Schedule-controlled operant behavior of rats following oral administration of perchloroethylene: time course and relationship to blood and brain solvent levels.
Previous studies have indicated that human exposure to perchloroethylene (PCE) produces subtle behavioral changes and other neurological effects at concentration at or below the current occupational exposure limit. Since comparable effects in animals may be reflected by changes in schedule-controlled operant behavior, the ability of orally administered PCE to alter fixed-ratio (FR) responding for a food reward was investigated in male Sprague-Dawley rats. Furthermore, since behavioral effects of solvents are likely to be more closely related to blood or target tissue (i.e, brain) concentrations than administered dose, the relationship between the pharmacokinetic distribution of PCE and its effects on operant responding was also evaluated. Rats trained to lever-press for evaporated milk on an FR-40 reinforcement schedule were gavaged with 160 or 480 mg/kg PCE and immediately placed in an operant test cage for 90 min. Separate animals gavaged with equivalent doses of PCE were used to determine profiles of blood and brain concentrations versus time. Perchloroethylene produced changes in responding that varied not only with dose but also among animals receiving the same dose. Changes in the response rates of rats receiving 160 mg/kg PCE were either not readily apparent, restricted to the first 5 min of the operant session, or attributable to gavage stress and the dosing vehicle. However, 480 mg/kg produced either an immediate suppression of responding for 15-30 min before a rapid recovery to control rates or a complete elimination of lever-pressing for the majority of the operant session. Although the two doses of PCE produced markedly different effects on operant behavior during the first 30 min of exposure, differences in brain concentrations of PCE were minimal. Furthermore, the majority of animals receiving 480 mg/kg PCE fully recovered from response suppression while blood and brain levels of the solvent continued to rise. Thus, relationships between blood and brain PCE levels and performance impairment were not discernible over the monitored time course. Since the rapid onset of response suppression suggests that the precipitating event occurs within the first few minutes of exposure, it is possible that altered responding is related to the rate of increase in blood or brain concentrations rather than the absolute solvent concentrations themselves. The relationship between the pharmacokinetic distribution of solvents and their effects on the central nervous system is obviously complex and may involve acute neuronal adaptation as well as the dynamics of solvent distribution among the various body compartments.
Warren
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DA
Department of Pharmacology and Toxicology, College of Pharmacy, University of Georgia, Athens, 30602-2356, USA.
Reigle
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TG
Muralidhara
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S
Dallas
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CE
D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002493:Central Nervous System Diseases / Q000139:chemically induced; D003216:Conditioning, Operant / Q000187:drug effects*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012055:Reinforcement Schedule; D012997:Solvents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D013750:Tetrachloroethylene / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D014018:Tissue Distribution
D012997:Solvents; D013750:Tetrachloroethylene