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Prenatal Ethanol Exposure Persistently Alters Endocannabinoid Signaling and Endocannabinoid-Mediated Excitatory Synaptic Plasticity in Ventral Tegmental Area Dopamine Neurons.
J Neurosci. 2017 06 14; 37(24):5798-5808.JN

Abstract

Prenatal ethanol exposure (PE) leads to increased addiction risk which could be mediated by enhanced excitatory synaptic strength in ventral tegmental area (VTA) dopamine (DA) neurons. Previous studies have shown that PE enhances excitatory synaptic strength by facilitating an anti-Hebbian form of long-term potentiation (LTP). In this study, we investigated the effect of PE on endocannabinoid-mediated long-term depression (eCB-LTD) in VTA DA neurons. Rats were exposed to moderate (3 g/kg/d) or high (6 g/kg/d) levels of ethanol during gestation. Whole-cell recordings were conducted in male offspring between 4 and 10 weeks old.We found that PE led to increased amphetamine self-administration. Both moderate and high levels of PE persistently reduced low-frequency stimulation-induced eCB-LTD. Furthermore, action potential-independent glutamate release was regulated by tonic eCB signaling in PE animals. Mechanistic studies for impaired eCB-LTD revealed that PE downregulated CB1 receptor function. Interestingly, eCB-LTD in PE animals was rescued by metabotropic glutamate receptor I activation, suggesting that PE did not impair the synthesis/release of eCBs. In contrast, eCB-LTD in PE animals was not rescued by increasing presynaptic activity, which actually led to LTP in PE animals, whereas LTD was still observed in controls. This result shows that the regulation of excitatory synaptic plasticity is fundamentally altered in PE animals. Together, PE leads to impaired eCB-LTD at the excitatory synapses of VTA DA neurons primarily due to CB1 receptor downregulation. This effect could contribute to enhanced LTP and the maintenance of augmented excitatory synaptic strength in VTA DA neurons and increased addiction risk after PE.SIGNIFICANCE STATEMENT Prenatal ethanol exposure (PE) is among many adverse developmental factors known to increase drug addiction risk. Increased excitatory synaptic strength in VTA DA neurons is a critical cellular mechanism for addiction risk. Our results show that PE persistently alters eCB signaling and impairs eCB-LTD at the excitatory synapses, an important synaptic plasticity that weakens synaptic strength. These effects combined with PE-induced anti-Hebbian long-term potentiation reported in a previous study could result in the maintenance of enhanced excitatory synaptic strength in VTA DA neurons, which in turn contributes to PE-induced increase in addiction risk. Our findings also suggest that restoring normal eCB signaling in VTA DA neurons could be a useful strategy for treating behavioral symptoms caused by PE.

Authors+Show Affiliations

Research Institute on Addictions and.Research Institute on Addictions and.Research Institute on Addictions and. Department of Psychology, University at Buffalo, New York 14203.Research Institute on Addictions and.Research Institute on Addictions and shen@ria.buffalo.edu.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

28476947

Citation

Hausknecht, Kathryn, et al. "Prenatal Ethanol Exposure Persistently Alters Endocannabinoid Signaling and Endocannabinoid-Mediated Excitatory Synaptic Plasticity in Ventral Tegmental Area Dopamine Neurons." The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, vol. 37, no. 24, 2017, pp. 5798-5808.
Hausknecht K, Shen YL, Wang RX, et al. Prenatal Ethanol Exposure Persistently Alters Endocannabinoid Signaling and Endocannabinoid-Mediated Excitatory Synaptic Plasticity in Ventral Tegmental Area Dopamine Neurons. J Neurosci. 2017;37(24):5798-5808.
Hausknecht, K., Shen, Y. L., Wang, R. X., Haj-Dahmane, S., & Shen, R. Y. (2017). Prenatal Ethanol Exposure Persistently Alters Endocannabinoid Signaling and Endocannabinoid-Mediated Excitatory Synaptic Plasticity in Ventral Tegmental Area Dopamine Neurons. The Journal of Neuroscience : the Official Journal of the Society for Neuroscience, 37(24), 5798-5808. https://doi.org/10.1523/JNEUROSCI.3894-16.2017
Hausknecht K, et al. Prenatal Ethanol Exposure Persistently Alters Endocannabinoid Signaling and Endocannabinoid-Mediated Excitatory Synaptic Plasticity in Ventral Tegmental Area Dopamine Neurons. J Neurosci. 2017 06 14;37(24):5798-5808. PubMed PMID: 28476947.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Prenatal Ethanol Exposure Persistently Alters Endocannabinoid Signaling and Endocannabinoid-Mediated Excitatory Synaptic Plasticity in Ventral Tegmental Area Dopamine Neurons. AU - Hausknecht,Kathryn, AU - Shen,Ying-Ling, AU - Wang,Rui-Xiang, AU - Haj-Dahmane,Samir, AU - Shen,Roh-Yu, Y1 - 2017/05/05/ PY - 2016/12/21/received PY - 2017/03/15/revised PY - 2017/04/05/accepted PY - 2017/5/10/pubmed PY - 2017/8/19/medline PY - 2017/5/7/entrez KW - CB1 receptors KW - addiction risk KW - endocannabinoid-mediated long-term depression KW - long-term potentiation KW - synaptic homeostasis KW - ventral tegmental area dopamine neurons SP - 5798 EP - 5808 JF - The Journal of neuroscience : the official journal of the Society for Neuroscience JO - J Neurosci VL - 37 IS - 24 N2 - Prenatal ethanol exposure (PE) leads to increased addiction risk which could be mediated by enhanced excitatory synaptic strength in ventral tegmental area (VTA) dopamine (DA) neurons. Previous studies have shown that PE enhances excitatory synaptic strength by facilitating an anti-Hebbian form of long-term potentiation (LTP). In this study, we investigated the effect of PE on endocannabinoid-mediated long-term depression (eCB-LTD) in VTA DA neurons. Rats were exposed to moderate (3 g/kg/d) or high (6 g/kg/d) levels of ethanol during gestation. Whole-cell recordings were conducted in male offspring between 4 and 10 weeks old.We found that PE led to increased amphetamine self-administration. Both moderate and high levels of PE persistently reduced low-frequency stimulation-induced eCB-LTD. Furthermore, action potential-independent glutamate release was regulated by tonic eCB signaling in PE animals. Mechanistic studies for impaired eCB-LTD revealed that PE downregulated CB1 receptor function. Interestingly, eCB-LTD in PE animals was rescued by metabotropic glutamate receptor I activation, suggesting that PE did not impair the synthesis/release of eCBs. In contrast, eCB-LTD in PE animals was not rescued by increasing presynaptic activity, which actually led to LTP in PE animals, whereas LTD was still observed in controls. This result shows that the regulation of excitatory synaptic plasticity is fundamentally altered in PE animals. Together, PE leads to impaired eCB-LTD at the excitatory synapses of VTA DA neurons primarily due to CB1 receptor downregulation. This effect could contribute to enhanced LTP and the maintenance of augmented excitatory synaptic strength in VTA DA neurons and increased addiction risk after PE.SIGNIFICANCE STATEMENT Prenatal ethanol exposure (PE) is among many adverse developmental factors known to increase drug addiction risk. Increased excitatory synaptic strength in VTA DA neurons is a critical cellular mechanism for addiction risk. Our results show that PE persistently alters eCB signaling and impairs eCB-LTD at the excitatory synapses, an important synaptic plasticity that weakens synaptic strength. These effects combined with PE-induced anti-Hebbian long-term potentiation reported in a previous study could result in the maintenance of enhanced excitatory synaptic strength in VTA DA neurons, which in turn contributes to PE-induced increase in addiction risk. Our findings also suggest that restoring normal eCB signaling in VTA DA neurons could be a useful strategy for treating behavioral symptoms caused by PE. SN - 1529-2401 UR - https://www.unboundmedicine.com/medline/citation/28476947/Prenatal_Ethanol_Exposure_Persistently_Alters_Endocannabinoid_Signaling_and_Endocannabinoid_Mediated_Excitatory_Synaptic_Plasticity_in_Ventral_Tegmental_Area_Dopamine_Neurons_ L2 - http://www.jneurosci.org/cgi/pmidlookup?view=long&pmid=28476947 DB - PRIME DP - Unbound Medicine ER -