ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2014
Overexpression of the steroidogenic enzyme cytochrome P450 side chain cleavage in the ventral tegmental area increases 3α,5α-THP and reduces long-term operant ethanol self-administration.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
18 citing papers in PubMed, 28 citations in OpenAlex.
- A randomized, double-blind, placebo-controlled trial of pregnenolone for bipolar depression.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2014Trial
- Neuroactive Steroids, Toll-like Receptors, and Neuroimmune Regulation: Insights into Their Impact on Neuropsychiatric Disorders.Life (Basel, Switzerland) · 2024Review
- Stress and gonadal steroid influences on alcohol drinking and withdrawal, with focus on animal models in females.Frontiers in neuroendocrinology · 2023Review
- Pharmacological administration of 3α,5α-THP into the nucleus accumbens core increases 3α,5α-THP expression and reduces alcohol self-administration.Alcohol, clinical & experimental research · 2023Article
- Hydroxylation of pregnenolone and dehydroepiandrosterone by zygomycete Backusella lamprospora VKM F-944: selective production of 7α-OH-DHEA.Applied microbiology and biotechnology · 2022Article
- A Rationale for Allopregnanolone Treatment of Alcohol Use Disorders: Basic and Clinical Studies.Alcoholism, clinical and experimental research · 2020Review
- Endogenous Neurosteroid (3α,5α)3-Hydroxypregnan-20-one Inhibits Toll-like-4 Receptor Activation and Pro-inflammatory Signaling in Macrophages and Brain.Scientific reports · 2019Article
- Histone Deacetylase Inhibitor Suberanilohydroxamic Acid Treatment Reverses Hyposensitivity to γ-Aminobutyric Acid in the Ventral Tegmental Area During Ethanol Withdrawal.Alcoholism, clinical and experimental research · 2018Article
- Dynamic Adaptation in Neurosteroid Networks in Response to Alcohol.Handbook of experimental pharmacology · 2018Article
- Androgen Regulation of the Mesocorticolimbic System and Executive Function.Frontiers in endocrinology · 2018Review
- Voluntary ethanol consumption reduces GABAergic neuroactive steroid (3α,5α)3-hydroxypregnan-20-one (3α,5α-THP) in the amygdala of the cynomolgus monkey.Addiction biology · 2017Article
- Cellular GABAergic Neuroactive Steroid (3α,5α)-3-Hydroxy-Pregnan-20-One (3α,5α-THP) Immunostaining Levels Are Increased in the Ventral Tegmental Area of Human Alcohol Use Disorder Patients: A Postmortem Study.Alcoholism, clinical and experimental research · 2017Article
- Effects of Gabra2 Point Mutations on Alcohol Intake: Increased Binge-Like and Blunted Chronic Drinking by Mice.Alcoholism, clinical and experimental research · 2016Article
- Neural circuit diagrams.Nature methods · 2016Article
- Neurosteroidogenesis Today: Novel Targets for Neuroactive Steroid Synthesis and Action and Their Relevance for Translational Research.Journal of neuroendocrinology · 2016Review
- Chronic Intermittent Ethanol Exposure Alters Stress Effects on (3α,5α)-3-hydroxy-pregnan-20-one (3α,5α-THP) Immunolabeling of Amygdala Neurons in C57BL/6J Mice.Frontiers in cellular neuroscience · 2016Article
- Effects of the neuroactive steroid allopregnanolone on intracranial self-stimulation in C57BL/6J mice.Psychopharmacology · 2014Article
- Chronic Alcohol, Intrinsic Excitability, and Potassium Channels: Neuroadaptations and Drinking Behavior.Handbook of experimental pharmacologyArticle
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 3 countries.
Funding
Abstract
Neuroactive steroids are endogenous neuromodulators capable of altering neuronal activity and behavior. In rodents, systemic administration of endogenous or synthetic neuroactive steroids reduces ethanol self-administration. We hypothesized this effect arises from actions within mesolimbic brain regions that we targeted by viral gene delivery. Cytochrome P450 side chain cleavage (P450scc) converts cholesterol to pregnenolone, the rate-limiting enzymatic reaction in neurosteroidogenesis. Therefore, we constructed a recombinant adeno-associated serotype 2 viral vector (rAAV2), which drives P450scc expression and neuroactive steroid synthesis. The P450scc-expressing vector (rAAV2-P450scc) or control GFP-expressing vector (rAAV2-GFP) were injected bilaterally into the ventral tegmental area (VTA) or nucleus accumbens (NAc) of alcohol preferring (P) rats trained to self-administer ethanol. P450scc overexpression in the VTA significantly reduced ethanol self-administration by 20% over the 3 week test period. P450scc overexpression in the NAc, however, did not alter ethanol self-administration. Locomotor activity was unaltered by vector administration to either region. P450scc overexpression produced a 36% increase in (3α,5α)-3-hydroxypregnan-20-one (3α,5α-THP, allopregnanolone)-positive cells in the VTA, but did not increase 3α,5α-THP immunoreactivity in NAc. These results suggest that P450scc overexpression and the resultant increase of 3α,5α-THP-positive cells in the VTA reduces ethanol reinforcement. 3α,5α-THP is localized to neurons in the VTA, including tyrosine hydroxylase neurons, but not astrocytes. Overall, the results demonstrate that using gene delivery to modulate neuroactive steroids shows promise for examining the neuronal mechanisms of moderate ethanol drinking, which could be extended to other behavioral paradigms and neuropsychiatric pathology.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.