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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 morphine-induced increase in locomotor activity in rats.(A) Injection sites were verified under light microscope. Left panel: Representative Nissl-stained photomicrograph of cannula tracts terminating in the VTA. Right panel: location of the injection cannula tips in the VTA of rats used in data analyses. Numbers indicate coordinates relative to bregma. (B) Influence of intra-VTA injection of the presynaptic GABAB receptor antagonist CGP36216 on intra-VTA injection of morphine inducing an increase in locomotor activity. Left panel: time course of locomotor activity before and after intra-VTA injection of saline or morphine (1 μg/rat), or morphine (1 μg/rat) with CGP36216 (20 µg/rat) (n = 6 rats). Right panel: average distance traveled by rats during 120 min after treatment with an intra-VTA injection of saline or morphine (1 μg/rat), or morphine (1 μg/rat) with CGP36216 (20 µg/rat) (n = 6 rats; *p < 0.05, compared with intra-VTA injection of saline, #p < 0.05, compared with intra-VTA injection of morphine. (C) Influence of intra-VTA injection of the presynaptic GABAB receptor antagonist CGP36216 on intraperitoneal (i.p.) morphine-induced increase in locomotor activity. Left panel: time course of locomotor activity before and after intra-VTA injection of saline co-administered with either i.p. saline (1 ml/kg) or morphine (10 mg/kg), and i.p. morphine (10 mg/kg) with intra-VTA injection of CGP36216 (20 μg/rat) (n = 6 rats). Right panel: average distance traveled by rats during 120 min after treatment with intra-VTA injection of saline co-administered with either i.p. saline (1 ml/kg) or morphine (10 mg/kg), and i.p. morphine (10 mg/kg) with intra-VTA injection of CGP36216 (20 μg/rat) (n = 6; *p < 0.05, compared with intra-VTA injection of saline co-administered with i.p. saline, #p < 0.05, compared with intra-VTA injection of saline co-administered with i.p. morphine). Data are shown as the mean ±s.e.m.DOI:http://dx.doi.org/10.7554/eLife.09275.013
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fig11: Influence of intra-ventral tegmental area (VTA) injection of the presynaptic GABAB receptor antagonist CGP36216 on morphine-induced increase in locomotor activity in rats.(A) Injection sites were verified under light microscope. Left panel: Representative Nissl-stained photomicrograph of cannula tracts terminating in the VTA. Right panel: location of the injection cannula tips in the VTA of rats used in data analyses. Numbers indicate coordinates relative to bregma. (B) Influence of intra-VTA injection of the presynaptic GABAB receptor antagonist CGP36216 on intra-VTA injection of morphine inducing an increase in locomotor activity. Left panel: time course of locomotor activity before and after intra-VTA injection of saline or morphine (1 μg/rat), or morphine (1 μg/rat) with CGP36216 (20 µg/rat) (n = 6 rats). Right panel: average distance traveled by rats during 120 min after treatment with an intra-VTA injection of saline or morphine (1 μg/rat), or morphine (1 μg/rat) with CGP36216 (20 µg/rat) (n = 6 rats; *p < 0.05, compared with intra-VTA injection of saline, #p < 0.05, compared with intra-VTA injection of morphine. (C) Influence of intra-VTA injection of the presynaptic GABAB receptor antagonist CGP36216 on intraperitoneal (i.p.) morphine-induced increase in locomotor activity. Left panel: time course of locomotor activity before and after intra-VTA injection of saline co-administered with either i.p. saline (1 ml/kg) or morphine (10 mg/kg), and i.p. morphine (10 mg/kg) with intra-VTA injection of CGP36216 (20 μg/rat) (n = 6 rats). Right panel: average distance traveled by rats during 120 min after treatment with intra-VTA injection of saline co-administered with either i.p. saline (1 ml/kg) or morphine (10 mg/kg), and i.p. morphine (10 mg/kg) with intra-VTA injection of CGP36216 (20 μg/rat) (n = 6; *p < 0.05, compared with intra-VTA injection of saline co-administered with i.p. saline, #p < 0.05, compared with intra-VTA injection of saline co-administered with i.p. morphine). Data are shown as the mean ±s.e.m.DOI:http://dx.doi.org/10.7554/eLife.09275.013

Mentions: Since enhanced DA function in the VTA has most often been assessed as increased locomotor activity at the behavioral level (Vezina, 2004), we also studied the contribution of the morphine-induced disinhibition of glutamatergic input in the VTA to behavioral changes produced by morphine. In behavioral experiments, to avoid morphine acting on other brain areas sensitive to morphine, we injected morphine locally into the VTA in rats. Injection sites were verified under light microscope (left panel of Figure 11A); the injection sites used for data analysis are shown in the middle and right panels of Figure 11A. We first observed the effect of CGP36216 on locomotor activity. The results showed that CGP36216 (20 μg/rat) increased locomotor activity. The distance traveled by rats was 6.3 ± 1.4 m in the control group compared with 12.2 ± 2.0 m in the CGP36216 group (n = 6 rats, independent t test, p < 0.05). Then we observed the influence of CGP36216 on the effect of morphine on locomotor activity in rats. As shown in Figure 11B, locomotor activity was significantly increased following intra-VTA injection of morphine (1 µg/rat). The distance traveled by rats was 6.3 ± 1.4 m in the control group compared with 37.6 ± 9.6 m in the morphine alone group (n = 6 rats, independent t test, p < 0.05, right panel of Figure 11B). However, in animals with intra-VTA injection of CGP36216 (20 µg/rat), the morphine-induced increase in locomotor activity disappeared (Figure 11B). The distance traveled by rats was 37.6 ± 9.6 m in the morphine alone group compared with 7.5 ± 1.4 m in the morphine plus intra-VTA CGP36216 group (n = 6 rats, independent t test, p < 0.05, right panel of Figure 11B). In addition, to evaluate the role of VTA GABAB receptors in the overall effect of intraperitoneal (i.p.) morphine, we observed the effect of intra-VTA injected CGP36216 on i.p. morphine-induced increase in locomotor activity. As shown in Figure 11C, locomotor activity was significantly increased by i.p. injection of morphine (10 mg/kg) plus intra-VTA injection of saline. The distance traveled by rats was 5.4 ± 0.8 m in the control group compared with 28.3 ± 5.7 m in the i.p. morphine (10 mg/kg) plus intra-VTA saline group (n = 6 rats, independent t test, p < 0.05, right panel of Figure 11C). However, in animals with intra-VTA injection of CGP36216 (20 µg/rat), the i.p. morphine-induced increase in locomotor activity disappeared (Figure 11C). The distance traveled by rats was 28.3 ± 5.7 m in the i.p. morphine (10 mg/kg) plus intra-VTA saline group compared with 6.6 ± 2.3 m in the i.p. morphine plus intra-VTA CGP36216 group (n = 6 rats, independent t test, p < 0.05, right panel of Figure 11C).10.7554/eLife.09275.013Figure 11.Influence of intra-ventral tegmental area (VTA) injection of the presynaptic GABAB receptor antagonist CGP36216 on morphine-induced increase in locomotor activity 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 morphine-induced increase in locomotor activity in rats.(A) Injection sites were verified under light microscope. Left panel: Representative Nissl-stained photomicrograph of cannula tracts terminating in the VTA. Right panel: location of the injection cannula tips in the VTA of rats used in data analyses. Numbers indicate coordinates relative to bregma. (B) Influence of intra-VTA injection of the presynaptic GABAB receptor antagonist CGP36216 on intra-VTA injection of morphine inducing an increase in locomotor activity. Left panel: time course of locomotor activity before and after intra-VTA injection of saline or morphine (1 μg/rat), or morphine (1 μg/rat) with CGP36216 (20 µg/rat) (n = 6 rats). Right panel: average distance traveled by rats during 120 min after treatment with an intra-VTA injection of saline or morphine (1 μg/rat), or morphine (1 μg/rat) with CGP36216 (20 µg/rat) (n = 6 rats; *p < 0.05, compared with intra-VTA injection of saline, #p < 0.05, compared with intra-VTA injection of morphine. (C) Influence of intra-VTA injection of the presynaptic GABAB receptor antagonist CGP36216 on intraperitoneal (i.p.) morphine-induced increase in locomotor activity. Left panel: time course of locomotor activity before and after intra-VTA injection of saline co-administered with either i.p. saline (1 ml/kg) or morphine (10 mg/kg), and i.p. morphine (10 mg/kg) with intra-VTA injection of CGP36216 (20 μg/rat) (n = 6 rats). Right panel: average distance traveled by rats during 120 min after treatment with intra-VTA injection of saline co-administered with either i.p. saline (1 ml/kg) or morphine (10 mg/kg), and i.p. morphine (10 mg/kg) with intra-VTA injection of CGP36216 (20 μg/rat) (n = 6; *p < 0.05, compared with intra-VTA injection of saline co-administered with i.p. saline, #p < 0.05, compared with intra-VTA injection of saline co-administered with i.p. morphine). Data are shown as the mean ±s.e.m.DOI:http://dx.doi.org/10.7554/eLife.09275.013
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fig11: Influence of intra-ventral tegmental area (VTA) injection of the presynaptic GABAB receptor antagonist CGP36216 on morphine-induced increase in locomotor activity in rats.(A) Injection sites were verified under light microscope. Left panel: Representative Nissl-stained photomicrograph of cannula tracts terminating in the VTA. Right panel: location of the injection cannula tips in the VTA of rats used in data analyses. Numbers indicate coordinates relative to bregma. (B) Influence of intra-VTA injection of the presynaptic GABAB receptor antagonist CGP36216 on intra-VTA injection of morphine inducing an increase in locomotor activity. Left panel: time course of locomotor activity before and after intra-VTA injection of saline or morphine (1 μg/rat), or morphine (1 μg/rat) with CGP36216 (20 µg/rat) (n = 6 rats). Right panel: average distance traveled by rats during 120 min after treatment with an intra-VTA injection of saline or morphine (1 μg/rat), or morphine (1 μg/rat) with CGP36216 (20 µg/rat) (n = 6 rats; *p < 0.05, compared with intra-VTA injection of saline, #p < 0.05, compared with intra-VTA injection of morphine. (C) Influence of intra-VTA injection of the presynaptic GABAB receptor antagonist CGP36216 on intraperitoneal (i.p.) morphine-induced increase in locomotor activity. Left panel: time course of locomotor activity before and after intra-VTA injection of saline co-administered with either i.p. saline (1 ml/kg) or morphine (10 mg/kg), and i.p. morphine (10 mg/kg) with intra-VTA injection of CGP36216 (20 μg/rat) (n = 6 rats). Right panel: average distance traveled by rats during 120 min after treatment with intra-VTA injection of saline co-administered with either i.p. saline (1 ml/kg) or morphine (10 mg/kg), and i.p. morphine (10 mg/kg) with intra-VTA injection of CGP36216 (20 μg/rat) (n = 6; *p < 0.05, compared with intra-VTA injection of saline co-administered with i.p. saline, #p < 0.05, compared with intra-VTA injection of saline co-administered with i.p. morphine). Data are shown as the mean ±s.e.m.DOI:http://dx.doi.org/10.7554/eLife.09275.013
Mentions: Since enhanced DA function in the VTA has most often been assessed as increased locomotor activity at the behavioral level (Vezina, 2004), we also studied the contribution of the morphine-induced disinhibition of glutamatergic input in the VTA to behavioral changes produced by morphine. In behavioral experiments, to avoid morphine acting on other brain areas sensitive to morphine, we injected morphine locally into the VTA in rats. Injection sites were verified under light microscope (left panel of Figure 11A); the injection sites used for data analysis are shown in the middle and right panels of Figure 11A. We first observed the effect of CGP36216 on locomotor activity. The results showed that CGP36216 (20 μg/rat) increased locomotor activity. The distance traveled by rats was 6.3 ± 1.4 m in the control group compared with 12.2 ± 2.0 m in the CGP36216 group (n = 6 rats, independent t test, p < 0.05). Then we observed the influence of CGP36216 on the effect of morphine on locomotor activity in rats. As shown in Figure 11B, locomotor activity was significantly increased following intra-VTA injection of morphine (1 µg/rat). The distance traveled by rats was 6.3 ± 1.4 m in the control group compared with 37.6 ± 9.6 m in the morphine alone group (n = 6 rats, independent t test, p < 0.05, right panel of Figure 11B). However, in animals with intra-VTA injection of CGP36216 (20 µg/rat), the morphine-induced increase in locomotor activity disappeared (Figure 11B). The distance traveled by rats was 37.6 ± 9.6 m in the morphine alone group compared with 7.5 ± 1.4 m in the morphine plus intra-VTA CGP36216 group (n = 6 rats, independent t test, p < 0.05, right panel of Figure 11B). In addition, to evaluate the role of VTA GABAB receptors in the overall effect of intraperitoneal (i.p.) morphine, we observed the effect of intra-VTA injected CGP36216 on i.p. morphine-induced increase in locomotor activity. As shown in Figure 11C, locomotor activity was significantly increased by i.p. injection of morphine (10 mg/kg) plus intra-VTA injection of saline. The distance traveled by rats was 5.4 ± 0.8 m in the control group compared with 28.3 ± 5.7 m in the i.p. morphine (10 mg/kg) plus intra-VTA saline group (n = 6 rats, independent t test, p < 0.05, right panel of Figure 11C). However, in animals with intra-VTA injection of CGP36216 (20 µg/rat), the i.p. morphine-induced increase in locomotor activity disappeared (Figure 11C). The distance traveled by rats was 28.3 ± 5.7 m in the i.p. morphine (10 mg/kg) plus intra-VTA saline group compared with 6.6 ± 2.3 m in the i.p. morphine plus intra-VTA CGP36216 group (n = 6 rats, independent t test, p < 0.05, right panel of Figure 11C).10.7554/eLife.09275.013Figure 11.Influence of intra-ventral tegmental area (VTA) injection of the presynaptic GABAB receptor antagonist CGP36216 on morphine-induced increase in locomotor activity 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