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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 intra-ventral tegmental area (VTA) injection of the presynaptic GABAB receptor antagonist CGP36216 on intra-VTA injected morphine-induced conditioned place preference (CPP) in rats.(A) Schematic representations of injection cannula tips in the VTA of rats used in data analyses. Numbers indicate coordinates relative to bregma. (B) A schematic of the experimental design for CPP and administration of drugs. (C) Influence of the presynaptic GABAB receptor antagonist CGP36216 on morphine-induced CPP in rats. Averaged CPP score of preconditioning and postconditioning in different groups (n = 6 rats in the every group; *p < 0.05, intra-VTA injection of morphine group compared with intra-VTA injection of saline group, #p < 0.05, intra-VTA injection of morphine plus CGP36216 group compared with intra-VTA injection of morphine group). Data are shown as the mean ±s.e.m.DOI:http://dx.doi.org/10.7554/eLife.09275.014
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fig12: Influence of intra-ventral tegmental area (VTA) injection of the presynaptic GABAB receptor antagonist CGP36216 on intra-VTA injected morphine-induced conditioned place preference (CPP) in rats.(A) Schematic representations of injection cannula tips in the VTA of rats used in data analyses. Numbers indicate coordinates relative to bregma. (B) A schematic of the experimental design for CPP and administration of drugs. (C) Influence of the presynaptic GABAB receptor antagonist CGP36216 on morphine-induced CPP in rats. Averaged CPP score of preconditioning and postconditioning in different groups (n = 6 rats in the every group; *p < 0.05, intra-VTA injection of morphine group compared with intra-VTA injection of saline group, #p < 0.05, intra-VTA injection of morphine plus CGP36216 group compared with intra-VTA injection of morphine group). Data are shown as the mean ±s.e.m.DOI:http://dx.doi.org/10.7554/eLife.09275.014

Mentions: We also observed the effect of the presynaptic GABAB receptor antagonist CGP36216 on morphine-induced conditioned place preference (CPP) in rats. Morphine (1 µg/rat) and CGP36216 (20 µg/rat) were locally injected into the VTA. Injection sites for data analysis are shown in Figure 12A. A schematic of the experimental design for CPP and drug application is shown in Figure 12B. As shown in Figure 12C, two-way ANOVAs conducted on the CPP score using treatment with different drugs as the between-subjects factors and test condition (preconditioning and postconditioning) as the within-subjects factor, revealed that there was a significant interaction of treatment (F(3,40) = 4.45; p = 0.008) and test condition (F(1,40) = 19.79; p < 0.001). Post-hoc analysis showed that after CPP training, the morphine group (n = 6 rats) exhibited greater CPP compared with the control group (n = 6 rats, p < 0.05) but in groups receiving CGP36216 (n = 6 rats), morphine-induced CPP was absent (p < 0.05). These results suggest that intra-VTA injection of a presynaptic GABAB receptor antagonist abolishes CPP induced by intra-VTA injection of morphine.10.7554/eLife.09275.014Figure 12.Influence of intra-ventral tegmental area (VTA) injection of the presynaptic GABAB receptor antagonist CGP36216 on intra-VTA injected morphine-induced conditioned place preference (CPP) 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)

Influence of intra-ventral tegmental area (VTA) injection of the presynaptic GABAB receptor antagonist CGP36216 on intra-VTA injected morphine-induced conditioned place preference (CPP) in rats.(A) Schematic representations of injection cannula tips in the VTA of rats used in data analyses. Numbers indicate coordinates relative to bregma. (B) A schematic of the experimental design for CPP and administration of drugs. (C) Influence of the presynaptic GABAB receptor antagonist CGP36216 on morphine-induced CPP in rats. Averaged CPP score of preconditioning and postconditioning in different groups (n = 6 rats in the every group; *p < 0.05, intra-VTA injection of morphine group compared with intra-VTA injection of saline group, #p < 0.05, intra-VTA injection of morphine plus CGP36216 group compared with intra-VTA injection of morphine group). Data are shown as the mean ±s.e.m.DOI:http://dx.doi.org/10.7554/eLife.09275.014
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4538365&req=5

fig12: Influence of intra-ventral tegmental area (VTA) injection of the presynaptic GABAB receptor antagonist CGP36216 on intra-VTA injected morphine-induced conditioned place preference (CPP) in rats.(A) Schematic representations of injection cannula tips in the VTA of rats used in data analyses. Numbers indicate coordinates relative to bregma. (B) A schematic of the experimental design for CPP and administration of drugs. (C) Influence of the presynaptic GABAB receptor antagonist CGP36216 on morphine-induced CPP in rats. Averaged CPP score of preconditioning and postconditioning in different groups (n = 6 rats in the every group; *p < 0.05, intra-VTA injection of morphine group compared with intra-VTA injection of saline group, #p < 0.05, intra-VTA injection of morphine plus CGP36216 group compared with intra-VTA injection of morphine group). Data are shown as the mean ±s.e.m.DOI:http://dx.doi.org/10.7554/eLife.09275.014
Mentions: We also observed the effect of the presynaptic GABAB receptor antagonist CGP36216 on morphine-induced conditioned place preference (CPP) in rats. Morphine (1 µg/rat) and CGP36216 (20 µg/rat) were locally injected into the VTA. Injection sites for data analysis are shown in Figure 12A. A schematic of the experimental design for CPP and drug application is shown in Figure 12B. As shown in Figure 12C, two-way ANOVAs conducted on the CPP score using treatment with different drugs as the between-subjects factors and test condition (preconditioning and postconditioning) as the within-subjects factor, revealed that there was a significant interaction of treatment (F(3,40) = 4.45; p = 0.008) and test condition (F(1,40) = 19.79; p < 0.001). Post-hoc analysis showed that after CPP training, the morphine group (n = 6 rats) exhibited greater CPP compared with the control group (n = 6 rats, p < 0.05) but in groups receiving CGP36216 (n = 6 rats), morphine-induced CPP was absent (p < 0.05). These results suggest that intra-VTA injection of a presynaptic GABAB receptor antagonist abolishes CPP induced by intra-VTA injection of morphine.10.7554/eLife.09275.014Figure 12.Influence of intra-ventral tegmental area (VTA) injection of the presynaptic GABAB receptor antagonist CGP36216 on intra-VTA injected morphine-induced conditioned place preference (CPP) 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