Effects of amphetamine-CNS depressant combinations and of other CNS stimulants in four-choice drug discriminations

Three pigeons were trained to discriminate among 5 mg/kg pentobarbital, 2 mg/kg amphetamine, a combination of these two drugs at these doses, and saline using a four-choice procedure (amphetamine-pentobarbital group). Three other pigeons were trained to discriminate among 5 mg/kg morphine, 2 mg/kg methamphetamine, a combination of these two drugs at these doses, and saline (methamphetamine-morphine group). After 10 to 13 months of training, the pigeons averaged more than 90% of their responses on the appropriate key during training sessions. In subsequent testing, dose-response curves were determined for the individual drugs, for a wide range of dose combinations of the training drugs, and for two drugs to which the pigeons had not been exposed previously (pseudoephedrine and nicotine). After low test doses of the training drugs, pigeons responded on the saline key. As the dose increased, responding on the key associated with that drug during training sessions increased. When training drugs were combined at doses that were not discriminable when given alone, responding occurred on the saline key. When a discriminable dose of one training drug was combined with a nondiscriminable dose of the other training drug, responding occurred on the key associated with the discriminable dose. When both drugs were given at discriminable doses, responding almost always occurred on the drug-combination key. The response-rate decreasing effects of pentobarbital and amphetamine were mutually antagonized when the drugs were combined, but the rate-decreasing effects of morphine and methamphetamine were not. After low doses of pseudoephedrine and nicotine, pigeons in both groups responded on the saline key. After higher doses of pseudoephedrine and nicotine, responding in the amphetamine-pentobarbital group occurred primarily on the amphetamine key. In the methamphetamine-morphine group, higher doses of pseudoephedrine and especially nicotine engendered more responding on the combination key than had occurred in the other group. The four-choice procedure can reveal subtle effects in the discrimination of individual drugs and drug combinations that are not apparent with procedures offering fewer response alternatives.     

Clock-delivered reinforcers in conjunctive and interlocking schedules

The effects of different temporal requirements in conjunctive and interlocking schedules of reinforcement were examined. The compound schedules were arranged so that a reinforcer could be delivered by either a rat's response or a clock. As the temporal requirements increased in the interlocking schedules, the overall rate of responding increased, but the pattern of responding remained relatively unchanged. As the temporal requirement increased in the conjunctive schedules, the overall rate decreased and a pause-and-run pattern of responding emerged. When the response requirement was reduced to one in the conjunctive schedule for one animal, a low and extremely stable rate of responding developed.     

Food and amphetamine self-administration by baboons: effects of alternatives.

The effects of the availability of an alternative reinforcer on responding maintained by food pellets or fluid solutions were examined in 6 adult male baboons (Papio cynocephalus anubis). During daily 23-hr experimental sessions, baboons had concurrent access to both food pellets and fluid, with responding maintained under fixed-ratio schedules of reinforcement that varied between the two commodities. The fixed-ratio requirement, or cost, for pellets was increased when (a) no fluid, (b) a dilute dextrose vehicle, (c) 0.002 mg/kg d-amphetamine, or (d) 0.004 mg/kg d-amphetamine was available. When given nonrestricted concurrent access to food pellets and amphetamine at minimal cost (FR 2), baboons self-administered sufficient amphetamine to decrease pellet intake. Increasing the response requirement for pellets decreased pellet intake at a similar rate regardless of the available fluid and increased fluid intake in a variable manner among baboons such that there were no statistically significant increases in fluid intake. In contrast, when access to pellets was restricted to 70% of maximal intake under nonrestricted conditions, increasing pellet cost decreased pellet intake and increased fluid intake more rapidly when the high amphetamine dose was available. Thus, amphetamine was more effective as an economic substitute for pellets when access to pellets was restricted. The response cost for vehicle and both amphetamine concentrations was increased when baboons had nonrestricted and restricted access to pellets. Increasing the response requirement for fluid delivery decreased intake of all three fluids similarly under both pellet-access conditions. The results indicate that substitution between commodities with minimal commonalities can be studied under controlled laboratory conditions and is dependent upon reinforcement schedule and commodity restrictions.     

Effects of methamphetamine and scopolamine on variability of response location.

Methamphetamine and scopolamine were studied in monkeys responding under a multiple fixed-ratio fixed-interval schedule of reinforcement. A response on any one of six levers could satisfy the schedule requirements. Variability of response location was evaluated in terms of switches, where a switch was defined as a response on one lever followed by a response on a different lever. Under baseline conditions the fixed-ratio schedule generated a high rate of responding and a low level of variability, while the fixed-interval schedule generated a low rate of responding and a high level of variability. Both methamphetamine (0.1 to 0.5 mg/kg) and scopolamine (2.4 to 240 microgram/kg) decreased overall response rate and increased variability of response location in each component of the multiple schedule with increasing doses of drug. At lower doses both drugs were found to decrease rate without affecting response variability.     

A parametric evaluation of the hedonic and motoric effects of drugs: pimozide and amphetamine

This study uses a curve-fitting approach to evaluate the effects of drugs on reinforced responding in rats. The subjects obtained reinforcement according to a series of five different variable-interval schedules (a five-component multiple schedule). For each rat, pimozide, a neuroleptic, decreased response rate, and the decrease was associated with (1) a decrease in the estimated asymptotic response rate and (2) an increase in the rate of reinforcement necessary for half-asymptotic responding. That is, pimozide decreased the proportion of responding maintained by a given rate of reinforcement. In contrast, intermediate doses of amphetamine increased response rate and increased the proportion of responding maintained by a given rate of reinforcement. It was proposed that the response rate asymptote indexes motor capacity, and the rate of reinforcement necessary for half-asymptotic responding indexes reinforcement efficacy; accordingly, pimozide decreased motor capacity and reinforcement strength and amphetamine increased reinforcement strength.     

Differential antagonism of cocaine self-administration and cocaine-induced disruptions of learning by haloperidol in rhesus monkeys

Six rhesus monkeys responding under a three-component multiple schedule were administered haloperidol to determine its effects on cocaine self-administration and on cocaine's disruptive effects on the repeated acquisition and performance of response chains. In the absence of haloperidol, 0.0032-0.032 mg/kg/infusion of cocaine increased response rate and the number of infusions in the self-administration component when compared to saline administration, whereas 0.1-0.32 mg/kg/infusion decreased response rate and the number of infusions. When compared to saline administration, the two lowest infusion doses of cocaine had little or no effect on responding in the acquisition and performance components; however, higher infusion doses of cocaine dose-dependently decreased response rate in these components. In addition, the higher doses of cocaine also increased the percentage of errors in the acquisition and performance components. Pretreatment with haloperidol (0.0032 or 0.01 mg/kg, i.m.) antagonized the effects of low doses of cocaine on the number of infusions in the self-administration component, whereas only the 0.01-mg/kg dose antagonized the effects of high doses of cocaine on the number of infusions. Neither dose of haloperidol antagonized the rate-decreasing effects of cocaine on responding in the acquisition and performance components significantly; the highest dose of haloperidol alone decreased rates of responding in each component. Antagonism of cocaine's error-increasing effects by haloperidol was only evident at one dose of cocaine (0.032 mg/kg/infusion), and was more complete in the performance components than in the acquisition components. Together, these data show the limited suitability of haloperidol for selectively antagonizing cocaine self-administration in the context of a multiple schedule involving transition behavior, and show the lack of uniform antagonism across operant behaviors.     

Differential effects of pentobarbital and cocaine on punished and nonpunished responding.

Similar rates of punished and nonpunished responding, maintained with equated rates of reinforcement, were established in pairs of rats. One subject of each pair was exposed to a random-ratio schedule of food presentation. The interreinforcement intervals for this subject comprised the intervals of a random-interval schedule of reinforcement for the other (yoked) rat. The random-ratio schedule maintained rates of responding higher than those maintained by the same rate of reinforcement schedule according to the yoked random-interval contingency. A random-ratio schedule of electric foot shock added to the random-ratio schedule of food presentation suppressed rates of responding such that similar rates of responding were observed in rats of both groups. Pentobarbital (3.0 to 17.0 mg/kg) increased punished responding at doses that had little effect on or decreased nonpunished responding, whereas cocaine (5.6 to 30 mg/kg) increased nonpunished responding at doses that decreased or did not alter punished responding. Qualitatively different effects of pharmacological agents on punished and nonpunished responding can be obtained using procedures that generate similar rates and temporal patterns of punished and nonpunished responding. The effects of pentobarbital and cocaine on responding can be determined by factors other than simply the baseline rate of responding.     

Repeated diazepam administration: effects on the acquisition and performance of response chains in humans.

The effects of repeated diazepam administration (80 mg) were assessed across a 12-hr time course with humans responding under a two-component multiple schedule of repeated acquisition and performance of response sequences. Subjects resided in an inpatient clinical research ward for the duration of the study. In each component of the multiple schedule, subjects completed sequences of 10 responses in a predetermined order using three keys of a numeric keypad. In the acquisition component, a new response sequence was to be acquired each session. In the performance component, the response sequence always remained the same. After stable responding was obtained and the effects of the placebo assessed, diazepam was administered for 3 consecutive days. The effects of repeated diazepam administration on overall percentage of errors across the two components of the multiple schedule were selective. In the acquisition component, the first dose of diazepam increased percentage errors with the magnitude of effects decreasing across the second and third days of diazepam administration. In the performance component, the percentage of errors was either minimally affected across all 3 days of diazepam administration or substantively increased on Day 1 with subsequent diazepam administrations having minimal effects. Effects on response rate were not selective. Diazepam decreased rates of responding in both schedule components, with the magnitude of effects decreasing across successive administrations. These results replicate previous findings in humans and nonhumans on the selective effects of diazepam on acquisition versus performance baselines. Also, the results suggest that the selective effects do not result from differences in reinforcement rate. Finally, the present results demonstrate that the selective recovery from repeated drug administration previously demonstrated in nonhumans using a repeated acquisition arrangement has generality to human behavior.     

An experimental analysis of the effects of d-amphetamine and cocaine on the acquisition and performance of response chains in monkeys.

In one component of a multiple schedule of food presentation, 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). Both d-amphetamine and cocaine, at the higher doses, disrupted the behavior in the learning component; the overall response rate decreased, the overall accuracy was impaired (i.e., percent errors increased), and there was less within-session error reduction. The performance component was generally less sensitive than the learning component to the disruptive effects of both drugs on rate and accuracy. After pre-feeding or during an extended session, the response rate decreased in both components, but accuracy was generally unaffected. When the four discriminative stimuli in both components were removed, the behavior was disrupted to a greater extent in the performance component. The disruptive effects of both drugs on behavior in the learning component were attenuated when the drugs were administered during the session after the response chain had been acquired. It was concluded that the greater sensitivity of the learning component to disruptive drug effects is related to the relatively weak stimulus control and/or the lower rate of reinforcement associated with that component.     

Selective antagonism of the error-increasing effect of morphine by naloxone in a repeated-acquisition task.

Pigeons acquired a different four-response chain each session by responding sequentially on three keys in the presence of four colors. The response chain was maintained by food presentation under a fixed-ratio schedule. Errors produced a brief timeout but did not reset the chain. When either morphine or naloxone was administered alone, the overall response rate decreased with increasing doses. The rate-decreasing effect was accompanied by an increase in percent errors with morphine but not with naloxone. Both effects of morphine were antagonized by doses of naloxone that were ineffective when given alone. The antagonism was selective in that naloxone (3 mg/kg) completely blocked the error-increasing effect but not the rate-decreasing effect of the higher doses of morphine. The view that naloxone is a specific narcotic antagonist was supported by the finding that naloxone failed to antagonize the rate-decreasing and error-increasing effects of d-amphetamine, pentobarbital, and phencyclidine.     

Effects of d-amphetamine and cocaine on strained ratio behavior in a repeated-acquisition task.

Pigeons acquired a different four-response chain each session by responding sequentially on three keys in the presence of four colors. When the fixed-ratio requirement for food presentation was five completions of the chain, d-amphetamine and cocaine disrupted the behavior. As the dose of each drug was increased, the overall response rate decreased, the overall accuracy was impaired (i,e., percent errors increased), and there was less within-session error reduction (acquisition). In contrast, when the fixed-ratio requirement was either 20 or 50 completions of the chain, certain doses of both drugs produced large increases in the overall response rate by eliminating the extended pausing (ratio strain) that was characteristic of the control sessions. These rate-increasing effects were accompanied by error-decreasing effects, both during acquisition and after the response chain had been acquired. Taken together, the results show that the effects of d-amphetamine and cocaine on behavior in a repeated-acquisition task can be modulated by manipulating the value of the fixed-ratio schedule maintaining the behavior.     

Effects of promazine, chlorpromazine, d-amphetamine, and pentobarbital on treadle pressing by pigeons under a signalled shock-postponement schedule.

The effects of promazine on treadle pressing to postpone the presentation of electric shock were studied in three pigeons. The effects of chlorpromazine, d-amphetamine, and pentobarbital were studied in two of these pigeons. Each treadle press postponed electric shock for 20 sec and presentation of a preshock stimulus for 14 sec. Selected doses of both promazine and chlorpromazine increased the rates of treadle pressing in all birds. The response-rate increases produced by promazine and chlorpromazine were due to increased conditional probabilities of treadle pressing both before and during the preshock stimulus. d-Amphetamine (1 and 3 mg/kg) slightly increased responding in one of the birds, but not to the extent that promazine or chlorpromazine did. In the other bird, the 10 mg/kg dose of d-amphetamine increased shock rate but did not change response rate. Some doses of d-amphetamine increased the conditional probabilities of responding both in the absence of the preshock signal and during the preshock signal in both birds. Pentobarbital only decreased response rates and increased shock rates.     

Effects of D-amphetamine on response acquisition with immediate and delayed reinforcement.

The present study examined in 8-hour sessions the effects of d-amphetamine (1.0, 5.6, and 10 mg/kg) on the acquisition of lever-press responding in rats that were exposed to procedures in which water delivery was delayed by 0, 8, or 16 seconds relative to the response that produced it. Both nonresetting- and resetting-delay conditions were studied. Although neither shaping nor autoshaping occurred, substantial levels of operative-lever responding developed under all conditions in which responses produced water. The lowest dose (1.0 mg/kg) of d-amphetamine either had no effect on or increased operative-lever pressing, whereas higher doses typically produced an initial reduction in lever pressing. Nonetheless, overall rates of operative-lever pressing at these doses were as high as, or higher than, those observed with vehicle. Thus, response acquisition was observed under all reinforcement procedures at all drug doses. In the absence of the drug, most responding occurred on the operative lever when reinforcement was immediate. Such differential responding also developed under both nonresetting- and resetting-delay procedures when the delay was 8 seconds, but not when it was 16 seconds. d-Amphetamine did not affect the development of differential responding under any procedure. Thus, consistent with d-amphetamine's effects under repeated acquisition procedures, the drug had no detrimental effect on learning until doses that produced general behavioral disruption were administered.     

d-amphetamine and fixed-interval performance: effects of operant history.

Sixteen rats were initially exposed for 50 sessions to either a fixed-ratio 40 or an interresponse-time-greater-than-11-second food reinforcement schedule, then shifted to a fixed-interval 15-second food reinforcement schedule. Animals with fixed-ratio 40 histories lever pressed at much higher rates under the fixed-interval schedule than did animals with inter-response-time-greater-than-11-second histories. This difference persisted across 93 sessions of fixed-interval exposure. The effects of d=amphetamine were assessed after 15 and 59 sessions of fixed-interval exposure. On both occasions, the low-rate responding of animals with interresponse-time-greater-than-11-second histories was typically increased by all doses of the drug, while the high-rate responding of animals with fixed-ratio 40 histories was typically decreased by all doses of the drug. These results suggest that control response rate under the fixed-interval schedule, which may be affected by a history of responding under another schedule, is the primary determinant of the relative effects of d-amphetamine.     

Molecular analyses of the effects of d-amphetamine on fixed-interval schedule performances of rats.

A series of doses (0.5 to 2.0 mg/kg) of d-amphetamine was administered to rats whose lever pressing was maintained by fixed-interval 30-s, 60-s, or 120-s schedules of reinforcement by sucrose delivery. Under both saline and d-amphetamine conditions, molecular features of responding were reliably described in terms of the distribution of postreinforcement pauses and local response rate following the onset of responding. Postreinforcement pause always varied from interval to interval but, on average, shortened under the drug. Local response rate (response rate exclusive of pause time) tended to decrease under the drug, and where acceleration occurred within runs of responses, it was reduced by the drug. All of these effects were dose-related. These findings suggest that fixed-interval behavior can be analyzed effectively at a molecular level, and that the effects of d-amphetamine are best described as disruption of temporal discrimination.     

Effects of chlordiazepoxide and cocaine on concurrent food and avoidance-of-timeout schedules.

Five rats were trained on a concurrent schedule in which responses on one lever produced a food pellet on a random-interval 30-s schedule during 10 s of food availability associated with distinctive exteroceptive stimuli. Responses on another lever postponed for 20 s the presentation of a 50-s timeout, during which all stimuli were extinguished and the schedule contingencies on the food lever were suspended. The response rates maintained by the random-interval schedule exceeded those maintained by the avoidance contingency, but both provided a stable baseline to assess the behavioral effects of different drugs. Low doses of cocaine hydrochloride (1 and 3 mg/kg) did not affect food-reinforced responding or avoidance response rates. Intermediate doses (5.6, 10, and 13 mg/kg) produced a dose-dependent decrease in food-maintained and avoidance response rates, and both types of responding were virtually eliminated after administration of the highest doses (17 and 30 mg/kg) of cocaine. Low doses of chlordiazepoxide (1 and 3 mg/kg) increased food-maintained and avoidance response rates, and both rates decreased systematically after 10 and 30 mg/kg of this drug. The effects of cocaine and chlordiazepoxide on response rates maintained by avoidance of timeout from food presentation were unlike those reported when subjects responded to avoid shock presentation. The results of this experiment thus provide evidence to suggest that the effects of drug administration on avoidance behavior may be a function of the nature of the consequent event to be avoided.     

The behavioral effects of depletions of brain serotonin induced by 5,7-dihydroxytryptamine vary with time after administration

Ether-anesthetized Sprague-Dawley rats were depleted of brain serotonin (5HT) by intraventricular injections of 50 micrograms 5,7-dihydroxtryptamine (57DHT). Oral pretreatment with 25 mg/kg desmethylimipramine was used to protect brain noradrenergic neurons from 57DHT. Liquid chromatographic assays revealed that this treatment did not significantly alter catecholamine levels but depleted hippocampal 5HT by 92% and striatal 5HT by 45%. Three or eleven days after lesioning, locomotor and exploratory behavior was characterized in separate groups of animals with a behavioral pattern monitor (BPM). On Days 4 and 12, the animals were retested following saline or 1.0 mg/kg amphetamine. Three days after depletion, lesioned rats exhibited a decrease rate of habituation of locomotor activity relative to controls. When challenged with amphetamine (1.0 mg/kg), 5HT-depleted rats exhibited increased corner and decreased center activity, as well as stereotyped patterns of locomotion. Eleven days following lesion, 5HT-depleted rats exhibited habituation rates greater than controls; amphetamine challenge yielded patterns of activity similar to those of control animals. These results show that central serotonergic pathways play an important role in modulating both spontaneous and amphetamine-elicited activity in rats, and that compensatory mechanisms operate over time to alter the behavioral effects of 57DHT-induced depletions of brain 5HT.     

Effects of cocaine and alcohol, alone and in combination, on human learning and performance.

The acute effects of cocaine hydrochloride (4 to 96 mg/70 kg) and alcohol (0 to 1.0 g/kg), administered alone and in combination, were assessed in two experiments with human volunteers responding under a multiple schedule of repeated acquisition and performance of response chains. Subjects were intermittent users of cocaine and regular drinkers who were not cocaine or alcohol dependent. Alcohol was mixed with orange juice and ingested in six drinks within 30 min; cocaine was administered intranasally 45 min after completion of drinking. In each component of the multiple schedule, subjects completed response sequences using three keys of a numeric keypad. In the acquisition component, a new sequence was learned each session. In the performance component, the response sequence always remained the same. Results were consistent in both experiments, despite variations in the order in which the drugs were tested alone and in combination. Alcohol administered alone increased overall percentage of errors and decreased rates of responding in the acquisition component, whereas responding in the performance component generally was unaffected. Cocaine administered alone decreased rates of responding but did not affect accuracy of responding in the acquisition component, and enhanced accuracy of responding without affecting rates of responding in the performance component. The combined doses of cocaine and alcohol attenuated the effects observed with alcohol and cocaine alone. These results suggest that, under the conditions investigated in this study, (a) alcohol produces greater behavioral disruption than cocaine or cocaine-alcohol combinations, (b) cocaine and alcohol each attenuate effects of the other, and (c) such attenuation is most pronounced for cocaine attenuating the disruptive effects of alcohol.     

Effects of barbiturates and other sedative hypnotics in pigeons trained to discriminate phencyclidine from saline.

Pigeons were trained to peck the center key (lighted white) of three response keys to turn off the center keylight and to light one of the side keys with a red keylight and the other side key with a green keylight. Five responses (fixed-ratio component) on either side key relighted the center key. Food was delivered following 10 fixed-ratio components on the red key if 1.5 mg/kg phencyclidine had been given before the session. The position of the red and green keylights on the side keys varied randomly each time they were lighted by a peck on the center key. Subsequently, increasing doses of phencyclidine, barbital, amobarbital, phenobarbital, methaqualone, methyprylon, diazepam, oxazepam, and d-amphetamine were substituted for the training dose of phencyclidine, using a cumulative dosing procedure. At low doses of the sedative hypnotics, birds pecked the keylight color associated with saline. At higher doses, birds pecked both key colors. At the highest doses of pentobarbital and amobarbital, some birds responded almost exclusively On he color associated with phencyclidine. When responding on keys of both colors occurred following administration of phencyclidine or other sedative hypnotics, this responding was controlled by key position rather than by key color.     

Drug-behavior interaction history: modification of the effects of morphine on punished behavior.

Squirrel monkeys were trained to respond under a multiple fixed-interval, fixed-interval schedule in which the first response after 5 min terminated a visual stimulus in the presence of which electric shocks could occur. During one component of the schedule, correlated with one color of stimulus lights, every 30th response also produced electric shock; responding was suppressed during this component to approximately 10 to 12% of that occurring in the alternate component in which responding was not punished. In contrast to previous research, morphine (0.03 to 1.0 mg/kg) increased punished responding. Unpunished responding, however, was either not affected or decreased at doses of morphine that increased punished responding. Increases in rate of punished responding also occurred when the single-schedule punishment condition was studied alone in these animals. Subsequent experimentation, which systematically analyzed the development of the rate-enhancing effects of morphine on punished responding, involved the study of drug effects in additional monkeys trained initially under a single-schedule punishment condition. The effects of morphine on punished responding were studied before, after, and then during exposure to the multiple schedule that included a component in which responding was not punished. Increases in response rate with morphine did not occur until it was administered during exposure to the multiple schedule that included a component in which responding was not punished. As with the other monkeys, once the rate increases in punished responding occurred under the multiple schedule, these effects of morphine persisted, even when the multiple schedule was removed.(ABSTRACT TRUNCATED AT 250 WORDS)