We have recently observed that rats exposed to alcohol for three consecutive days via indwelling intragastric cannulae (Model A) showed the expected initial rise in plasma ACTH and corticosterone levels, but that upon a re-challenge with the drug 3-12 days later, these hormone responses were significantly blunted.
Under Specific Aim 1, we will test hypothesis related to the mechanisms responsible for the decreased HPA axis in this model of short-term alcohol treatment. We will first determine whether pituitary responsiveness to CRF and/or vasopressin is reduced. If this is the case, we will test the hypothesis that steady-state MRNA levels of pituitary CRF-R1 and/or POMC are decreased, and/or that the pituitary is more sensitive to glucocorticoid feedback. Using transcript levels of the immediate early gene NGFI-B, we will also determine whether hypothalamic neuronal activation is blunted during a second alcohol challenge. If they are reduced, we will test the hypothesis that this is accompanied by decreased CRF synthesis in the hypothalamus, possibly via increased sensitivity to CRF neurons to glucocorticoid feedback. In parallel studies, we will also use a model of chronic alcohol treatment (Model B), in which rats are exposed to intermittent alcohol vapors for 2 weeks, then re-challenged with this drug following a period of protracted abstinence. We will first determine whether animals of Model B also show neuroendocrine tolerance when re-exposed to alcohol or whether, as observed with other long-term stress paradigms, they will exhibit an exacerbated response of their HPA axis. In either case, the mechanisms responsible for these changes will be investigated. Experiments carried out under Specific Aim 2, on the other hand, will use knock-out mice to investigate the importance of CRF and its receptors on the response of the HPA axis to alcohol. In CRF-deficient mice, we will test the hypothesis that CRF is the sole mediator of this response. In mice homozygous for a null CRF-R1 allele, we will test the hypothesis that pituitary and/or hypothalamic CRF-R1 participate in alcohol-induced ACTH release. Finally in CRF-R/2 knock-out mice, we will test the hypothesis that pituitary and/or hypothalamic CRF-R2 are not necessary for this ACTH response.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Specialized Center (P50)
Project #
3P50AA006420-16S1
Application #
6097641
Study Section
Project Start
1998-12-01
Project End
1999-11-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
16
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Takashima, Yoshio; Mandyam, Chitra D (2018) The role of hippocampal adult neurogenesis in methamphetamine addiction. Brain Plast 3:157-168
Takashima, Yoshio; Fannon, McKenzie J; Galinato, Melissa H et al. (2018) Neuroadaptations in the dentate gyrus following contextual cued reinstatement of methamphetamine seeking. Brain Struct Funct 223:2197-2211
Berger, Anthony L; Henricks, Angela M; Lugo, Janelle M et al. (2018) The Lateral Habenula Directs Coping Styles Under Conditions of Stress via Recruitment of the Endocannabinoid System. Biol Psychiatry 84:611-623
Galinato, Melissa H; Takashima, Yoshio; Fannon, McKenzie J et al. (2018) Neurogenesis during Abstinence Is Necessary for Context-Driven Methamphetamine-Related Memory. J Neurosci 38:2029-2042
Ehlers, Cindy L; Wills, Derek; Gilder, David A (2018) A history of binge drinking during adolescence is associated with poorer sleep quality in young adult Mexican Americans and American Indians. Psychopharmacology (Berl) 235:1775-1782
Serrano, Antonia; Pavon, Francisco J; Buczynski, Matthew W et al. (2018) Deficient endocannabinoid signaling in the central amygdala contributes to alcohol dependence-related anxiety-like behavior and excessive alcohol intake. Neuropsychopharmacology 43:1840-1850
Kirson, Dean; Oleata, Christopher Shaun; Parsons, Loren Howell et al. (2018) CB1 and ethanol effects on glutamatergic transmission in the central amygdala of male and female msP and Wistar rats. Addict Biol 23:676-688
Fannon, McKenzie J; Mysore, Karthik K; Williams, Jefferson et al. (2018) Hippocampal neural progenitor cells play a distinct role in fear memory retrieval in male and female CIE rats. Neuropharmacology 143:239-249
de Guglielmo, Giordano; Conlisk, Dana E; Barkley-Levenson, Amanda M et al. (2018) Inhibition of Glyoxalase 1 reduces alcohol self-administration in dependent and nondependent rats. Pharmacol Biochem Behav 167:36-41
Kononoff, Jenni; Melas, Philippe A; Kallupi, Marsida et al. (2018) Adolescent cannabinoid exposure induces irritability-like behavior and cocaine cross-sensitization without affecting the escalation of cocaine self-administration in adulthood. Sci Rep 8:13893

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