Delta 9-tetrahydrocannabinol: aversive effects in rat at high doses.

Water-deprived rats were administered a single dose of Delta(9)-tetrahydrocannabinol either orally or intraperitoneally immediately after their first taste of a saccharine solution. In tests beginning 47 hours after drug administration, a dose-related reversal of rats' normal preference for saccharine was found. The data suggest that the drug produces aversive effects at doses of 1 to 32 milligrams per kilogram.

9 -tetrahydrocannabinol: dose-related effects on timing behavior in chimpanzee.

Delta(9)-Tetrahydrocannabinol, at doses within the effective range for humans, was administered orally to chimpanzees with stable, efficient timing performances maintained by multilink chained schedules of food reinforcement. Reinforcements decreased with increasing dose, because of decreased frequencies of total operant timing responses and decreased accuracy of the timing performances which did occur. Higher doses exerted an effect for up to 3 days.

Inhibition of normal growth by chronic administration of delta-9-tetrahydrocannabinol.

Body weight, food and water intake, and feces weight of 20 albino rats were recorded daily for 70 days. On days 11 to 40, 12 rats received behaviorally effective doses of Delta-9-tetrahydrocannabinol, either orally or intraperitoneally. These rats ate significantly less than placebo-dosed controls during the treatment period, and gained significantly less weight. Food intake recovered in the 30-day posttreatment period, but the former drug group still weighed less than the controls on day 70. In addition, all rats who had received intraperitoneal injections of Delta-9-tetrahydrocannabinol showed evidence of chronic diffuse nonsuppurative peritonitis.

Tolerance to behavioral effects of physostigmine under interval schedules of positive or negative reinforcement.

The present experiments examined whether the rate and type of events maintaining responding help determine physostigmine's behavioral effects. The first two experiments examined the acute and chronic effects of physostigmine, respectively, on lever pressing of rats under variable-interval schedules of food presentation. The third examined the chronic effects of physostigmine on lever pressing under random-interval schedules of shock avoidance. Three different variable intervals (18, 56, and 180 s) and two different random intervals (20 and 60 s) were studied, each associated with a distinctive stimulus. Baseline rates of responding were directly related to the scheduled rate of food delivery or shock avoidance. Acute administration of 0.154-1.233 mumol/kg (0.1-0.8 mg/kg) physostigmine sulfate produced monotonic decreases in overall response rate under all schedules of food presentation. Acute effects (per cent of control response rate) did not differ systematically under the various interval values. Large doses (i.e., 0.4 or 0.8 mg/kg) suppressed the rate of food delivery as well. When initially administered, 0.967 mumol/kg (0.4 mg/kg) physostigmine salicylate also suppressed avoidance response rates and per cent shocks avoided. Tolerance developed to the effects of this dose of physostigmine salicylate on pellet or shock-avoidance frequency more rapidly than to effects on overall response rate. Tolerance to the latter developed only very gradually and could in the case of shock-avoidance response rates be considered partial at best. Tolerance was not affected by the scheduled rate of food or shock presentation. Blood acetylcholinesterase levels showed no recovery during chronic physostigmine. Tolerance is discussed in terms of the reinforcement-loss hypothesis.

Environmental influences on the development of tolerance to the effects of physostigmine on schedule-controlled behavior.

The influence of environmental variables on the development of tolerance to physostigmine's effects in rats was examined using multiple fixed-ratio, extinction schedules of food presentation. Initial administration of physostigmine (0.4 mg/kg) produced nearly maximal decreases in the number of food pellets delivered, running response rate, and overall response rate, under multiple FR 10, EXT and multiple FR 50, EXT schedules. With repeated administration, tolerance to physostigmine's effects was observed when 10 responses were required to produce reinforcement but was not observed when 50 responses were required to produce reinforcement. Tolerance under the multiple FR 10, EXT schedule of reinforcement was also observed when physostigmine was administered post-session. When tolerance was acquired, it was retained for up to 25 drug-free days. These results suggest that tolerance to physostigmine's effects on schedule-controlled behavior is strongly influenced by response requirement, independently of physostigmine-induced reinforcement loss. Additionally, tolerance is not dependent on experience with the schedule while under the effects of physostigmine, and is retained for a substantial period of time in the absence of continued physostigmine administration.

Tolerance to oxotremorine's effects on schedule-controlled behavior in physostigmine-tolerant rats.

Tolerance to the effects of physostigmine and oxotremorine in rats was evaluated using a multiple fixed-ratio 10, extinction schedule of food presentation. Physostigmine was administered either once daily or three times daily for 18 consecutive days. Tolerance to physostigmine's response decreasing effects was observed under both administration regimens. Cumulative dose-effect functions for oxotremorine (0.0056-0.562 mg/kg) were determined before and after chronic physostigmine administration. Oxotremorine's potency to produce response rate suppression decreased in rats receiving physostigmine three times daily but did not substantially change in rats receiving single daily injections. These results demonstrate that the dose or duration of action of physostigmine can determine whether tolerance to physostigmine's effects is accompanied by cross-tolerance to oxotremorine's effects.

Effects of sustained avoidance/escape on demand for food.

Rats were concurrently exposed to a sustained avoidance/escape (SAE) procedure and a procedure for assessing demand for food. In the sustained SAE procedure, signalled shock avoidance/escape trials were presented at varying intervals averaging five minutes. The shock could be avoided by pulling on a ceiling chain early in the trial, or escaped by pulling on the chain later in the trial. Demand curves for food were generated by requiring 1, 5, 10, 20, 40, 80, 160, and 320 lever presses for each food pellet on successive days. The demand curve procedure was introduced after either brief (3 or 5 days) or extended (21 or 23 days) exposure to SAE. Following brief exposure to SAE, SAE animals showed decreased food intake and less elasticity of demand relative to non-SAE controls. Following extended exposure to SAE, these effects were diminished or absent.

The role of reinforcement loss in tolerance to chronic delta9-tetrahydrocannabinol effects on operant behavior of rhesus monkeys.

Two monkeys were trained on a multiple fixed-interval (FI) 120 sec, differential reinforcement of low rate (DRL) 120 sec schedule of food reinforcement for lever pressing in which the two schedules, each correlated with a distinctive cue, alternated throughout an experimental session. Under chronic daily treatment with delta-9-tetrahydrocannabinol in a dose of 7 mg per os (1 mg/kg), for 40 consecutive days, responding increased in both schedules. Performance on the DRL schedule was affected less dramtically than that on the FI schedule. Even though reinforcement frequency on the DRL schedule remained suppressed and FI reinforcement frequency was unaffected during chronic drug treatment, DRL performance showed greater tolerance than FI performance.

Effects of atropine and azaprophen on matching and detection in rhesus monkeys.

The effects of the anticholinergic atropine and azaprophen, a novel, conformationally restricted analog of atropine, were examined in rhesus monkeys using delayed match-to-sample and detection tasks. Both compounds (0.01-0.32 mg/kg) produced dose-dependent decreases in the rate of responding under both tasks. Drug effects on the match-to-sample task correlated with drug effects on the detection task. Both compounds produced decreases in the percentage of correct responses on the match-to-sample task when choice trials occurred 4 or 16 sec, but not 0.01 sec, following sample presentation. Doses of atropine and azaprophen decreasing accuracy on the match-to-sample task also decreased the number of responses on the task. In general, atropine was slightly more potent than azaprophen on both tasks. These results further characterize azaprophen's anticholinergic effects.

Relationship of the behavioral effects of aprophen, atropine and scopolamine to antagonism of the behavioral effects of physostigmine.

Behavioral effects of aprophen, atropine and scopolamine, in rats, were examined under a multiple schedule of food presentation and at different injection-test times. The effects of the varied treatments were compared to the ability of the drugs, under identical conditions, to prevent the behavioral effects of the anticholinesterase, physostigmine. Potencies of the antagonists to decrease response rates varied across three log units. All three antagonists produced dose-related attenuation of the response suppressant effects of physostigmine. In general, aprophen was a better antagonist than scopolamine or atropine. It blocked behavioral effects of physostigmine across a wider range of doses than the other compounds, and did so with less behavioral disruption. Although substantial differences between the three antagonists were observed, the behavioral effects of all three antagonists (when administered alone) were positively correlated with their efficacy as antagonists of the response suppressant effects of physostigmine.

Scopolamine-induced impairment in concurrent fixed-interval responding in a radial maze task.

The present study investigated the effects of scopolamine hydrobromide (SCOP: 0.06-1.0 mg/kg IP) and its quartenary analogue, scopolamine methylbromide (SCOPMB), on performance in a radial arm maze foraging task, to dissociate general drug-induced alterations of motor performance from measurement of impairments on more complex behaviors involving timing and memory. In this paradigm. rats are trained to free run a radial maze under an eight-alternative concurrent fixed-interval (FI) schedule of food reinforcement. The eight FIs (55 to 759 s) were assigned randomly to the arms of the maze, with a different pattern for each animal. SCOP produced dose-dependent degradation in response patterning and response rates in the concurrent FI schedules without significantly affecting the rates of arm entries or arm traversal latencies. The peripheral cholinergic antagonist, SCOPMB, generally produced small to moderate depressions in all measures with the exception of patterning of arm entries and pellets earned, but there were no clear dose-response relationships evident in the data. These results are consistent with the notion that central cholinergic mechanisms are involved in the mediation of complex conditioned behaviors.

Reduction of heroin intake in baboons by an economic constraint.

Baboons earned their total food ration in a situation where they were periodically given an opportunity to choose between food and an intravenous infusion of heroin. As the number of daily choices was restricted, food intake remained relatively constant, while heroin intake decreased dramatically.

Atropine effects on delayed discrimination performance of rats.

The effects of atropine sulfate (ATS) and atropine methyl nitrate (ATM) on the conditional discrimination behavior of rats were investigated in eight-hour experimental sessions. Responding of rats was reinforced on either a lighted or a darkened lever depending on whether lights over both levers had been on during the preceding sample portion of the trial. Zero-delay and four-second-delay trials were randomly interspersed. Quality of performance was analyzed using the A' sensitivity measure of signal detection theory. Both drugs reduced both sensitivity and the percentage of trials on which responding occurred (percent response) below saline treatment levels. The two drugs did not reliably differ from each other in their effects on sensitivity during the zero-delay condition, but reliable differences between the two drugs emerged during the four-second-delay condition at doses above 0.8 mg/kg. Percent response recovered more rapidly for animals treated with ATS than responding occurred (percent response) below saline treatment levels. The two drugs did not reliably differ from each other in their effects on sensitivity during the zero-delay condition, but reliable differences between the two drugs emerged during the four-second-delay condition at doses above 0.8 mg/kg.(ABSTRACT TRUNCATED AT 250 WORDS)

Duration discrimination: effects of probability of stimulus presentation.

Monkeys initiated a stimulus by pressing on the center of three levers and the stimulus terminated independently of behavior 60, 80, 90, or 100 sec later. Presses on the right lever were reinforced with food following the three briefer durations, and presses on the left lever, following the 100-sec duration. Incorrect responses produced a 10-sec timeout. Probability of presenting the 100-sec duration was manipulated in the range from 0.25 to 0.75, with the probabilities of the briefer durations remaining equal and summing to one minus the probability of the 100-sec duration. Percentage of responses on either side lever was functionally related to both the probability of presenting the 100-sec stimulus and to stimulus duration. An analysis of the data based on the theory of signal detection resulted in operating characteristics that were linear when plotted on normal-normal coordinates. The percentage of responses on either lever approximated the optimal values for maximizing reinforcement probability in each condition of the experiment.

Control of responding by stimulus duration.

Pigeons were trained on a procedure in which the key was white for 30 sec, alternating with periods of darkness, or timeout. In a nondifferential training procedure, timeout duration was held constant at either 9 or 21 sec for different animals, and pecks on the white key were reinforced on a variable-interval 36-sec schedule. After 30 sessions an extinction generalization test was conducted where the duration of the timeout was varied from 3 to 27 sec. This test showed no differences in responding following timeouts of different durations. In a differential training procedure, timeout durations of either 9 or 21 sec were randomly scheduled for each animal. The variable-internal schedule was in effect following the same timeout duration as in the prior nondifferential procedure. No pecks were reinforced after the other timeout duration. In 40 sessions, differences in response rates following the two durations gradually developed. A maintained generalization procedure was then imposed in which timeout durations were varied from 3 to 27 sec, with the variable-interval schedule in effect following only the same duration as in the previous procedures. The first maintained generalization session showed that the prior differential training had established control of the animals' behavior by the timeout duration. In continued training on the maintained generalization procedure, control by the timeout duration decreased.

An eight-alternative concurrent schedule: foraging in a radial maze.

In two experiments conducted in an eight-arm radial maze, food pellets were delivered when a photocell beam was broken at the end of each arm via a nose poke, according to either fixed-interval or random-interval schedules of reinforcement, with each arm providing a different frequency of reinforcement. The behavior of rats exposed to these procedures was well described by the generalized matching law; that is, the relationships between log behavior ratios and log pellet ratios were approximated by linear functions. The slopes of these log-log functions, an index of sensitivity to reinforcement frequency, were greatest for nose pokes, intermediate for time spent in an arm, and least for arm entries. Similar results were obtained with both fixed-interval and random-interval schedules. Addition of a 10-s changeover delay in both experiments eliminated the slope differentials between nose pokes and time spent in an arm by reducing the slopes of the nose-poke functions. These results suggest that different aspects of foraging may be differentially sensitive to reinforcement frequency. With concurrent fixed-interval schedules, the degree of temporal control exerted by individual fixed-interval schedules was directly related to reinforcement frequency.

Taking fatigue seriously: I. Variations in fatigue sampled repeatedly in healthy controls.

OBJECTIVE: The four objectives of this study were to test the ability of a 1-item fatigue scale to correlate with the fatigue subscale of the Profile of Mood States (POMS), to test the acceptability of recording hourly fatigue ratings, to examine the chronobiological variation in self-reports of fatigue, and finally to examine the degree to which self-report of fatigue correlated with actigraphy findings. METHODS: Ten healthy normal controls completed the POMS fatigue subscale hourly for three days. The same 10 healthy subjects wore an actigraph for 72 consecutive hours. The actigraph was modified to incorporate two event buttons which subjects were asked to push hourly to report their level of fatigue. RESULTS: The 1-item fatigue rating correlated significantly (mean r = 0.61) with the rest of the POMS subscale for fatigue. Subjects had no difficulty using the event button on the actigraph in entering the 1-item fatigue ratings. Fatigue ratings revealed marked differences in how healthy subjects report fatigue. There was no consistent diurnal patterning of fatigue. The fatigue ratings in general were not correlated with actigraphic measures. DISCUSSION: The study documents that fatigue can be repeatedly assessed with an ambulatory device and that self-reported fatigue levels vary enormously from hour to hour in a healthy normal sample.

Central vs peripheral anticholinergic effects on repeated acquisition of behavioral chains.

Monkeys that were required to repeatedly learn new sequences of responses to obtain food were injected with 0.2 mg/kg of atropine sulfate or methylatropine nitrate. Effects lasted 8 to 12 hr following injection. Both drugs decreased the rate at which the animals worked, but only atropine sulfate increased the number of attempts required to solve the problem and decreased overall accuracy, suggesting a peripheral mode of action for rate-decreasing effects, and a central mode of action for effects of atropine on qualitative aspects of performance.