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Connexin‐36‐positive gap junctions in ventral tegmental area GABA neurons sustain opiate dependence.

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Title: Connexin‐36‐positive gap junctions in ventral tegmental area GABA neurons sustain opiate dependence.
Authors: Maal‐Bared, Geith (AUTHOR), Yee, Mandy (AUTHOR), Harding, Erika K. (AUTHOR), Ghebreselassie, Martha (AUTHOR), Bergamini, Michael (AUTHOR), Choy, Roxanne (AUTHOR), Kim, Ethan (AUTHOR), Di Vito, Stephanie (AUTHOR), Patel, Maryam (AUTHOR), Amirzadeh, Mohammadreza (AUTHOR), Grieder, Taryn E. (AUTHOR), Coles, Brenda L. (AUTHOR), Nagy, James I. (AUTHOR), Bonin, Robert P. (AUTHOR), Steenland, Hendrik W. (AUTHOR), van der Kooy, Derek (AUTHOR)
Source: European Journal of Neuroscience. Jun2024, Vol. 59 Issue 12, p3422-3444. 23p.
Subjects: Dopaminergic neurons, Narcotics, Nucleus accumbens, Neurons, GTPase-activating protein, Drug addiction, Dopamine
Abstract: Drug dependence is characterized by a switch in motivation wherein a positively reinforcing substance can become negatively reinforcing. Put differently, drug use can transform from a form of pleasure‐seeking to a form of relief‐seeking. Ventral tegmental area (VTA) GABA neurons form an anatomical point of divergence between two double dissociable pathways that have been shown to be functionally implicated and necessary for these respective motivations to seek drugs. The tegmental pedunculopontine nucleus (TPP) is necessary for opiate conditioned place preferences (CPP) in previously drug‐naïve rats and mice, whereas dopaminergic (DA) transmission in the nucleus accumbens (NAc) is necessary for opiate CPP in opiate‐dependent and withdrawn (ODW) rats and mice. Here, we show that this switch in functional anatomy is contingent upon the gap junction‐forming protein, connexin‐36 (Cx36), in VTA GABA neurons. Intra‐VTA infusions of the Cx36 blocker, mefloquine, in ODW rats resulted in a reversion to a drug‐naïve‐like state wherein the TPP was necessary for opiate CPP and where opiate withdrawal aversions were lost. Consistent with these data, conditional knockout mice lacking Cx36 in GABA neurons (GAD65‐Cre;Cx36fl(CFP)/fl(CFP)) exhibited a perpetual drug‐naïve‐like state wherein opiate CPP was always DA independent, and opiate withdrawal aversions were absent even in mice subjected to an opiate dependence and withdrawal induction protocol. Further, viral‐mediated rescue of Cx36 in VTA GABA neurons was sufficient to restore their susceptibility to an ODW state wherein opiate CPP was DA dependent. Our findings reveal a functional role for VTA gap junctions that has eluded prevailing circuit models of addiction. [ABSTRACT FROM AUTHOR]
Copyright of European Journal of Neuroscience is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Data: Connexin‐36‐positive gap junctions in ventral tegmental area GABA neurons sustain opiate dependence.
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  Data: <searchLink fieldCode="AR" term="%22Maal‐Bared%2C+Geith%22">Maal‐Bared, Geith</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Yee%2C+Mandy%22">Yee, Mandy</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Harding%2C+Erika+K%2E%22">Harding, Erika K.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Ghebreselassie%2C+Martha%22">Ghebreselassie, Martha</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Bergamini%2C+Michael%22">Bergamini, Michael</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Choy%2C+Roxanne%22">Choy, Roxanne</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Kim%2C+Ethan%22">Kim, Ethan</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Di+Vito%2C+Stephanie%22">Di Vito, Stephanie</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Patel%2C+Maryam%22">Patel, Maryam</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Amirzadeh%2C+Mohammadreza%22">Amirzadeh, Mohammadreza</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Grieder%2C+Taryn+E%2E%22">Grieder, Taryn E.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Coles%2C+Brenda+L%2E%22">Coles, Brenda L.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Nagy%2C+James+I%2E%22">Nagy, James I.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Bonin%2C+Robert+P%2E%22">Bonin, Robert P.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Steenland%2C+Hendrik+W%2E%22">Steenland, Hendrik W.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22van+der+Kooy%2C+Derek%22">van der Kooy, Derek</searchLink> (AUTHOR)
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  Data: <searchLink fieldCode="JN" term="%22European+Journal+of+Neuroscience%22">European Journal of Neuroscience</searchLink>. Jun2024, Vol. 59 Issue 12, p3422-3444. 23p.
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  Data: <searchLink fieldCode="DE" term="%22Dopaminergic+neurons%22">Dopaminergic neurons</searchLink><br /><searchLink fieldCode="DE" term="%22Narcotics%22">Narcotics</searchLink><br /><searchLink fieldCode="DE" term="%22Nucleus+accumbens%22">Nucleus accumbens</searchLink><br /><searchLink fieldCode="DE" term="%22Neurons%22">Neurons</searchLink><br /><searchLink fieldCode="DE" term="%22GTPase-activating+protein%22">GTPase-activating protein</searchLink><br /><searchLink fieldCode="DE" term="%22Drug+addiction%22">Drug addiction</searchLink><br /><searchLink fieldCode="DE" term="%22Dopamine%22">Dopamine</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Drug dependence is characterized by a switch in motivation wherein a positively reinforcing substance can become negatively reinforcing. Put differently, drug use can transform from a form of pleasure‐seeking to a form of relief‐seeking. Ventral tegmental area (VTA) GABA neurons form an anatomical point of divergence between two double dissociable pathways that have been shown to be functionally implicated and necessary for these respective motivations to seek drugs. The tegmental pedunculopontine nucleus (TPP) is necessary for opiate conditioned place preferences (CPP) in previously drug‐naïve rats and mice, whereas dopaminergic (DA) transmission in the nucleus accumbens (NAc) is necessary for opiate CPP in opiate‐dependent and withdrawn (ODW) rats and mice. Here, we show that this switch in functional anatomy is contingent upon the gap junction‐forming protein, connexin‐36 (Cx36), in VTA GABA neurons. Intra‐VTA infusions of the Cx36 blocker, mefloquine, in ODW rats resulted in a reversion to a drug‐naïve‐like state wherein the TPP was necessary for opiate CPP and where opiate withdrawal aversions were lost. Consistent with these data, conditional knockout mice lacking Cx36 in GABA neurons (GAD65‐Cre;Cx36fl(CFP)/fl(CFP)) exhibited a perpetual drug‐naïve‐like state wherein opiate CPP was always DA independent, and opiate withdrawal aversions were absent even in mice subjected to an opiate dependence and withdrawal induction protocol. Further, viral‐mediated rescue of Cx36 in VTA GABA neurons was sufficient to restore their susceptibility to an ODW state wherein opiate CPP was DA dependent. Our findings reveal a functional role for VTA gap junctions that has eluded prevailing circuit models of addiction. [ABSTRACT FROM AUTHOR]
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  Data: <i>Copyright of European Journal of Neuroscience is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=pbh&AN=177904129
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        Value: 10.1111/ejn.16366
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        Text: English
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        PageCount: 23
        StartPage: 3422
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      – SubjectFull: Dopaminergic neurons
        Type: general
      – SubjectFull: Narcotics
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      – SubjectFull: Nucleus accumbens
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      – SubjectFull: Drug addiction
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      – SubjectFull: Dopamine
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      – TitleFull: Connexin‐36‐positive gap junctions in ventral tegmental area GABA neurons sustain opiate dependence.
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