Bidirectional plasticity in the primate inferior olive induced by chronic ethanol intoxication and sustained abstinence
Open accessAbstract
The brain adapts to chronic ethanol intoxication by altering synaptic and ion-channel function to increase excitability, a homeostatic counterbalance to inhibition by alcohol. Delirium tremens occurs when those adaptations are unmasked during withdrawal, but little is known about whether the primate brain returns to normal with repeated bouts of ethanol abuse and abstinence. Here, we show a form of bidirectional plasticity of pacemaking currents induced by chronic heavy drinking within the inferior olive of cynomolgus monkeys. Intracellular recordings of inferior olive neurons demonstrated that ethanol inhibited the tail current triggered by release from hyperpolarization ( I tail ). Both the slow deactivation of hyperpolarization-activated cyclic nucleotide-gated channels conducting the hyperpolarization-activated inward current and the activation of Ca v 3.1 channels conducting the T-type calcium current ( I T ) contributed to I tail , but ethanol inhibited only the I T component of I tail . Recordings of inferior olive neurons obtained from chronically intoxicated monkeys revealed a significant up-regulation in I tail that was induced by 1 y of daily ethanol self-administration. The up-regulation was caused by a specific increase in I T which ( i ) greatly increased neurons’ susceptibility for rebound excitation following hyperpolarization and ( ii ) may have accounted for intention tremors observed during ethanol withdrawal. In another set of monkeys, sustained abstinence produced the opposite effects: ( i ) a reduction in rebound excitability and ( ii ) a down-regulation of I tail caused by the down-regulation of both the hyperpolarization-activated inward current and I T . Bidirectional plasticity of two hyperpolarization-sensitive currents following chronic ethanol abuse and abstinence may underlie persistent brain dysfunction in primates and be a target for therapy.
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These calcium channels are an increasingly recognized target for investigational therapeutics and are abundantly expressed in the primate IO.
“These calcium channels are an increasingly recognized target for investigational therapeutics, and are abundantly expressed in the primate IO [47].”
From Consensus Paper: Pathological Role of the Cerebellum in Autism (2012) · cites this paper as [47]
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Consensus Paper: Pathological Role of the Cerebellum in Autism
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- Authors
- Welsh, J. P., Han, V. Z., Rossi, D. J., Mohr, C., Odagiri, M., Daunais, J. B., & Grant, K. A.
- Affiliations
- University of Washington (US)
- Seattle Children's Research Institute (US)
- Oregon Health & Science University (US)
- Oregon National Primate Research Center (US)
- Wake Forest University Health Sciences (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-06-03
- Volume
- 108
- Issue
- 25
- Pages
- 10314-10319
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3121872
- OpenAlex
- W1979778462
- Cited by
- 42
- References
- 58
- Citations by year
- 2025: 2 · 2024: 2 · 2023: 3 · 2022: 1 · 2021: 4 · 2019: 1 · 2018: 3 · 2017: 7 · 2016: 3 · 2015: 2 · 2014: 8 · 2013: 2 · 2012: 4
- FWCI
- 1.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Alcohol Abuse and Alcoholism (U01AA013641, R01AA016748, P60AA010760, U01AA013510, R24AA019431)
- National Institute of Neurological Disorders and Stroke (R01NS031224, R01 NS31224-17)
- National Center for Research Resources (P51RR000163)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Neurology › Alcoholism and Thiamine Deficiency
- Keywords
- inferior olive, chronic alcohol intoxication, ethanol withdrawal, bidirectional synaptic plasticity, hyperpolarization-activated current, T-type calcium current, HCN channels, rebound excitation, intention tremor, delirium tremens, alcohol self-administration, Macaca fascicularis
- MeSH terms
- Action Potentials, Ethanol, Alcoholism, Animals, Female, Macaca fascicularis, Male, Neuronal Plasticity, Olivary Nucleus, Phenotype, Substance Withdrawal Syndrome, Patch-Clamp Techniques
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