Document xjbm8y2qzOEn1jDX6b6EZzxKE

Behavioral Effects on Rats of Organic Lead Compounds William N. Dember Alfred B. Kristoffarson Department of Psychology University of Cincinnati The following proposal formalizes the outcome of informal discuss ions that we have had with staff members of the Kettering Lab over the past few months. It is proposed below that we conduct research on the behavioral effects on rats of various organic lead confounds and that this research be supported by funds from the Kettering Lab. The pro posed research is meant to supplement with behavioral studies the on going research program of the Kettering Lab on the physiological, biochemical, neurological, and, to some extent, behavioral effects of organie lead compounds. I. Research Elan The general purpose of the research is to find behavioral indic ations of the effects of organic lead compounds, preferably indications that appear prior to the obvious physical signs of illness that previous research at Kettering has uncovered. Ultimately, the discovery of such behavioral indications might facilitate early diagnosis of poisoning^ it also might increase understanding of the loci of damage, partic ularly to the CNS, produced by organic lead compounds and thereby per haps lead to the development of therapeutic techniques to arrest or alleviate such damage. At this point it would be our aim simply to discover one or more behavioral effects, and to develop methods for providing quantitative estimates of these effects. 0003440 - 2- A series of proposed studies follows, with the items listed in approximate order of priority. The proposed studies sample a fairly wide variety of behaviors. Some of the studies are suggested by existing data and hypotheses on the effects of organic lead compounds, while some are frankly exploratory. (1) Food and water consumption. From the Kettering data, and from our own informal impressions, it appears that weight loss is one of the earliest appearing physical signs of lead-poisoning. Weight loss may be the result of decreased metabolic efficiency and/or decreased consumption of food and water. The first study (which can be carried out concomitantly with some of the others) will measure food and water consumption in poisoned and control rats. (2) Forced feeding. If the first study shows a substantial re duction in food and water intake by poisoned rats, it should be in structive to determine the effect of forced-feeding on the course of the lead-syndrome. The second study, then, is contingent on the out come of the first, and if done will involve force-feeding one group of poisoned rats with an amount of food and water necessaxy to make up the deficit in their normal daily diet. The force-fed rats will be compared with a control group of poisoned rats on such gross indices as time till appearance of tremors and time till death. (3) Operant conditioning with food reinforcement. The third study is related to the first one in that it involves behavior that is food-oriented. 0003441 - 3- In this case, however, the behavior under investigation is not food consump tion per se, but rather behavior that is instrumental in obtaining food. The animal is trained, or conditioned, to press a bar which delivers a food pellet. Once a stable rate of bar pressing has been established, it is possible to use bar-pressing rate as an indicator of changes in the animal, for example, changes in hunger level. The operant conditioning technique is probably the one most frequently employed in current psychopharmacological research. It is mainly for this reasonj i.e., its successful use in drug research, that we propose to study operant conditioning behavior in lead-poisoned rats. In addition, there is some suggestion in the Russian literature (see Tolgskaya and Reznikov, 195k; Tolgskaya, 1955) that lead-poisoned animals perform diff erently in the conditioning situation from normals. (U) Discriminated operant conditioning. The operant conditioning situation also provides an excellent opportunity to study the sensory cap acities of poisoned rats. For example, the rat can be trained to press the bar only after the onset of a light. This training can be accomplished b y reinforcing the animal only for bar presses which follow light onset, and b y delivering no reinforcement for any other bar press. Once such a "discriminated operant" has been established, it can be used as an indicator of visual deficit incurred b y lead poisoning. (The technique, of course, can be applied to other sense modalities.) Since there has been some question raised about the possibility of blindness in lead-poisoned rats, this study should be of especial interest. H E 0003442 -u- ($) Alternation behavior. In a previous pilot study we obtained some evidence of decreased frequency of alternation in rats administered and affected by TML. Alternation behavior and the rationale for its use in the present setting are described in our report of that study. The argument, in essence, is that alternation is sensitive to memory deficit and that rats having low alternation scores may be suffering from damage to CNS structures that mediate recent memory. It is proposed here that we follow up the previous pilot study in an attempt to assess the reliability of the results obtained in that study. (6) In the pilot study referred to above, we failed to observe the hyperaggressiveness that previous Kettering research had found in poisoned rats. We propose to explore this finding further by comparing aggressive behavior in rats administered different compounds (e.g., TML vs. TEL) and different doses. In addition, it might be of interest to investigate the possible effect on aggressiveness of the amount of handling that the poisoned animals receive. In our pilot study the rats received several minutes of handling each day, and this may account for their failure to show the antic ipated hyperaggressiveness. (7) Assuming that we can find conditions that yield hyperaggressiveness, we propose two further studies. The first is an attempt to locate the source of the aggressive behavior. The hypothesis that we propose to test is that the hyperaggressiveness is a manifestation of hypersensitivity to painful stimulation. To test this hypothesis we propose to measure pain thresholds in poisoned and control rats, using electric shock and/or heat to the feet as the pain stimulus. - -S' (8) The second study related to the issue of hyperaggressiveness in volves a direct test of the poisoned rats* aggressive-dominant behavior in a competitive situation with another rat. In brief, the two rats are given access to a desired object, but the object is so located that only one rat at a time can make contact with it. A rat that is highly aggressive should dominate such a situation. The attempt here will be to develop a quantitative index of aggressiveness. The eight studies outlined above will make up the core of the research that we would hope to be able to complete in one year. Of course, it is difficult to predict in advance where the most profitable directions for research will be, and we anticipate that once into the program outlined above we will discover other promising lines of research. ^ 0003 44 4 - 6- II. Budget Personnel 1 graduate assistant, half-time 9 months, full-time 2 months 1 undergraduate assistant, fourth-time 9 months, full-time 2 months animal caretaker, contribution to full-time salary Animals and supplies Permanent equipment 2 operant conditioning devices, @ 7 7 0 . each mazes for alternation test and other apparatus TOTAL $ 2800. 1080. 200. 1*00. 15U0. 200. $ 6220.00 0003445