Ethanol withdrawal is characterized by subjective symptoms such as anxiety. Typically these symptoms occur earlier and last longer than overt physical signs of withdrawal. Because they are subjective, their relevance to drug dependence has been difficult to study in animal models. These experiments will use a pentylenetetrazol (PTZ) discrimination paradigm to quantify and detect symptoms of withdrawal from ethanol in animals. Rats can be trained to discriminate the stimulus properties of PTZ. Drugs that minimize or block the PTZ stimulus correspondingly provoke or diminish anxiety in humans. Furthermore, spontaneous or precipitated withdrawal from benzodiazepines produces a PTZ-like stimulus. These observations suggest that the discrimination of PTZ may be a suitable model for investigating subjective events related to dependence/withdrawal phenomena for ethanol. The primary objective of this research is to establish the degree to which withdrawal from ethanol produces internal stimuli that mimic those of PTZ in rats previously trained to discriminate PTZ. Further objectives include establishing that withdrawal can be detected more readily by the PTZ discrimination than by measuring overt signs; that the intensity of withdrawal signs and symptoms can be related to dose and duration of ethanol administration; and that anxiolytic and sedative-hypnotic drugs share features of cross-dependence with ethanol as measured by the PTZ discrimination method. Rats will be trained to select one lever after PTZ injections and a second lever after saline injections. After training, they will receive chronic ethanol administrations by gavage. Subsequently, ethanol administrations will be halted, and subjects will be tested for detection of the PTZ-like stimulus and observed for overt signs of withdrawal. Additional experiments will determine the degree to which ethanol, pentobarbital, diazepam, clinidine, morphine and narcotic antagonists modify detection of the PTZ-like stimulus during ethanol withdrawal. These experiments are significant because they will provide a model for objectively quantifying a subjective symptom of drug withdrawal in animals, and they will provide a novel tool to investigate behavioral and biological factors in ethanol dependence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project (R01)
Project #
5R01AA006890-03
Application #
3110309
Study Section
Alcohol Biomedical Research Review Committee (ALCB)
Project Start
1986-03-01
Project End
1989-09-28
Budget Start
1988-03-01
Budget End
1989-09-28
Support Year
3
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Texas College of Osteopathic Medicine
Department
Type
Schools of Osteopathy
DUNS #
City
Fort Worth
State
TX
Country
United States
Zip Code
76107
Gatch, M B; Wallis, C J; Lal, H (2000) Effects of ritanserin on ethanol withdrawal-induced anxiety in rats. Alcohol 21:7-Nov
Gatch, M B; Wallis, C J; Lal, H (1999) Effects of NMDA antagonists on ethanol-withdrawal induced ""anxiety"" in the elevated plus maze. Alcohol 19:207-11
Gatch, M B; Wallis, C J; Lal, H (1999) The effects of adenosine ligands R-PIA and CPT on ethanol withdrawal. Alcohol 19:9-14
Wallis, C J; Rezazadeh, S M; Lal, H (1995) GM1 ganglioside reduces ethanol intoxication and the development of ethanol dependence. Alcohol 12:573-80
Bhadra, S; Prather, P L; Elkhayat, I et al. (1993) Anxiogenic effect of disulfiram evaluated in an animal model. J Stud Alcohol 54:5-10
Rezazadeh, S M; Prather, P L; Lal, H (1993) Sensitization to 5-HT1C receptor agonist in rats observed following withdrawal from chronic ethanol. Alcohol 10:281-3
Lal, H; Prather, P L; Rezazadeh, S M (1993) Potential role of 5HT1C and/or 5HT2 receptors in the mianserin-induced prevention of anxiogenic behaviors occurring during ethanol withdrawal. Alcohol Clin Exp Res 17:411-7
Prather, P L; Lal, H (1992) Protracted withdrawal: sensitization of the anxiogenic response to cocaine in rats concurrently treated with ethanol. Neuropsychopharmacology 6:23-9
Prather, P L; Rezazadeh, S M; Chen, J P et al. (1991) Modulation of benzodiazepine agonist and inverse-agonist receptor binding by GABA during ethanol withdrawal. Prog Neuropsychopharmacol Biol Psychiatry 15:921-34
Prather, P L; Rezazadeh, S M; Lal, H (1991) Mianserin in the treatment of ethanol withdrawal in the rat: prevention of behaviors indicative of anxiety. Psychopharmacol Bull 27:285-9

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