middle panel: typical time course of the frequency of sEPSCs before and after GABA (10 μM) in the presence of PTX (100 μM). Right panel: average frequency of sEPSCs before and after GABA (10 μM) in the presence of PTX (100 μM) (n = 6 cells from four rats, p < 0.05, compared to PTX before GABA). (B) Influence of the GABAB receptor antagonist CGP54626 on the effect of exogenous application of GABA of VTA-DA neurons in rats. Left panel: typical current traces of sEPSC before and after GABA (10 μM) in the presence of CGP54626 (2 μM). Middle panel: typical 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 cells from four rats, p = 0.87). (C) Influence of the GABAB receptor antagonist CGP54626 on 470 nm light-induced inhibition of the frequency of sEPSCs of VTA-DA neurons in mice. Left panel: typical current traces of sEPSCs before and after blue light (470 nm) stimulation in the presence of CGP54626 (2 μM). Middle panel: typical time course of the frequency of sEPSCs before and after blue light (470 nm) stimulation in the presence of CGP54626 (2 μM). Right panel: average frequency of sEPSCs before and after blue light (470 nm) stimulation in the presence of CGP54626 (2 μM) (n = 6 cells from five mice, p = 0.21). Data are shown as the mean ±s.e.m. *p < 0.05.DOI:http://dx.doi.org/10.7554/eLife.09275.008
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fig6: Influence of the GABAA receptor antagonist PTX and the GABAB receptor antagonist CGP54626 on the effect of exogenous application of GABA as well as the influence of the GABAB receptor antagonist CGP54626 on 470 nm light-induced inhibition of the frequency of sEPSCs in VTA-DA neurons.(A) Influence of the GABAA receptor antagonist PTX on the effect of exogenous application of GABA of VTA-DA neurons in rats. Left panel: typical current traces of sEPSC before and after GABA (10 μM) in the presence of PTX (100 μM). Middle panel: typical time course of the frequency of sEPSCs before and after GABA (10 μM) in the presence of PTX (100 μM). Right panel: average frequency of sEPSCs before and after GABA (10 μM) in the presence of PTX (100 μM) (n = 6 cells from four rats, p < 0.05, compared to PTX before GABA). (B) Influence of the GABAB receptor antagonist CGP54626 on the effect of exogenous application of GABA of VTA-DA neurons in rats. Left panel: typical current traces of sEPSC before and after GABA (10 μM) in the presence of CGP54626 (2 μM). Middle panel: typical 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 cells from four rats, p = 0.87). (C) Influence of the GABAB receptor antagonist CGP54626 on 470 nm light-induced inhibition of the frequency of sEPSCs of VTA-DA neurons in mice. Left panel: typical current traces of sEPSCs before and after blue light (470 nm) stimulation in the presence of CGP54626 (2 μM). Middle panel: typical time course of the frequency of sEPSCs before and after blue light (470 nm) stimulation in the presence of CGP54626 (2 μM). Right panel: average frequency of sEPSCs before and after blue light (470 nm) stimulation in the presence of CGP54626 (2 μM) (n = 6 cells from five mice, p = 0.21). Data are shown as the mean ±s.e.m. *p < 0.05.DOI:http://dx.doi.org/10.7554/eLife.09275.008
Mentions: We also studied which kinds of GABA receptors (GABAA or GABAB receptors) mediated the decreasing effect of GABA on presynaptic glutamate release in VTA-DA neurons by examining the influence of the GABAA or GABAB receptor antagonist on the effect of GABA on the frequency of sEPSCs in rats. The results showed that the GABAA receptor antagonist PTX (100 µM) had no significant influence on the effect of GABA (Figure 6A). The average frequency of sEPSCs still decreased from 4.0 ± 0.3 Hz before to 3.0 ± 0.2 Hz for 10–15 min after GABA application in the presence of PTX (n = 6 cells from four rats, paired t test, p < 0.05, compared to PTX before GABA, right panel of Figure 6A). The percentage of GABA-produced response in the presence of PTX (−25.8 ± 3.8%) was not statistically significant (n = 6, independent t test, p > 0.05) compared to that without PTX (−29.2 ± 6.0%). However, in the presence of the GABAB receptor antagonist CGP54626, the effect of GABA on the frequency of sEPSCs disappeared (Figure 6B). The average frequency of sEPSCs was 3.8 ± 0.4 Hz before and 3.8 ± 0.4 Hz for 10–15 min after GABA application in the presence of CGP54626 (2 µM) (n = 6 cells from four rats, paired t test, p > 0.05, compared to CGP54626 before GABA, right panel of Figure 6B). These results suggest that it is GABAB receptors, rather than GABAA receptors, that mediate the decreasing effect of GABA on presynaptic glutamate release in VTA-DA neurons.10.7554/eLife.09275.008Figure 6.Influence of the GABAA receptor antagonist PTX and the GABAB receptor antagonist CGP54626 on the effect of exogenous application of GABA as well as the influence of the GABAB receptor antagonist CGP54626 on 470 nm light-induced inhibition of the frequency of sEPSCs in VTA-DA neurons.

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