Differential effects of acute and chronic ethanol exposure on orexin expression in the perifornical lateral hypothalamus
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BACKGROUND: Recent reports support the involvement of hypothalamic orexigenic peptides in stimulating ethanol intake. Our previous studies have examined the effects of ethanol on hypothalamic peptide systems of the paraventricular nucleus (PVN) and identified a positive feedback loop in which PVN peptides, such as enkephalin and galanin, stimulate ethanol intake and ethanol, in turn, stimulates the expression of these peptides. Recently, orexin (OX), a peptide produced mainly by cells in the perifornical lateral hypothalamus (PFLH), has been shown to play an important role in mediating the rewarding aspects of ethanol intake. However, there is little evidence showing the effects that ethanol itself may have on the OX peptide system. In order to understand the feedback relationship between ethanol and the OX system, the current investigation was designed to measure OX gene expression in the PFLH following acute as well as chronic ethanol intake. METHODS: In the first experiment, Sprague-Dawley rats were trained to voluntarily consume a 2 or 9% concentration of ethanol, and the expression of OX mRNA in the PFLH was measured using quantitative real-time polymerase chain reaction (qRT-PCR). The second set of experiments tested the impact of acute oral gavage of 0.75 and 2.5 g/kg ethanol solution on OX expression in the PFLH using qRT-PCR, as well as radiolabeled in situ hybridization. Further tests using digoxigenin-labeled in situ hybridization and immunofluorescence histochemistry allowed us to more clearly distinguish the effects of acute ethanol on OX cells in the lateral hypothalamic (LH) versus perifornical (PF) regions. RESULTS: The results showed chronic consumption of ethanol versus water to dose-dependently reduce OX mRNA in the PFLH, with a larger effect observed in rats consuming 2.5 g/kg/d (-70%) or 1.0 g/kg/d (-50%) compared to animals consuming 0.75 g/kg/d (-40%). In contrast to chronic intake, acute oral ethanol compared to water significantly enhanced OX expression in the PFLH, and this effect occurred at the lower (0.75 g/kg) but not higher (2.5 g/kg) dose of ethanol. Additional analyses of the OX cells in the LH versus PF regions identified the former as the primary site of ethanol's stimulatory effect on the OX system. In the LH but not the PF, acute ethanol increased the density of OX-expressing and OX-immunoreactive neurons. The increase in gene expression was detected only at the lower dose of ethanol (0.75 g/kg), whereas the increase in OX peptide was seen only at the higher dose of ethanol (2.5 g/kg). CONCLUSION: These results lead us to propose that OX neurons, while responsive to negative feedback signals from chronic ethanol consumption, are stimulated by acute ethanol administration, most potently in the LH where OX may trigger central reward mechanisms that promote further ethanol consumption.
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Prepro-Hcrt mRNA increased in the lateral hypothalamus in inbred alcohol-preferring rats after chronic alcohol consumption but decreased in the perifornical area in Sprague-Dawley rats.
“For alcohol, prepro-Hcrt mRNA increased in the lateral hypothalamus in inbred alcohol-preferring rats after chronic alcohol consumption(Lawrence et al., 2006) but decreased in the perifornical area in Sprague-Dawley rats(Morganstern et al., 2010).”
From Drug Addiction: Hyperkatifeia/Negative Reinforcement as a Framework for Medications Development (2021) · cites this paper as Morganstern et al., 2010
The Results (Experiment 1; page not available) report that chronic ethanol consumption reduced OX mRNA in Sprague-Dawley rats. The measurement was in the perifornical lateral hypothalamus (PFLH), however, not the perifornical (PF) area separately; the paper’s separate LH-versus-PF analysis concerned acute ethanol. The claim about alcohol-preferring rats is attributed to a different citation and is not judged here. (LLM, conf=0.85)
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- Authors
- Morganstern, I., Chang, G., Barson, J. R., Ye, Z., Karatayev, O., & Leibowitz, S. F.
- Affiliations
- Princeton University (US)
- Corresponding author
- Leibowitz, Sarah F.
- Venue
- Alcoholism Clinical and Experimental Research
- Publisher
- Wiley
- Published
- 2010-04-23
- Volume
- 34
- Issue
- 5
- Pages
- 886-896
- ISSN
- 0145-6008 (ISSN-L)
- 1530-0277
- PMC
- PMC5266519
- OpenAlex
- W2098122723
- Cited by
- 79
- References
- 74
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 4 · 2023: 2 · 2022: 4 · 2021: 1 · 2020: 6 · 2019: 3 · 2018: 5 · 2017: 3 · 2016: 7 · 2015: 8 · 2014: 7 · 2013: 5 · 2012: 9
- FWCI
- 2.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Alcoholism Clinical and Experimental Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- U.S. Public Health Service
- National Institute on Alcohol Abuse and Alcoholism (AA12882, R01AA012882)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Life Sciences › Neuroscience › Cognitive Neuroscience › Sleep and Wakefulness Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Keywords
- orexin, lateral hypothalamus, acute ethanol administration, chronic alcohol consumption, voluntary ethanol consumption, ethanol reward, enkephalin, galanin, paraventricular nucleus, ethanol dose-response, ethanol self-administration, alcohol withdrawal, alcohol craving
- MeSH terms
- Orexins, Alcohol Drinking, Ethanol, Animals, Biofeedback, Psychology, Dose-Response Relationship, Drug, Gene Expression Regulation, Hypothalamic Area, Lateral, Male, Neuropeptides, Reward, Rats, Sprague-Dawley, Intracellular Signaling Peptides and Proteins, Rats
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