DRUG-INDUCED SELF-BITING IN RODENTS: IMPLICATIONS FOR THE LESCH-NYHAN SYNDROME
AuthorMueller, Kathyrne Jean
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PublisherThe University of Arizona.
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AbstractSelf-mutilation is a serious clinical problem. In humans self-mutilation is a characteristic of the Lesch-Nyhan syndrome and the de Lange syndrome. Several common drugs have been reported to produce self-biting in animals. The purpose of this project is to begin to determine whether drug-induced self-biting in animals shares behavioral or biochemical characteristics with self-biting in the Lesch-Nyhan syndrome. Availability of such an animal model would greatly facilitate development of rational therapies and elucidation of neurochemical mechanisms. The Lesch-Nyhan syndrome is the result of a genetic defect in purine metabolism. Purines may function as neural transmitters or purines may be released along with classical neurotransmitters, or purines may modulate neural transmission. This research is based on the assumption that the self-mutilation which accompanies the Lesch-Nyhan syndrome is the result of (a) decreased availability of purinergic neuroregulators, (b) increased amounts of hypoxanthine in the central nervous system, (c) a combination of the above. The behavioral characteristics of three types of drug-induced self-biting (caffeine, clonidine, and pemoline) were examined. Then various purines were administered in an attempt to modify drug-induced self-biting. Pemoline was administered orally to rats in doses of 140 and 220 mg/kg. Self-biting of the medial digits and dorsomedial aspect of the foreleg was commonly observed and appeared to result from intense grooming of these areas. The severity of self-biting was dose-related and self-biting was somewhat environmentally modifiable. The animals' behavior was characterized by poor response to sensorimotor stimuli and by highly repetitive behaviors. Caffeine was administered orally to rats for 14 days (185 mg/kg/day). There was a low incidence (less than 7%) of mild self-biting of the dorsomedial aspect of the forefoot. In all other respects the animals' behavior was normal. Clondine (40 mg/kg) was administered to mice and produced self-biting of the medial digits of the foreleg in 30% of mice placed in a glass beaker. Mice placed in a wire enclosure with biting objects never exhibited self-biting. The animals' behavior was characterized by generalized biting. No evidence was obtained that purines are directly involved in the etiology of drug-induced self-biting. Treatment of neonatal rats with a purinergic enzyme inhibitor did not render them more susceptible to pemoline-induced self-biting as adults. Adenosine had no effect on clonidine-induced self-biting. Contrary to expectations, hypoxanthine, a purine found in very high quantities in the central nervous system of Lesch-Nyhan patients, reduced the severity of pemoline-induced self-biting in rats. Behavior was also normalized to some degree by hypoxanthine. This phenomenon may be due to the benzodiazepinergic actions of hypoxanthine. These three types of drug-induced self-biting were discussed in relation to self-biting exhibited by animals under other circumstances and in relation to self-biting exhibited by humans. In general, self-biting in animals and humans appears to be similar. In particular, the pemoline-treated rat appears to be a good model for the de Lange syndrome and the pemoline- and hypoxanthine-treated rat appears to be a good model for the Lesch-Nyhan syndrome. A hypothesis was advanced that several distinctly different types of self-biting exist, one of which can be described (for both animals and humans) as exaggerated displacement grooming. The latter is associated with stimulants and/or with stress and becomes more severe as behavior becomes more stereotyped.
Degree ProgramGraduate College