Comparison of the effects of typical and atypical anxiolytics on learning in monkeys and rats.

Atypical anxiolytics such buspirone have been reported to produce fewer disruptive effects on complex behaviors than some typical anxiolytics from the benzodiazepine class. To extend this analysis, several drugs from both drug classes were directly compared in two species (rhesus monkeys and rats) using a repeated-acquisition procedure. In monkeys responding under a multiple schedule of reinforcement consisting of acquisition (learning) and performance components, buspirone (0.032-0.52 mg/kg), 8-hydroxy-dipropylaminotetralin (8-OH-DPAT;0.032-0-56 mg/kg), chlordiazepoxide (CDZP; 1-56 mg/kg) and alprazolam (0.032-0.32 mg/kg) produced dose-dependent decreases in overall response rate in all subjects. However, with buspirone and 8-OH-DPAT, these rate-decreasing effects occurred in acquisition at lower doses than in performance. The effects on overall accuracy (i.e., percent errors) in monkeys were variable across drugs and drug classes. Both 8-OH-DPAT and alprazolam produced large increases in percent errors in acquisition at doses that had little or no effect on errors in performance. Buspirone also had differential effects on percent errors across components, but the error-increasing effects in acquisition were smaller. CDZP administered either orally or intramuscularly produced only small increases in errors, and these occurred at doses that substantially decreased the overall rate of responding in both components of the multiple schedule. In rats responding under a repeated-acquisition procedure, buspirone (1-5.6 mg/kg), 8-OH-DPAT (0.056-3.2 mg/kg) and CDZP (1.8-32 mg/kg) produced dose-dependent decreases in overall response rate. Similar to acquisition data in monkeys, buspirone and 8-OH-DPAT also increased percent errors to a greater extent than CDZP. These data indicate that learning is sensitive to disruption by drugs with 5-HT1A agonist properties, and that atypical anxiolytics with 5-HT1A agonist properties are no less disruptive to "cognitive" processes than typical anxiolytics such as the benzodiazepine alprazolam.

Discriminative stimulus properties of lithium chloride in rats.

1. Adult male rats were trained to discriminate between an injection of lithium chloride (56 or 75 mg/kg) and saline in a two-lever operant chamber during a 20-minute session. 2. On training days, responding on the designated lever was reinforced under a fixed-ratio 20 (FR 20) schedule of food presentation, whereas responding on the other level had no programmed consequences. 3. Generalization testing with LiCl (10-100 mg/kg) was conducted after each subject reached a criterion of nine of ten sessions where 95% of overall responding occurred on the designated lever, and fewer than twenty responses were made on the other lever before presentation of the first reinforcer. 4. Substituting both lower and higher doses produced decreases in responding on the LiCl-appropriate lever while only higher doses decreased overall response rate. 5. Following generalization tests, animals were divided into two groups and varying doses of LiCl were given in combination with intraperitoneal injections of either dexamethasone (1 and 3.2 mg/kg) or ondansetron (0.32 and 1 mg/kg). 6. At doses that had little or no effect alone, neither ondansetron nor dexamethasone pretreatment blocked the discriminative stimulus properties of LiCl. 7. This research shows that LiCl can act as a highly discriminable stimulus in an operant drug-discrimination paradigm and suggests that the stimulus properties of LiCl do not derive from either direct activation of serotonin type-3 receptors or release of adrenocorticotropic hormone.

Differential effects of ionizing radiation on the acquisition and performance of response sequences in rats.

To compare the effects of ionizing radiation on the acquisition and performance of response sequences, rats responding under a multiple schedule of food reinforcement were each administered 0.5-6 Gy of 60Co gamma radiation. In one component of the multiple schedule, subjects acquired a different three-response sequence each session by responding sequentially on one of three response keys in the presence of three consecutively presented colors (repeated acquisition). In the other component, the three-response sequence was the same each session (performance). The response sequence in each component was maintained by food presentation under a second-order fixed-ratio (FR) 2 schedule. Errors in both components produced a 5-sec timeout but did not reset the sequence. In all subjects, 0.5-6 Gy of gamma radiation dose-dependently decreased response rates in both components for 1-5 days postexposure. These gamma-ray doses also produced dose-dependent increases in errors in both components, but only at doses that substantially decreased response rate. Unlike the effects on response rate in both components, which were comparable over the 5-day period after exposure, the effects on accuracy were generally different for the two components. More specifically, the largest increases in percent errors in the performance component occurred on day 2 postexposure, whereas the largest increases in percent errors in the acquisition component occurred on day 4 postexposure. Taken together, these results indicate that (1) acute sublethal doses of gamma radiation differentially affect the acquisition and performance of response sequences, (2) these doses of gamma radiation differentially affect the measures of rate and accuracy within each condition of behavior, and (3) using a sensitive baseline, which includes an accuracy measure, provides important information about the disruptive effects of radiation that could not be predicted from the effects on response rate alone.

Gamma radiation-induced disruption in schedule-controlled performance in rats.

Adult male rats responded under a multiple fixed-interval 2-min, fixed-ratio 50 (multiple FI FR) schedule of milk delivery. Four groups of rats were given acute whole-body doses of 2.25, 4.5, 6.75, or 9.0 gray (Gy) of 60Co gamma-photon radiation; a fifth group of rats received sham irradiation. During the session that began 10 min after exposure (day 1), multiple FI FR performance was not significantly affected in any treatment group. Neither the sham nor the 2.25-Gy irradiation produced significant alterations in performance over 6 weeks postexposure. Over days 2-4 postexposure, the 4.5-Gy and 6.75-Gy doses reduced response rates approximately 50% and increased postreinforcement pause durations under both the FI and FR schedules. The 9.0-Gy dose produced a progressive decline in both FI and FR responding over the first week postexposure, with response rates decreasing to approximately 10% of pre-irradiation control levels on day 5. Frequently, FI rates decreased more than FR rates after exposure to 4.5-9.0 Gy. Substantial recovery of pre-irradiation response rates was evident in all treatment groups over weeks 2-4 postexposure; behavioral recovery was essentially complete during postexposure weeks 5 and 6. Eight weeks after irradiation, two groups of rats were irradiated a second time. In the group given two 6.75-Gy exposures, performance decrements were similar after each exposure. In the group given two 9.0-Gy exposures, performance declined more rapidly and showed less recovery after the second exposure than after the first. Re-irradiation produced a dose-dependent increase in the incidence of lethality. Overall, gamma radiation disrupted schedule-controlled responding in a dose-related manner; both the magnitude and time course of this disruption varied as a function of dose. Exposure to higher doses of gamma radiation resulted in residual damage that was expressed following re-irradiation challenge.

Effects of chlordiazepoxide, 8-OH-DPAT and ondansetron on radiation-induced decreases in food intake in rats.

Studies of radiation effects on performance are often complicated by concurrent radiation-induced decreases in feeding behavior (i.e., "anorexia"). To evaluate the pharmacological specificity of these decreases in food intake, the interactions of radiation with three prototypical drugs were studied. Single daily i.p. administration of a dose of chlordiazepoxide, ondansetron or 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was given to groups of rats for 5 days after either a single nonlethal 4.5-Gy dose of ionizing radiation (bremsstrahlung or gamma rays) or a sham exposure. The food intake for each group was measured 60 min and 24 hr after food presentation. Radiation alone significantly decreased food intake during the 60-min test on each treatment day and for the 5-day period when data were averaged. Chlordiazepoxide (1.8-18 mg/kg) and 8-OH-DPAT (0.1-1 mg/kg) produced significant dose-dependent increases in food intake during the 60-min test in both irradiated and sham-irradiated groups, whereas ondansetron (0.1-1 mg/kg) did not alter food intake at any dose tested. The dose effects at 60 min were significant on each treatment day for chlordiazepoxide, on 4 of 5 days for 8-OH-DPAT and for both drugs when data for all 5 days were combined. In no case, however, was a significant interaction obtained for radiation and any dose of the three drugs. After 24 hr, decreases in intake were obtained in a few subjects in 3 of 12 total radiation groups. These results suggest that radiation-induced decreases in food intake do not result from damage to the mechanisms by which chlordiazepoxide and 8-OH-DPAT increase food intake and that hyperphagic agents from these two different classes may have therapeutic value for attenuating radiation-induced anorexia.

Effects of sublethal doses of ionizing radiation on repeated acquisition in rats.

To extend previous research on the effects of ionizing radiation on learning, dose-effect data with 60Co gamma-rays were collected for individual rats responding under a repeated-acquisition procedure. Under this procedure, subjects acquired a different three-response chain each session by responding (nose push) on one of three transilluminated response keys in the presence of each of three sequentially ordered colors. The response chain was maintained under a second-order fixed ratio (FR) 2 schedule of food presentation. An error produced a 5-s timeout but did not reset the three-response chain. Acquisition of each response chain was defined by a decrease in errors as the session progressed (i.e., within-session error reduction). Each session ended after 200 reinforcements or 90 min, whichever occurred first. When day-to-day acquisition for all four subjects reached a steady state, the effects of three or four doses of gamma-rays were assessed. In general, radiation doses of 1, 3, 4.5, and 8 Gy of gamma radiation delivered at a dose rate of 2.5 Gy/min produced a dose-dependent decrease in the overall response rate for 24-72 h after exposure in all four subjects. Radiation exposure also produced an increase in percent errors but only at doses that substantially decreased overall rate of responding. Unlike the effects on response rate, which were relatively consistent over a 72-h period, the effects on accuracy were greater at 72 h than at 24 h in three of four subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Cisplatin-induced conditioned taste aversion: attenuation by dexamethasone but not zacopride or GR38032F.

The 5-HT3 receptor antagonists zacopride and GR38032F are highly effective inhibitors of emesis induced by ionizing radiation and chemotherapeutic drugs such as cisplatin. The present study evaluated zacopride and GR38032F for efficacy in inhibiting the formation of the conditioned taste aversion (CTA) induced by cisplatin or lithium chloride in rats. The glucocorticoid dexamethasone, which has been reported to be effective against both the emetic and CTA-inducing effects of cisplatin, was included as a reference compound. When administered alone by i.p. injection, zacopride (0.1-10 mg/kg), GR38032F (10 mg/kg) and cisplatin (0.32-1.8 mg/kg) induced a CTA to an 0.1% saccharin solution; lower doses of each compound were ineffective. When administered as a pretreatment, neither zacopride (0.001-0.1 mg/kg) nor GR38032F (0.01-10 mg/kg) attenuated the CTA induced by cisplatin (0.32 and 0.56 mg/kg) or lithium chloride (10 mg/kg). In contrast, dexamethasone (0.32 and 1.0 mg/kg) attenuated the CTA induced by 0.32 but not 0.56 mg/kg of cisplatin. In an attempt to evaluate higher doses of zacopride against cisplatin without the potentially confounding factor that these doses by themselves induce a CTA, rats were injected with zacopride on three separate days prior to the aversion conditioning session. This pre-exposure treatment blocked the formation of the zacopride-induced CTA, but did not improve the efficacy of zacopride in attenuating the cisplatin-induced CTA. These results suggest that neither the cisplatin- nor the lithium-induced CTA in rats are due to effects that are sensitive to 5-HT3 receptor blockade.

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.

Behavioral evaluation of perinatal PCB exposure in rhesus monkeys: fixed-interval performance and reinforcement-omission.

Two experiments were conducted to examine the prolonged behavioral effects of perinatal exposure to polychlorinated biphenyls (PCBs, Aroclor 1248) in rhesus monkeys. Experiment I involved testing a group of three monkeys whose mothers had been fed 2.5 ppm PCBs in their diets both before and throughout gestation and nursing (concurrent exposure condition), and a group of three control monkeys whose mothers had received no added dietary PCBs. These offspring began testing at approximately 60 months of age. In experiment II the same group of female breeders which were fed PCBs in experiment I underwent a second round of breeding after being off the contaminated diet for an average of 20 months (postexposure condition). Additionally, another group of female monkeys underwent breeding while receiving concurrent exposure to 0.5 ppm PCBs in their diet. Control female monkeys received no added dietary PCBs. Four offspring from the 2.5 ppm postexposure condition, four from the 0.5 ppm concurrent exposure condition and five control offspring survived to begin testing here at approximately 40 months of age. All monkeys from experiments I and II were tested under a series of fixed-interval schedules of food reinforcement consisting of FI 30 sec (10 sessions) and FI 60, 300 and 600 sec (15 sessions each). Performance measures included overall response rate, index of curvature (IC) and postreinforcement pause (PRP). There were no consistent differences in FI performance between PCB and respective control groups except for a slightly though significantly lower IC in the PCB groups of experiment II under FI 300 and 600.(ABSTRACT TRUNCATED AT 250 WORDS)

Brain sites involved in the mediation of the behavioral effects of intraventricularly administered (-)-nicotine.

Fifteen hooded rats were trained to lever press for food under a fixed ratio (FR) 32 schedule. When lever pressing stabilized all rats were implanted with two cannulae, one in the lateral ventricle (LV) and the second in one of the following brain structures: dorsal hippocampus (DH), locus ceruleus (LC), lateral hypothalamus (LH), reticular formation (RF), or the vestibular nucleus (VN). All rats when infused with 5.0 micrograms (-)-nicotine (LV) showed an increased latency to complete the first ratio. Infusions of (-)-nicotine (0.25 microgram) into specific brain sites showed that qualitatively and quantitatively similar effects on FR performance could be produced when nicotine was infused into the VN. When lidocaine (5.0 micrograms) was applied to the RF the latency to complete the first ratio following 5.0 micrograms (-)-nicotine infusion into the LV was decreased by 55%. Lidocaine infused into the VN completely blocked the effect of LV (-)-nicotine. Neither lidocaine nor (-)-nicotine had any effect on responding when applied to the other brain structures. The results suggest that a primary site of central action of (-)-nicotine is the VN and that inhibition of the RF will attenuate the behavioral effects of LV infusions of (-)-nicotine.

Intravenous self-administration of pentobarbital and ethanol in rats.

Rats provided with unlimited access to intravenous doses of ethanol (30, 60, 90, 180, and 360 mg/kg/infusion) failed to initiate and maintain lever pressing that resulted in ethanol delivery. When pentobarbital (0.5 mg/kg/infusion) was substituted for ethanol, lever pressing increased. There were three indications of the positive reinforcing effects of pentobarbital: (1) a greater number of lever presses occurred when pentobarbital was response-contingent than when saline was available; (2) a greater number of responses were made on the pentobarbital lever than on a control "activity" lever; and (3) systematic changes in lever pressing were a function of pentobarbital dose (0.125, 0.25, 0.5, 1.0, and 2.0 mg/kg/infusion). Sequential substitution of ethanol (30, 90, 360 mg/kg/infusion) for pentobarbital failed to maintain lever pressing. However, access to combinations of ethanol (1, 3, 10, 30, 60 mg/kg/infusion) and a nonreinforcing dose of pentobarbital (0.125 or 0.25 mg/kg/infusion) did maintain lever pressing. As the dose of ethanol increased, the daily number of infusions first increased then decreased. Following a history of self-administration of ethanol-pentobarbital combinations, a retest of ethanol alone (10 or 30 mg/kg/infusions) followed by pentobarbital alone (0.125 or 0.25 mg/kg/infusion) failed to maintain lever pressing.

Prolonged behavioral effects of early postnatal lead exposure in rhesus monkeys: fixed-interval responding and interactions with scopolamine and pentobarbital.

Three groups of rhesus monkeys (N = 4/group) were administered daily doses of lead acetate dissolved in milk throughout the first year of life. The doses of lead administered were 0.9 mg/kg/day (high lead group), 0.3 mg/kg/day (low lead group), and no added dietary lead (control group). These doses resulted in mean blood lead concentrations over the first year of 65, 32 and 4 micrograms/dl for the high lead, low lead and control groups, respectively. Lead administration was terminated at the end of the first year and blood lead concentrations fell steadily over the next 44 months. At no time were overt signs of toxicity apparent. The effects of prior lead exposure on a fixed-interval (FI) schedule of food presentation were examined beginning at 33 months of age, at which time blood lead concentrations of all animals were less than 12 micrograms/dl. Acquisition of the bar press response varied widely among individual monkeys and no group differences were observed. Throughout 20 sessions of responding under an FI 60 sec food schedule, the lead treated animals had a significantly lower index of curvature (IC) than controls indicating a less pronounced positively accelerated pattern of responding. The magnitude and consistency of this effect were directly related to the dose of lead administered. Overall FI response rate, running rate and postreinforcement pause duration were not altered by lead treatment. Pentobarbital (2.5-10 mg/kg) decreased IC and increased response rate; these effects were not altered by lead treatment.(ABSTRACT TRUNCATED AT 250 WORDS)