Comparison of behavioral and radioprotective effects of WR-2721 and WR-3689.

The behavioral effects of the radioprotectant agents ethiofos, S-2-(3-aminopropylamino)ethylphosphorothioic acid (WR-2721) and S-2-(3-methylaminopropyl)aminoethylphosphorothioic acid (WR-3689) were evaluated in rats trained to respond under a multiple fixed-interval 120-s, fixed-ratio 50-response (mult FI FR) schedule of milk reinforcement. Each compound produced dose-dependent reductions in responding under both schedules over the same dose range (100-180 mg/kg, IP); ED50s indicated that WR-3689 was slightly more potent than WR-2721. On several performance measures, WR-3689 produced greater decrements during a second dose-effect determination, whereas WR-2721 had more pronounced effects during the initial one. In a second series of studies, low (56 mg/kg) and high (180 mg/kg) doses of both drugs were tested for radioprotective effects in rats responding under an FR-50 schedule of milk reinforcement and exposed to a nonlethal (5 gray, Gy) or lethal (10 Gy) dose of ionizing radiation (60Co gamma rays). Neither dose of radiation altered FR response rates on the day of exposure (day 1). Five Gy of gamma radiation produced a 25-40% reduction in response rates on days 2-5 (24-72 h) after exposure. Neither dose of WR-2721 or WR-3689 provided significant protection against these performance decrements. All groups exposed to 10 Gy experienced a progressive decline in FR responding on days 2-5 after exposure. Performance of groups that received pretreatment with the 180-mg/kg dose of either drug or the 56-mg/kg dose of WR-3689 was maintained at significantly higher levels than saline-treated controls on days 4-5 after exposure to 10 Gy; however, even at these higher levels of performance response rates remained below 50% of preirradiation control levels. Subsequently, 56 and 180 mg/kg WR-3689 and 180 mg/kg WR-2721 were found to provide protection against the lethal consequences of the 10-Gy exposure. Thus, neither WR-2721 nor WR-3689 afforded any significant short-term protection against radiation-induced performance decrements when these drugs were administered at either behaviorally ineffective or behaviorally disruptive doses. Rather, the beneficial effects of these drugs paralleled their ability to antagonize radiation-induced lethality.

Effects of ionizing radiation on fixed-ratio escape performance in rats.

Adult male rats pressed a lever to terminate scrambled footshock according to a fixed-ratio 20 schedule (FR escape). Separate groups of rats received a single whole-body exposure to 4.5 or 7.5 Gray (Gy) of gamma photon radiation or were sham irradiated. The first postirradiation test session began 5 min after the end of the irradiation. The 4.5 Gy dose failed to produce any significant changes in performance over six weeks of testing after exposure. In contrast, response rates after irradiation with 7.5 Gy were decreased over the first four weeks postexposure. Reductions in response rate were due to both an increase in the latency to the first response of a ratio and to a reduction in running response rate. Performance recovered to preirradiation control levels during weeks 5-6 after exposure to 7.5 Gy. Body weights were decreased dose-dependently to a minimum of 91% of preirradiation control values during the third week after exposure to 7.5 Gy. A significant positive correlation existed for changes in the weekly average response rates and body weights at this dose. When a total dose of 7.5 Gy was delivered as 1.5 Gy per day for five consecutive days (dose fractionation), there were no significant changes in performance over eight weeks of testing although reversible decreases in response rates occurred in three of six rats. By comparison with previous studies these results demonstrate that FR escape performance may provide a more sensitive index of radiation-induced behavioral disruption than performance maintained by several other schedules of negative reinforcement.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of sublethal doses of ionizing radiation on schedule-controlled performance in rats.

Male rats responded under a fixed-ratio (FR) 50 or a fixed-interval (FI) 120 sec schedule of milk delivery. Separate groups were acutely exposed to 0.5, 1.5, 4.5 or 0 (FI only) Gray (Gy) of cobalt-60 gamma radiation 3 times at 43-day intervals. All rats received an acute dose of 6.5 Gy 64 days after the last of these exposures. One-half and 1.5 Gy did not alter FR or FI performance significantly. After 4.5 Gy, no observable changes in performance occurred within 1 hr of exposure. Maximal reductions in FR response rates occurred 24 hr after exposure and recovery followed over the subsequent 72 hr. Postreinforcement pause was increased and running response rate was decreased by 4.5 Gy. Similar effects were found after each 4.5 Gy exposure. In contrast, FI performance (overall response rate, postreinforcement pause, running response rate, index of curvature) was not altered reliably by 4.5 Gy. Both FR and FI response rates were reduced by 6.5 Gy beginning 24 hr after exposure; FR rates tended to be reduced more than FI rates 24-72 hr after exposure. Response rates under both schedules recovered gradually over 7 weeks. The behavioral effects of 6.5 Gy did not vary as a function of irradiation history. In contrast, irradiation history affected survival in that 4/9 rats previously exposed to 4.5 Gy died during weeks 4-5 after 6.5 Gy, whereas there were no deaths in the rats previously exposed to lower doses. Radiogenic disruption of operant performance was dose-related, reversible, noncumulative and dependent on the schedule of reinforcement.

Effects of mixed neutron-gamma total-body irradiation on physical activity performance of rhesus monkeys.

Behavioral incapacitation for a physical activity task and its relationship to emesis and survival time following exposure to ionizing radiation were evaluated in 39 male rhesus monkeys (Macaca mulatta). Subjects were trained to perform a shock avoidance activity task for 6 hr on a 10-min work/5-min rest schedule in a nonmotorized physical activity wheel. Following stabilization of performance, each subject received a single, pulsed dose of mixed neutron-gamma, whole-body radiation (n/gamma = 3.0) ranging between 1274 and 4862 rad. Performance testing was started 45 sec after exposure. A dose-response function for early transient incapacitation (ETI) during the first 2 hr after irradiation was fitted, and the median effective dose (ED50) was calculated to be 1982 rad. More subjects experienced both incapacitation and emesis in this study than has been reported for other behavioral tasks in similar radiation fields. Analysis done on the relationship of dose to ETI, emesis, and survival time found (a) a significant relationship between the radiation dose and the number and duration of ETIs; (b) no correlation between emesis and dose, survival time, or ETI; (c) no relation between survival time and ETI at any dose; and (d) no significant difference in survival time for dose groups between 1766 +/- 9 (SEM) and 2308 +/- 23 rad.

Acute and chronic propylene glycol dinitrate exposure in the monkey.

Rhesus monkeys (Macaca mulatta) were exposed to propylene glycol 1,2-dinitrate (PGDN) vapors on either an acute (4-h) or chronic (125-d) schedule. During acute exposures, PGDN concentrations ranged from a low of 2 ppm (parts per million) to a high of 33 ppm. Free operant avoidance behavior and visual evoked responses were monitored and free operant avoidance was not affected at any dose level. The late positive (100-150 ms) wave of the visual evoked response increased 20% at 2 ppm and decreased 25% at concentrations up to 33 ppm. Although these changes were statistically different from control values, they were within the limits caused by distracting events (+/-40%), and might possibly have been caused by the irritating or distracting properties of the vapor. Other monkeys were exposed to successively increasing concentrations of PGDN vapors at 0.3-4.2 ppm. 23 h/d, for 125 d. Daily performance testing included alternating sessions of discrete-trial cued avoidance and free operant avoidance. Non of the PGDN concentrations had a discernible effect on either type of avoidance performance.