Effects of phencyclidine,pentobarbital, and d-amphetamine on the acquisition and performance of conditional discriminations in monkeys

In each of two components of a multiple schedule, monkeys were required to respond on a right or left lever depending upon the stimulus combination (a color and a geometric form) presented. Reinforcement of a response in the presence of one stimulus (the form) was therefore conditional upon the other stimulus (the color). The completion of a two-member chain of discriminations produced a food pellet. Errors produced a brief timeout. One component of the multiple schedule was a repeated-acquisition task where the discriminative stimuli for left- and right-lever responses wer changed each session (learning). In the other component, the discriminative stimuli for left- or right-lever responses were the same each session (performance). Phencyclidine, pentobarbital, and d-amphetamine each produced dose-related decreases in the overall rate of responding in both components of the multiple schedule. At high doses each drug increased the percent errors in each component. At lower doses, however, the three drugs produced selective effects on accuracy. Errors were increased in the learning component at lower doses than those required to disrupt the discrimination in the performance component. A signal detection analysis of the data revealed that none of the drugs tested increased errors by selectively affecting either discriminability or bias.     

Effects of combinations of phencyclidine and pentobarbital on schedule-controlled behavior in the squirrel monkey.

Three squirrel monkeys trained on a variable interval schedule of food presentation were used to examine the interaction between phencyclidine (PCP) and pentobarbital (PB). First, dose-response curves for each drug given alone were obtained. PCP caused small response rate increases at low doses, and a dose-dependent decrease in responding at higher doses. PB caused only dose-dependent decreases in responding. The PB dose-response curve was then redetermined in the presence of four doses of PCP. Little support was found for the hypothesis that PCP enhances the depressant properties of PB. In fact, most dose combinations caused less disruption of responding than expected from simple addition of the effects of each drug given alone. These results are discussed in terms of species differences, measurement of different dipendent variables and rate-dependency.     

Effects of phencyclidine, d-amphetamine and pentobarbital on spaced responding in mice

The effects of acute IP administration of phencyclidine (PCP), d-amphetamine (AMPH) and pentobarbital (PB) were determined in 10 mice trained to lever press on a differential reinforcement of low rate 10 sec schedule of sweetened milk presentation. The effects of PCP were highly consistent, with large response rate increases (and a corresponding shift toward shorter interresponse times) at doses of 1 and 3 mg/kg. Higher doses generally decreased response rates and resulted in a bimodal interresponse time distribution. The effects of AMPH were similar to PCP but less consistent. Although some of the subjects showed substantial response rate increases at doses between 0.3 and 10 mg/kg, half of the subjects did not show increased response rates at any dose. The effects of AMPH on the interresponse time distribution were similar to PCP. The effects of PB were least like those of PCP. The effect in most subjects was to produce a dose-related decrease in response rate and a flattening of the interresponse time distribution. Occasional small response rate increases were observed with PB.     

Effects of pentobarbital and d-amphetamine on oral phencyclidine self-administration in rhesus monkeys

The purpose of this study was to examine the benzodiazepine-like activity of fominoben-HCl, a compound with prominent antitussive and respiratory stimulant actions. Towards this end we examined the anticonvulsant actions of fominoben as well as its ability to displace benzodiazepine (BDZ) binding from brain membranes. Scatchard analysis of binding data demonstrated that fominoben displaced 3H-flunitrazepam binding from rat cortical membrane preparations. Furthermore when tested against 3H-ethyl-beta-carboline-3-carboxylate, the addition of GABA resulted in a mean (+/- SE) shift of the IC50 from 4.05 +/- 0.10 microM to 2.2 +/- 0.05 microM, a characteristic of benzodiazepine agonists. Seizures were induced in male, Swiss Webster mice with pentylenetetrazol (PTZ) or 3-mercaptoproprionic acid (3-MP). Fominoben (50 and 100 mg/kg) completely protected mice from seizures induced by 50 mg/kg PTZ and elevated the seizure latency against 75 mg/kg of PTZ. The anticonvulsant effects of fominoben were less pronounced against 3-MP-induced seizures. The benzodiazepine antagonist Ro 15-1788 antagonized the anticonvulsant action of fominoben against both convulsants. Taken together, these data suggest that the anticonvulsant action of fominoben may be mediated by agonistic actions at benzodiazepine binding sites.     

Effects of phencyclidine,haloperidol, and naloxone on fixed-interval performance in rats

Phencyclidine (PCP), haloperidol, and naloxone were administered alone and in combination to rats responding under a fixed-interval schedule for water presentation. Lower doses of PCP (0.25–2.0 mg/kg) and naloxone (0.001–0.1 mg/kg) produced increases while higher doses produced dose-dependent decreases in response rate. Haloperidol (0.0625–0.5 mg/kg) produced a monotonic dose-dependent decrease in responding. When a dose of naloxone (8.0 mg/kg) that did not alter responding was administered prior to the PCP, the PCP dose-response curve was shifted to 6.5-fold lower doses of PCP. When a dose of haloperidol (0.0625 mg/kg) that did not alter responding was administered prior to the PCP, the PCP dose-response curve was shifted to 1.5-fold higher dose of PCP. These observations are discussed in relation to current views of the mechanism of PCP action.     

Effects of chronic phencyclidine on fixed-ratio responding: No relation to neurotransmitter receptor binding in rat cerebral cortex

The effects of chronic phencyclidine (3.2 mg/kg for 25 days) on responding maintained under a fixed-ratio 30 schedule of food presentation were studied in rats. Initially phencyclidine produced large decreases in the overall rate of responding. This decrease was due primarily to long pauses in responding and secondarily to a decrease in local rates of responding. Although tolerance developed to the rate-decreasing effects of phencyclidine in each subject, the extent and pattern of its development differed among the subjects. After the chronic drug regimen, the rats were sacrificed. Ligand binding to muscarinic cholinergic, opiate, adrenergic, and serotonergic receptors in cortex was then compared to that in rats which received saline with operant training, phencyclidine alone, or saline alone. Neither operant behavior alone, phencyclidine alone, nor the interaction of phencyclidine and operant behavior was found to alter binding to these receptors. The results indicate that behavioral tolerance develops to phencyclidine, but it is not accompanied by changes in binding to the receptors studied.     

Effects of fixed ratio size and dose on phencyclidine self-administration by rats

Female Sprague-Dawley rats were trained to self-administer phencyclidine (PCP; 0.125, 0.25, or 0.5 mg/kg/injection) on a fixed ratio (FR) schedule of reinforcement under limited access conditions (3 h). Initial training began with cocaine, which was later replaced with ketamine and then one of the three unit doses of PCP. Baseline rates of injection were determined at RF 10. The size of the ratio was then incremented geometrically every fifth daily session. Increasing the ratio resulted in a decrease in the number of injections per session. Furthermore, this decrease was greater for the 0.25 mg/kg dose than for the 0.5 mg/kg unit dose. The self-administration of the 0.125 mg/kg dose was variable and rapidly extinguished upon the increase in fixed ratio. The results indicate that PCP is self-administered by rats under the conditions imposed in this study. Furthermore, the relative reinforcing efficacy of the different unit doses of PCP could be discriminated using this type of response cost procedure.     

Effects of morphine,d-amphetamine,and pentobarbital on shock and light discrimination performance in rats

The effects of 2 and 4 mg/kg morphine sulfate, 0.5 and 1 mg/kg d-amphetamine sulfate, and 6 and 12 mg/kg pentobaribital sodium were tested in rats in two different discrete-trial two-choice discrimination tasks. The discriminative stimuli for one task were high and low intensity shocks. In the other, correct choices were signaled by the position of a brief light flash. Morphine (4 mg/kg) significantly disrupted performance of both tasks, with more reliable disturbance occurring in the shock discrimination animals. Pentobarbital (12 mg/kg), while exerting noticeable effects on gross motor behavior, had little effect on discrimination performance; d-amphetamine (1 mg/kg) was disruptive of discrimination performance in only some animals. The results indicate that much of the effect of relatively low doses of morphine on the shock discrimination performance of rats may be due not to its putative specific antinociceptive properties, but to alterations in conceptual-judgmental processes or decreases in motivation (e.g., hunger) unrelated to pain.     

Effects of pentobarbital and progesterone on random ratio responding in male and female rats

Intact male and ovariectomized female rats were trained to lever press under a random ratio (RR) schedule of food reinforcement. Effects of different doses of pentobarbital (1–16 mg/kg) and progesterone (10–80 mg/kg) on response output were studied. Low doses of pentobarbital increased responding, high doses decreased responding. Sex differences were observed in the rate-decreasing effects of high doses of pentobarbital. Progesterone increased the response rate of ovariectomized females, but did not affect responding in intact males.     

Effects of opioids and phencyclidine in combination with naltrexone on the acquisition and performance of response sequences in monkeys

In each of three components of a multiple schedule, monkeys were required to emit a different sequence of four responses in a predetermined order on four levers. Sequence completions produced food under a fixed-ratio schedule. Errors produced a brief timeout. One component of the multiple schedule was a repeated-acquisition task where the four-response sequence changed each session (learning). The second component of the multiple schedule was also a repeated-acquisition task, but acquisition was supported through the use of a stimulus fading procedure (faded learning). In a third component of the multiple schedule, the sequence of responses remained the same from session to session (performance). Heroin, methadone, cyclazocine and phencyclidine each produced dose-related decreases in overall response rate. At high doses which produced equivalent rate-decreasing effects, cyclazocine and phencyclidine generally produced greater disruption of accuracy in the learning component than did heroin or methadone. Naltrexone 5.6 microgram/kg shifted to the right by approximately 1/2-log unit the heroin and methadone dose-effect curves, but produced little or no change in the cyclazocine dose-effect curves. At 56 micrograms/kg naltrexone completely antagonized both the rate-decreasing and error-increasing effects of heroin and methadone. The same dose of naltrexone tended to produce greater antagonism of the effects of cyclazocine on accuracy than on rate, which was shifted by only 1/4-log unit. In contrast, naltrexone failed to antagonize the effects of phencyclidine on either rate or accuracy. Thus it would appear that while cyclazocine and phencyclidine produce similar disruptions in the accuracy of a discrimination, the effects of each are differentially sensitive to antagonism by naltrexone.     

Differential effects of phencyclidine and MDA on complex operant behavior in monkeys

In one component of a multiple schedule, patas monkeys acquired a different four-response chain each session by responding sequentially on three keys in the presence of four geometric forms (learning). In the other component, the four-response chain was the same each session (performance). The response chain in each component was maintained by food presentation under a fixed-ratio schedule. Errors produced a brief timeout but did not reset the chain. With increasing doses of phencyclidine the overall response rate in each schedule component decreased, the percent errors in each component increased, and there was less within-session error reduction (acquisition) in the learning component. MDA (3,4-methylenedioxyamphetamine), a hallucinogen that is self-administered in nonhuman primates, was similar to phencyclidine in producing dose-related rate-decreasing effects in both schedule components. Unlike phencyclidine, however, MDA had little or no effect on accuracy in either learning or performance.     

Effects of phenytoin on schedule-controlled performance of rats

The present study examined the effects of acute administrations of phenytoin on the lever pressing of rats maintained under fixed-ratio, fixed-interval, and interresponse-time-greater-than-T schedules of food delivery. The drug typically produced dose-dependent decreases in response rates under fixed-ratio and fixed-interval schedules, while response rates under the interresponse-time-greater-than-T schedule were affected little by the drug. These findings indicate that phenytoin effects on schedulecontrolled responding differ from those of other anticonvulsants.     

d-Amphetamine and phencyclidine alone and in combination: Effects on fixed-ratio and interresponse-time-greater-than-t responding of rats

The effects of three doses of d-amphetamine (0.5, 1.0, and 2.0 mg/kg) and phencylidine (0.5, 1.0, and 2.0 mg/kg), alone and in combination, were assessed in rats performing under fixed-ratio 30 and interresponse-time-greater-than-15-sec food reinforcement schedules. When given alone, phencyclidine and d-amphetamine produced similar increases in responding under the interresponse-time-greater-than-t schedule, and decreases in responding under the fixed-ration 30 schedule. Each drug decreased the number of reinforcers (food pellets) earned relative to control values under both schedules. The effects of the two drugs in combination were nearly always less than additive. That is, the effects of a given dose of phencyclidine and d-amphetamine together were less than an arithmetic summation of the effects of the drugs given alone.     

Effects of phencyclidine on shock-induced aggression in rats

The effects of phencyclidine were assessed under two distinctive paradigms. In a traditional laboratory assay where pairs of rats received intermittent foot shocks, phencyclidine at doses of 0.5 to 2.0 mg/kg decreased the number of shock-elicited fighting bouts in dose-dependent fashion. Similar dose-dependent decreases in biting were also observed under a procedure where single restrained rats received intermittent tail shocks, which evoked biting of an inanimate target.     

Tolerance to the behavioral effects of phencyclidine: The importance of behavioral and pharmacological variables

The effects of phencyclidine (PCP) on the behavior of rats responding to a fixed-interval 1 min schedule of water delivery were determined before, during, and after a period of daily PCP injections. The effects of acute PCP on overall response rate were biphasic: low doses increased and high doses decreased rates. In addition, PCP produced a dose-related decrease in quarter-life and high doses of PCP decreased the number of reinforcers delivered. During the daily injection regimen roughly a two-fold tolerance developed to the effects of 8.0 mg/kg PCP on response rate in animals receiving either presession or post-session injections of this dose, emphasizing the predominance of pharmacological variables in PCP tolerance. However, slight differences between these groups in tolerance development and in the rate of tolerance loss demonstrate that behavioral variables can influence tolerance to the behavioral effects of PCP.     

Effects of d-amphetamine and ethanol alone and in combination on schedule-controlled responding of pigeons

Key pecking by pigeons was maintained under either a 5-min fixed-interval or a 30-response fixed-ratio schedule of food delivery. d-Amphetamine (0.1–1.0 mg/kg) either increased or did not affect overall rates of responding under the fixed-interval schedule; the lowest dose of ethanol (0.5 g/kg) did not affect or slightly decreased response rates, whereas higher doses (1.0–2.0 g/kg) substantially decreased rates. Combinations of low noneffective ethanol doses with most doses of d-amphetamine increased rates of responding under the fixed-interval schedule above those obtained with d-amphetamine alone; decreases produced by the higher doses of ethanol were attenuated by most doses of d-amphetamine. Doses of d-amphetamine (0.1–1.0 mg/kg) and ethanol (0.5–1.5 g/kg) alone generally had no effect on responding maintained under the fixed-ratio schedule; higher doses of these drugs decreased responding. The effects of dose combinations other than the highest ones generally differed little from those obtained with ethanol alone; the effects of high doses of each drug were antagonized by low to moderate doses of the other. Combinations of ethanol with d-amphetamine can result in higher rates of responding than are obtained with either drug alone. Further, effects of the drugs alone and in combination depend on the schedule under which behavior is maintained.     

Effects of d-amphetamine on speaking in isolated humans

The effects of oral d-amphetamine, 5–20 mg were studied in isolated humans who produced speech monologues during experimental sessions. Drug effects were studied under double-blind conditions by making repeated observations within each subject after placebo or active drug. In the first experiment, d-amphetamine 15 mg was studied in 4 isolated subjects who had received instructions that they should talk some of the time during experimental sessions. All subjects spoke more after active drug than after placebo. In the second experiment, d-amphetamine 5–20 mg was studied in 4 subjects who were instructed to talk, but who also earned points under a fixed interval 5 min schedule by speaking (i.e. by closure of a voice operated relay). Point delivery did not generally influence patterns of speech over time. Reliable drug produced increases in amount of talking were observed in 3 of 4 subjects. Adjective checklist self report scores indicating a stimulant drug effect were also sensitive to effects of d-amphetamine. Under controlled laboratory conditions, an increase in speaking is a reliable behavioral effect of d-amphetamine in isolated humans producing speech monologues.     

Effects of phencyclidine and ketamine in pigeons on behavior suppressed by brief electrical shocks

Pigeons were trained to respond under fixed-ratio 30 (FR30) schedules of grain presentation. The schedule consisted of two FR30 components. In one component, every 30th response produced access to grain; FR30. In the second component, every 30th response produced access to grain, but responding was suppressed by having every response produce a brief electrical shock; FR30 (shock). In one phase of the experiment, there were no visual stimuli associated with the separate components; mixed FR30 FR30 (shock), and in the second phase, a distinctive stimulus was associated with each of the two components; mult FR30 FR30 (shock). High rates of responding (～ 2.0 responses/sec) were maintained in the FR30 components, and responding was almost totally suppressed (<0.02 response/sec) in the FR30 (shock) components. The effects of phencyclidine and ketamine were compared with pentobarbital, d-amphetamine and morphine. Phencyclidine and ketamine, over a narrow dose range, produced small increases in responding under the FR30 (shock) component of both the mixed and multiple schedules. By comparison, pentobarbital produced very large increases in responding under the FR30 (shock) component of both schedules. Increasing doses of d-amphetamine and morphine either had no effect on or decreased the response rate in both components of the mixed and multiple schedules. The results suggest that phencyclidine and ketamine may have some properties qualitatively like pentobarbital and unlike d-amphetamine and morphine in attenuating the suppression of behavior produced by brief electrical shocks.     

Effects of d-amphetamine on temporal and spatial discrimination in rats

Rats were trained to lever-press for food reinforcers on a multiple schedule that had a fixed-interval (FI) and a differential reinforcement of low rate (DRL) component. Illumination of a stimulus light above the right-hand lever indicated that responses on this lever would be reinforced according to a FI 60-s schedule while responses on the left-hand lever were without programmed consequences. However, when the light above the left-hand lever was illuminated only responses on this lever were reinforced according to a DRL 15-s schedule. When the behaviour of the subjects had been brought under schedule control so that characteristic patterns of FI and DRL responding were emitted and there were relatively few responses on the incorrect levers, the effects of several doses of d-amphetamine (0.25, 0.5, 1.0, and 2.0 mg/kg) were assessed. The drug increased preference for responding on the right-hand lever. Thus, as dosage increased performance tended towards a constant high rate of responding on the right-hand lever throughout a session, with a much lower response rate on the left-hand lever. This result emphasises that the behavioural effects of drugs depend not only on patterns of ongoing behaviour but also on the context in which this behaviour occurs.     

Effects of terminating chronic phencyclidine on schedule-controlled behavior in rats

Six rats were trained to respond under a multiple fixed-ratio 30, fixed-interval 3-min schedule for food presentation. Acute administration of phencyclidine (0.1-3.2 mg/kg, IP) produced decreases in fixed-ratio response rates at doses above 0.3 mg/kg, but fixed-interval response rates were only decreased at the highest dose. However, the pattern of fixed-interval responding (as evidenced by quarter-life values) was affected at doses above 0.3 mg/kg. Osmotic minipumps were implanted, SC, which infused saline (2 rats) or phencyclidine (4 rats, 10.0 mg/kg/day) for 10 days, and then removed. Daily behavioral sessions were conducted during infusions and for 10 days afterwards. The effects of phencyclidine infusions on fixed-ratio responding were variable. Fixed-interval response rate and quarter-life values were only modestly affected during drug infusion. All three parameters were markedly affected upon cessation of chronic phencyclidine dosing, but there did not appear to be differential effects between the schedule components. No effects on responding were observed during or after saline infusions.