Joint effects of d-amphetamine and ethanol or pentobarbital in pigeons

Drug interactions were examined in pigeons keypecking under a multiple fixed ratio 30-response, fixed interval 5-minute (mult FR 30, FI 5-min) schedule of food presentation. Low to intermediate doses of d-amphetamine attenuated the rate-decreasing effects of ethanol under both components of the multiple schedule; however, these same doses of d-amphetamine seldom attenuated the rate-decreasing effects of pentobarbital. Increases in rates of responding produced by ethanol or pentobarbital under FI components were often enhanced following low to intermediate doses of d-amphetamine. Higher doses of d-amphetamine generally enhanced the rate-decreasing effects produced by either ethanol or pentobarbital alone. Results indicate that the joint effects of two drugs cannot be predicted from a knowledge of either their individual or their rate-dependent effects.     

Effects of MK-801 stereoisomers on schedule-controlled behavior in rats

Behavioral effects of (+)MK-801 (0.03–0.32 mg/kg) and (–)MK-801 (0.32–3.20 mg/kg) were evaluated in rats using a multiple fixed-ratio, fixed-interval (FR20, FI2) schedule of food presentation. Both enantiomers produced dose-dependent decreases in response rate under the FR20 and in this respect (+)MK-801 was approximately ten times as potent as (–)MK-801. Under the FI2 schedule component, the (+) enantiomer produced substantial increases as well as decreases in response rate whereas the (–) enantiomer produced only decreases. When 0.178 mg/kg (+)MK-801 and 1.78 mg/kg (–)MK-801 were administered for 11 consecutive days, tolerance developed to the decrease in response rate under the FR20 schedule component. Tolerance to the effects of the (+) enantiomer under the FI2 schedule component was indicated by progressively larger increases in response rate than those observed during acute administration. These results support potential therapeutic applications of MK-801.In conducting the research described in this report, the investigators adhere to the Guide for the Care and Use of Laboratory Animals, as promulgated by the Committee on Care and Use of Laboratory Animals of the Institute of Laboratory Animal Resources, National Research Council. The views of the authors do not purport to reflect the position of the Department of the Army or the Department of Defense (para 4–3, AR 360–5).     

Effect of repeated intraperitoneal injections of soman on schedule-controlled behavior in the rat

Intraperitoneal (IP) administration of the acetylcholinesterase inhibitor, soman (10–40 g/kg), suppressed in a dose-related manner response rates in rats maintained under a multiple fixed-interval 50-s fixed-ratio 25 schedule of food delivery. Chronic administration of soman at weekly intervals resulted in tolerance to the response. When soman administration was separated by 2–5 weeks in individual rats, the suppressive effects of the agent again became apparent. Analysis of acetylcholinesterase activity revealed that enzyme inhibition was limited to gastrointestinal areas near the site of injection. There was no significant effect on brain acetylcholinesterase even following IP injection of doses which completely suppressed responding. The IP route may be useful for studying tolerance and other chronic effects of soman without producing generalized toxicity.     

Role of dose order in the development of tolerance to effects of cocaine on schedule-controlled behavior in pigeons

Abstract Rationale. Tolerance to behavioral effects of cocaine can be produced by exposure to varying doses. The degree to which tolerance develops may depend on dose order. Objective. To investigate the relationships between three sequences of doses of cocaine in a daily, variable-dosing regimen and the development of tolerance to effects on schedule-controlled behavior. Methods. Twelve pigeons responded daily under a fixed-ratio 20 schedule of reinforcement, and performance was investigated under a range of doses of cocaine (0.3–10.0 mg/kg, i.m.) by administering the drug once every 7 days (acute effects). After determination of acute effects of cocaine, the drug was administered daily with dose varying from day to day. Dose order varied systematically across three groups of four pigeons; doses were delivered in ascending, descending, or "sawtooth" (ascending then descending) sequences. This variable-dosing regimen continued until drug effects were stable (at least 13 cycles through all doses). Results. During the acute-dosing regimen, response rates following small cocaine doses were similar to those under control conditions; following moderate-to-high doses, responding was diminished relative to control rates. During the variable-dosing regimen, tolerance to the rate-decreasing effects of cocaine was observed in all groups, regardless of the order in which the drug was delivered, and the magnitude of tolerance was similar across groups. Systematic differences in the rate of recovery from initial response decrements were observed across groups, with rate of recovery fastest under the ascending sequence. Conclusions. These results suggest that dose order under a variable-dosing regimen does not significantly affect the final attainment of tolerance, although it may contribute to the speed with which tolerance develops. Electronic Publication     

Pyrethroid effects on schedule-controlled behavior: Time and dosage relationships

Pyrethroid insecticides have been divided into Types I and II based on behavioral profiles of toxicity produced by life-threatening dosages. In order to assess potential alterations in acquired (operant) behavior, acute dosage-effect and time-course determinations for permethrin (Type I) and cypermethrin (Type II) were made. Long-Evans rats responded for food according to a multiple schedule consisting of four different variable-interval schedules. Permethrin (100-400 mg/kg) and cypermethrin (7.5-60 mg/kg) were administered PO 1.5 hr pre-session and their effects on response rates and between-component response patterning determined. Permethrin reduced responding in a manner which was independent of the baseline response rate, while the rate reductions following cypermethrin administration showed a dependence on the baseline levels of responding, with low response rates showing differential sensitivity to disruption. When select dosages of each compound were delivered at various pre-session times, onset of and recovery from the rate-decreasing effects were more rapid with cypermethrin, with rates returning to baseline levels by 12 hr post-dosing. Responding was maximally suppressed 24 hr after administration of permethrin and returned to baseline levels 48 hr after administration. The disruption of response patterning following cypermethrin was maximal at 1.5 hr after administration, with complete recovery 12 hr post-dosing. Differential effects on response patterning, in potency, and in the time-course of effects of permethrin and cypermethrin suggest a type-specificity for pyrethroid effects on schedule-controlled behavior at dosages far below those producing lethality in rats.     

Pyrazoloquinoline benzodiazepine receptor ligands: effects on schedule-controlled behavior in dogs

The effects of diazepam and the pyrazoloquinoline benzodiazepine receptor ligands CGS8216, CGS9896, and CGS9895 on schedule-controlled responding were studied in dogs. Responding was maintained under a multiple fixed-interval (FI) 5-min fixed-ratio (FR) 30 response schedule of food presentation. Diazepam (PO) produced dose-related decreases in response rates under FR component. Under the FI, rates first increased and then decreased with increasing doses of diazepam. Diazepam also produced a dose-related disruption of the temporal pattern of responding under the FI as measured by decreases in quarter-life values. CGS8216 IV produced dose-related decreases in response rates under both components. The highest oral dose of CGS8216 also decreased rates in both components. CGS8216 was approximately 100 times more potent by the IV route as compared to the oral route. CGS9896 IV had no significant effect on responding under either component of the multiple schedule. However, with increasing doses of CGS9896 PO, response rates under both components first decreased and then returned to control values. CGS9895 PO was without significant effect on responding. When CGS8216 was administered concomitantly with graded doses of diazepam, the former drug blocked the rate-decreasing effects of diazepam under the FR component, but not the rate-increasing effects of diazepam under the FI. The present results demonstrate that although these three pyrazoloquinolines are benzodiazepine receptor ligands, they do not exhibit diazepam-like effects on schedule-controlled behavior.     

Opioid receptor subtype-specific cross-tolerance to the effects of morphine on schedule-controlled behavior in mice

Key-press responding of mice was maintained under a fixed-ratio (FR) 30-response schedule of food presentation. Successive 3-min periods during which the experimental chamber was illuminated and the schedule was in effect were preceded by 10-min time-out (TO) periods during which all lights were out and responses had no scheduled consequences. Intraperitoneal (IP) injections of saline or of cumulative doses of drugs were given at the start of each TO period. Successive saline injections had little or no effect on response rates, whereas the -opioid agonists morphine (0.1–10.0 mg/kg) and levorphanol (0.1–3.0 mg/kg), the -opioid agonist ethylketazocine (0.03–3.0 mg/kg), the mixed -/-opioid agonist metkephamid (0.1–10.0 mg/kg), and the nonopioid dissociative anesthetic ketamine (1.0–100.0 mg/kg) generally produced dose-related decreases in response rates. Following chronic administration of morphine (100.0 mg/kg/6 h), tolerance developed to the effects of morphine on rates of responding. In addition, a comparable degree of cross-tolerance developed to the effects of levorphanol and metkephamid. On the other hand, there was no evidence of cross-tolerance to the effects of ethylketazocine or ketamine. These results are consistent with the evidence suggesting that different opioid agonists exert their behavioral effects through distinct classes of opioid receptors.     

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 selective central muscarinic blockade on schedule-controlled behavior and on the rate-decreasing effects of physostigmine

N-(4-diethylamino-2-butynyl)-succinimide, or DKJ-21, is a muscarinic receptor antagonist with a high degree of selectivity for the central nervous system. In the present study of 6 rats maintained under a fixed-interval 50-sec schedule of food reinforcement, atropine and methylatropine reduced responding in a dose dependent manner, while DKJ-21 had little or no effect. Our findings suggest that the suppression caused by atropine and methylatropine may be the result of the dry mouth induced by these agents. Doses of DKJ-21 which had no effect on schedule performance antagonized the ratelowering effects of physostigmine in all of the animals. Neither atropine nor methylatropine consistently antagonized the inhibitory effects of physostigmine. Some antagonism may be inferred, however, from the findings that response rates were suppressed less by combinations of atropine and physostigmine than by either drug alone.     

Interactions of clonidine and naloxone on schedule-controlled behavior in opioid-naive mice

Schedule-controlled responding was maintained under a fixed-ratio schedule in mice. Administered alone, clonidine, morphine and naloxone produced dose-related decreases in rates of responding, with clonidine about 100 times more potent than morphine which was about ten times more potent than naloxone. Decreases in response rates produced by high doses of naloxone were antagonized by clonidine (0.003–0.1 mg/kg) in a dose-dependent manner; however, decreases in response rates produced by clonidine (0.3 mg/kg) were not antagonized by naloxone (1.0–100 mg/kg). Effects of high doses of naloxone (100 mg/kg) were not antagonized by morphine (1.0–100 mg/kg) whereas effects of morphine (17.0 mg/kg) were antagonized by naloxone (0.01–1.0 mg/kg). Thus, clonidine can reverse behavior-disrupting effects of naloxone in non-dependent subjects, indicating that at least some of the interactions of these two drugs are not specific to the opioid-dependent state.     

Effects of ethylketazocine and morphine alone and in combination with naloxone on schedule-controlled behavior in pigeons

The behavioral effects of morphine and ethylketazocine were compared in pigeons responding under multiple fixed-interval, fixed-ratio schedules of food presentation. Both morphine and ethylketazocine produced dose-related decreases in rates of responding maintained under either schedule. Maximal effects of morphine were observed about 15–45 min after injection and typically lasted the entire session (about 60 min). Effects of ethylketazocine had a faster onset (maximal effects were observed within 15 min after injection), and shorter duration (effects diminished within the session). Ethylketazocine and morphine had similar potencies. Dose-effect curves for both drugs were shifted to a similar degree by naloxone.     

Effects of Δ9-THC and a water soluble ester of Δ9-THC on schedule-controlled behavior

Δ⁹-Tetrahydrocannabinol (Δ⁹-THC) and one of its water soluble esters (SP-111) decreased the rates of responding by pigeons working under a variable interval 3-min schedule of food presentation, or a multiple fixed-ratio 30, fixed-interval 5-min schedule of food presentation. Δ⁹-THC was 3–6 times more potent than SP-111 and had a faster onsetof effects on behavior.     

Effects of repeated administration of cocaine on schedule-controlled behavior of rats

The effects of cocaine (4.0–32 mg/kg) on schedule-controlled behavior of rats were determined before and during a period of repeated administration of cocaine. In rats trained to lever press on a fixed ratio 40 schedule for food delivery, cocaine (8.0–32 mg/kg) initially decreased response rate in a dose-related manner. During the period of repeated administration, the effects of cocaine on response rate and running rate were attenuated in 2 rats and did not change in 2 others. When dose-effect functions of cocaine were determined, a shift to the right was observed in several measures indicating the development of tolerance to these effects of cocaine on performance. In rats trained to lever press on a DRL 20″ schedule for food delivery, cocaine (4.0–32 mg/kg) increased response rates, decreased number of reinforcements per session and shifted interresponce time distributions to the left (shorter IRT's in all rats). During the period of repeated administration, the effects of the daily dose of cocaine (16 mg/kg) on all these measures were attenuated. Tolerance to cocaine was further indicated by a shift in the dose effect function of cocaine to the right during the redetermination.     

Tolerance to the disruptive effects of arecoline on schedule-controlled behavior

The roles of dispositional, physiological, and behavioral factors in the development of tolerance to the effects of arecoline on operant behavior were assessed. In Experiment I, rats were trained to press a lever on a variable-interval 15-s schedule for milk reinforcement. Dose-effect relationships were assessed prior to and during chronic arecoline (1.74 mg/kg/day) treatment. After 21 days of arecoline administration prior to each session, the dose-effect relationship for total number of responses did not shift. However, the dose-effect relationship for total number of reinforcers shifted to the right. In Experiment II, rats were trained to respond on a fixed-ratio 20 schedule for milk reinforcement. Dose-effect relationships were assessed prior to and during chronic arecoline (0.87 mg/kg/day) administration. One group of rats received daily injections of arecoline prior to the session and a second group received arecoline injections 30 min after the session. Daily administration of arecoline resulted in a greater shift to the right of the dose-effect relationship for the presession group than it did for the postsession group. These data demonstrate the importance of behavioral factors in the development of tolerance to arecoline.     

Rate-dependent effects of d- and l-amphetamine on schedule-controlled responding in pigeons and squirrel monkeys

The effects of d- and l-amphetamine were studied on key-pressing responses of squirrel monkeys maintained under fixed-interval schedules of electric shock presentation, and on key-pecking responses of pigeons maintained under multiple fixed-ratio, fixed-interval schedules of food presentation. Under the fixed-interval schedules, responding followed a pause and occurred at increasing rates as the interval elapsed. Both isomers produced comparable increases in rates of responding under relatively long fixed-interval schedules with small to intermediate doses; maximal effects of the d-isomer were obtained at doses one-half log unit smaller than the doses of the l-isomer. Responding of pigeons maintained under relatively short fixed-interval schedules was only decreased by either amphetamine isomer. Responding of pigeons maintained under fixed-ratio schedules occurred at the highest rates and was also only decreased by either amphetamine isomer. Decreases in response rate produced by the d-isomer were generally obtained at doses one-half log unit smaller than doses of the l-isomer that produced comparable effects. Both isomers increased responding that occurred at low rates early in the fixed-interval to a proportionally greater extent than higher rates from later in the interval. The highest rates in the fixed-interval were generally decreased. Differences in potency between the two isomers in producing rate-dependent effects were small, most noticable with larger doses, and less than the potency differences between the two isomers in producing changes in response rate.     

Effects of pentobarbital on punished behavior: Persistent increases with chronic administration

Food maintained responding by pigeons was suppressed by response-dependent electric shock presentation (punishment). Administration of 5.6 mg/kg pentobarbital IM for 25 days and, later, 10.0 mg/kg pentobarbital for 30 days resulted in profound, sustained, dose-related increases in punished responding and shock presentation.     

Effects of chlorpromazine and d-amphetamine on schedule-controlled and schedule-related behavior of rabbits

A lever-lifting response by Dutch Belted and New Zealand White rabbits was maintained in water-deprived animals by 0.25% saccharin solution and in food-deprived animals by food pellets under a multiple 3-min fixed-interval (FI) 30-response fixed-ratio (FR) schedule. Rabbits responding for the saccharin solution had food freely available during the session and in the home cage, whereas those responding for pellets had water continuously available during the session as well as in the home cage. Under nondrug conditions the FR and FI schedules controlled different rates and patterns of responding in the rabbit that were characteristic of those found with other species. In addition, eating or drinking occurred during the inital portion of the FI under the saccharin solution and initial food presentation schedules, respectively. Doses of d-amphetamine (0.1–10.0 mg/kg) increased responding under the FI and FR schedules of food delivery, but increased only FI responding maintained by the saccharin solution. Doses of 3.0–10.0 mg/kg d-amphetamine produced extremely high (300–800% of control) rates of stereotyped perseverative lever responding. Schedule-related eating or drinking were unaffected or decreased at doses of d-amphetamine that increased schedule-controlled responding. Chlorpromazine (0.03–0.3 mg/kg) increased FI responding maintained both by saccharin and food, whereas FR responding generally was unaffected at these dose levels; eating but not drinking was increased with chlorpromazine. Since the behavioral effects of drugs such as amphetamine and chlorpromazine differ somewhat in the rabbit from those found with other typically studied nonhuman mammals, further studies with the rabbit may yield useful information for comparative behavioral pharmacology.     

Stereoselective effects of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) on schedule-controlled behavior

The effects of R(?)?, S(+) and R, S-1-2-5-dimethoxy-4-methylphenyl)-2-Aminopropane (DOM) were studied using rats responding under a fixed interval two-min schedule of food presentation. All three drugs decreased average rates of responding in a dose-related manner, with R-DOM being five to six times more potent than S-DOM but only about 1.2 times more potent than R,S-DOM. Relatively high doses of R,S-DOM and S-DOM increased the low response rates occurring at the beginning of the fixed interval and decreased the higher response rates occuring at the end of the interval (rate-dependent effects). These results are discussed in terms of the stereoselective metabolism of DOM and of the structural similarities between R-DOM and the behaviorally active isomer of LSD.     

d-amphetamine3induced changes in social interaction patterns

The behavioral effects of d-amphetamine were studied in a group of stumptail macaques in a large outdoor enclosure. d-Amphetamine altered characteristic patterns of aggressive and affiliative behaviors in adult males that received the drug. Each monkey that received d-amphetamine increased its aggression toward non-adult animals in the group and decreased aggression toward adult members. In subjects for which genealogy was known, d-amphetamine increased aggression toward kin-related members of the group and decreased aggression toward non-kin monkeys. The effects of the drug on affiliative behaviors were less uniform and, therefore, less conclusive. Three subjects decreased affiliation and two increased affiliation toward non-adult monkeys. The results demonstrate that d-amphetamine can alter substantially the behavior of drug-treated members of a group and, in addition, that that drug can indirectly affect specific subsets of the group even though they did not receive the drug.     

Some effects of chlorimipramine and imipramine on the schedule-controlled behavior of the pigeon

The effects of imipramine and chlorimipramine on schedule-controlled behavior were compared by examining the effects of both drugs on the performance of pigeons under a multiple fixed-interval 600-s fixed-ratio 30-response (mult FI 600 FR 30) schedule of grain presentation and under a mult FI 200 FI 200 schedule in which responding in one component was punished. Imipramine decreased the rate of FR 30 responding at slightly lower doses than or the same doses as those needed to decrease the rate of FI 600 responding. In contrast, chlorimipramine decreased the rate of FI 600 responding at lower doses than those needed to decrease the rate of FR responding. These effects of chlorimipramine were similar to those of chlorpormazine subsequently determined in the same pigeons. Imipramine and chlorimipramine increased proportionally more or decreased proportionally less the lower rates of responding during the first half of the FI 600 than the higher rates of responding during the second half. When the effects of imipramine or chlorimipramine on performance under the mult FI 200 FI 200 schedule were determined, both imipramine and chlorimipramine affected the rates of punished responding and unpunished responding similarly. Thus, while some effects of chlorimipramine on the schedule-controlled behavior of the pigeon are similar to the effects of imipramine, other effects of chlorimipramine more strongly resemble those of chlorpromazine in the pigeon.