Effects of sigma receptor ligands on schedule-controlled behavior of rats: relation to sigma and PCP receptor binding affinity

Eleven drugs were examined for their ability to inhibit sigma and phencyclidine (PCP) receptor binding, as labelled by (+)[³H]-R-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP), [³H]ditolylguanidine (DTG), (+)[³H]N-allylnormetazocine (NANM) and [³H]1-(1-(2-thienyl)cyclohexyl)piperidine (TCP), in membrane preparations from whole rat brain. The same drugs were studied for their effects under a fixed-ratio (FR) schedule of food reinforcement in rats. The relative potency order of the drugs for decreasing FR responding was: haloperidol>(+)-3-PPP>(-)NANM>BMY 14802> PCP>(+)NANM>DTG>rimcazole> JO 1783>JO1784>(-)butaclamol.The binding affinities of all 11 drugs for either the [³H]DTG, (+)[³H]-3-PPP, (+)[³H]NANM or [³H]TCP site did not correlate significantly with the potenties of the same drugs for decreasing FR behavior. Rimcazole, (+)-3-PPP and haloperidol, at behaviorally inactive doses, were studied for their effects as antagonists of the rate-decreasing effects of JO 1784, DTG and (+)NANM: rimcazole attenuated the effects of DTG and (+)NANM but not JO 1784; (+)-3-PPP attenuated the effects of (+)NANM but not JO 1784 and DTG; and haloperidol was devoid of antagonistic actions. Moreover, BMY 14802 did not attenuate the rate-decreasing effects of (+)-3-PPP. These results further indicate that it is difficult to distinguish between purported sigma agonist and antagonist drugs.     

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.     

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.     

Acute effects of the organophosphate paraoxon on schedule-controlled behavior and esterase activity in rats: Dose-response relationships

The effects of acute intraperitoneal administration of paraoxon on behavioral and biochemical parameters were studied in male rats. Rats were trained to press a lever under an FR10 schedule of reinforcement. Rats were injected with 3 sublethal doses of paraoxon (0.5, 0.75, and 1.0 mg/kg) and performance was monitored for four days after exposure. Response rates were depressed significantly for days 1 and 2 with 0.75 and 1.0 mg/kg, but not 0.5 mg/kg, even though there was inhibition of brain and plasma cholinesterases at all doses. Performance recovered prior to brain AChE recovery. There was no clear-cut threshold of brain AChE inhibition required to yield performance deficits, nor was there a direct correlation between significant inhibition in peripheral enzymes which could serve as markers (plasma aliesterases, butyrylcholinesterase, non-iso-OMPA-sensitive cholinesterase, and hepatic aliesterases) and performance deficits, suggesting that other noncholinergic targets may play a role in OP-induced behavioral deficits.     

Naloxone effects on schedule-controlled behavior in morphine-pelleted rats

The effects of morphine pellet implantation and naloxone administration were examined in rats lever pressing under inter-response time schedules of food presentation. Subcutaneous implantation of a morphine pellet initially decreased lever-pressing rates. Tolerance to this effect developed within 3–4 days. Naloxone (0.25–1.0 mg/kg) decreased response rates in morphine-pelleted rats in a dose-dependent and time-dependent manner. All doses of naloxone severely decreased rates of lever pressing on days four to nine post-pellet. This rate-decreasing effect persisted 7–17 days for 0.25 mg/kg naloxone, 9–22 days for 0.50 mg/kg, and 13–28 days for 1.0 mg/kg. Decreases in response rate were due to an increased frequency of long pauses and not to marked shifts in the temporal patterning of those lever presses that did occur. Changes in response rate after naloxone were accompanied by body weight loss. Area values summarizing the naloxone-induced changes in response rate or body weight over time after pellet implantation increased as a function of naloxone dose. Naloxone (0.25–1.0 mg/kg) did not alter performance by placebo-pelleted rats.     

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.     

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.     

Joint effects of ethanol and caffeine on schedule-controlled responding in the pigeon

Interactions between ethanol and caffeine were studied in pigeons keypecking under a multiple fixed ratio 30 fixed interval 5-min schedule of food presentation. When ethanol was administered alone, rates of responding under both components of the multiple schedule were generally decreased in a dose-related manner. Caffeine alone either decreased or had no effect on rates of responding under both the fixed ratio and fixed interval components. When caffeine and ethanol were combined, doses of caffeine which did not decrease rates of responding when given alone attenuated the rate-decreasing effects of ethanol.     

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.     

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     

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.     

The effects of cimetidine on schedule-controlled responding and locomotor activity in rats

The effect of intraperitoneal injections of cimetidine, a selective histaminergic H₂-receptor blocking agent, on operant behavior and locomotor activity were examined in rats. Cimetidine (1–100 mg/kg) failed to show any significant effect on responding maintained under a fixed-ratio (FR) 30 fixed-interval (FI) 5-min schedule of food presentation. A higher dose of cimetidine (300 mg/kg) produced decreases in both FR and FI rates of responding. In contrast, 100 mg/kg of cimetidineincreased the response rate and decreased reinforcement rate in rats performing under a schedule requiring the temporal spacing of responses (DRL-10 sec). Cimetidine (10–300 mg/kg) did not induce significant changes in locomotor activity in the rat. These data suggest that cimetidine is more potent in altering the steady low rate of responding under a DRL schedule of food presentation, than responding maintained under a multiple FR FI schedule, and that cimitidine is even less potent in altering locomotor activity.     

The effects of some putative antidepressant agents on the schedule-controlled behavior of the pigeon

Numerous second-generation antidepressants with pharmacological profiles and chemical structures different from those of the tricyclic antidepressants have recently been developed. We examined the actions of four of these compounds (mianserin, maprotiline, trazodone and fluvoxamine) on the responding of pigeons under two different multiple (mult) schedules of grain presentation (a mult fixed-interval (FI) 600-s fixed-ratio (FR) 30-response and a mult FI 200-s FI 200-s in which responding in one component was punished by intermittent presentation of a brief electric shock). The rate of FI 600-s responding was greatly increased by several doses of maprotiline and mianserin, which either did not affect or produced only small increases in the rate of FR 30 responding. Fluvoxamine and trazodone did not produce similar differential effects. Relatively low doses of maprotiline, mianserin and trazodone decreased the FI quarter-lifes. Fluvoxamine only decreased the FI quarter-life at a dose that largely eliminated responding. Mianserin produced proportionally greater increases in the rate of punished FI 200-s responding than in the rate of unpunished FI 200-s responding. Selective effects on punished responding were not seen with maprotiline, fluvoxamine and trazodone.     

Effects of acute and chronic administration of phenobarbital and d-amphetamine on schedule-controlled behavior

The effects of acute and chronic administration of phenobarbital and d-amphetamine were determined in rats responding under a multiple fixed-interval five minute fixed-ratio 30 (mult FI 5 FR 30) schedule of food presentation. After determining the acute effects of each drug, the drugs were injected daily with one group of rats receiving the drugs before each behavioral session while another group received the drugs immediately after each daily session. After four to seven consecutive injections, tolerance developed to the effects of phenobarbital on the average rates of responding under FI and FR schedule components only if the drug was administered before each session. Tolerance was more pronounced for responding during the terminal portions of the FI component than for responding during either the initial portions of the FI or the FR component. Evidence for a selective tolerance to the effects of the drug on responding during the final segments of the FI was also obtained in rats responding under an FI 5 schedule. In contrast, injections of d-amphetamine for seven to eight consecutive days failed to produce any tolerance to the effects of the drug on responding under mult FI 5 FR 30, FI 5, or FR 30 schedules. These results indicate that the development of tolerance to the effects of phenobarbital depended both upon the temporal relationship of the drug effects to the behavioral testing and upon the schedules controlling behavior. These findings are discussed in terms of theories of behavioral tolerance.     

Psychomotor stimulant effects ofd-amphetamine,MDMA and PCP: aggressive and schedule-controlled behavior in mice

The objective of the present experiments was to characterize psychomotor stimulant effects ofd-amphetamine, methylenedioxymethamphetamine (MDMA) and phencyclidine (PCP) on conditioned performance and on aggressive behavior in mice. In a novel protocol with alternating periods of schedule-controlled responding and aggressive behavior toward an intruder it was possible to assess a range of species-specific agonistic acts, postures, and motor activities as well as response rates and patterns engendered by a multiple Fixed Interval (FI) and Fixed Ratio (FR) schedule within the same animal. Initially, it was confirmed thatd-amphetamine and, less reliably, MDMA and PCP, increased FI, but not FR responding in mice. In the next experiment, mice confronted an intruder at the midpoint of the 1-h daily session; following the display of aggressive behavior, the rate of FI responding showed an amphetamine-like increase, whereas only a transient change occurred after non-aggressive encounters. Thirdly, using this new protocol, PCP,d-amphetamine and MDMA altered FI and FR responding in a way that was closely similar to the first experiment. Low PCP andd-amphetamine doses increased aggressive behavior erratically in certain individuals, but not reliably for the group. MDMA dose-dependently decreased aggressive behavior, and all drugs disrupted aggressive behavior at higher doses. The characteristic increases in walking and decreases in rearing after higher doses of PCP andd-amphetamine were greatly attenuated when the intruder was present. The rate-increasing effects ofd-amphetamine, MDMA and PCP occurred in the early portion of the fixed interval when the control rate is typically low; by contrast, low attack rates during the later portion of the confrontation with the intruder remained unaffected. The dose-dependent quantitatively and qualitatively differentiated profile of effects on schedule-controlled responding, motor activity and aggressive behavior suggest that the common properties ofd-amphetamine, MDMA and PCP pertain mostly to the disruption of organized behavior patterns and activation of repetitive motor routines at high doses, but point to different mechanisms for modulating aggressive behavior and conditioned performance at lower doses.     

Ethanol and isopropanol effects on schedule-controlled responding

The effects of ethanol and isopropanol were studied on responding by pigeons under multiple fixed-ratio (FR), fixed-interval (FI) schedules of food presentation and under a fixed-interval (FI) schedule of food presentation where responding was decreased by punishment. The ethanol was rapidly absorbed into blood and decreased responding within 15 min after intubation to the opening of the proventriculus. Dose-effect determinations of the effects of ethanol showed that ethanol decreased responding in both the FR and FI components of the multiple schedules at similar doses, but there were increases in responding under an FR 100 schedule at lower doses. Isopropanol tended to decrease FR responding at doses that either increased FI responding or did not affect FI responding. Both ethanol and isopropanol (1 g/kg) produced effects on the local rates of responding within the FI which were rate-dependent in that they increased low rates while not affecting or actually decreasing the high rates of responding. Both ethanol and isopropanol increased punished responding if it was not severely suppressed by the punishment procedures.     

Attenuation of the behavioral effects of meperidine and normeperidine by daily administration of diazepam

The effects of meperidine, normeperidine, morphine, pentobarbital and d-methadone were determined on the key-pecking behavior of pigeons responding under a multiple fixed-ratio (FR), fixed-interval (FI) schedule of grain presentation. Dose-effect curves were obtained for each drug alone and during daily administration of 10 mg/kg of diazepam. The daily administration of diazepam had little effect on the behavior itself. Meperidine and normeperidine caused dose-related decreases in both FI and FR responding. The dose-effect curves for these drugs during daily administration of diazepam were shifted to the right compared to the dose-effect curves determined in the absence of daily diazepam. In contrast, the effects of morphine, d-methadone and pentobarbital either were not affected by daily administration of diazepam or were shifted to the left by daily administration of diazepam. These data further support the hypothesis that the behavioral effects of meperidine and normeperidine are due to a proconvulsive action produced by these drugs. In contrast, the effects of morphine, d-methadone and pentobarbital are not due to such a proconvulsive action.     

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 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.