Decreases In Rates Of Responding Research Articles

Role of mu-opioid agonist efficacy on antinociceptive interactions between mu agonists and the nociceptin opioid peptide agonist Ro 64-6198 in rhesus monkeys

Mu-opioid receptor agonists are clinically effective analgesics, but also produce undesirable effects that limit their clinical utility. The nociceptin opioid peptide (NOP) receptor system also modulates nociception, and NOP agonists might be useful adjuncts to enhance the analgesic effects or attenuate the undesirable effects of mu-opioid agonists. The present study determined behavioral interactions between the NOP agonist (−)-Ro 64-6198 and mu-opioid ligands that vary in mu-opioid receptor efficacy (17-cyclopropylmethyl-3,14β-dihyroxy-4,5α-epoxy-6α-[(3 ́-isoquinolyl)acetamindo]morphinan (NAQ) < buprenorphine < nalbuphine < morphine = oxycodone < methadone) in male rhesus monkeys. For comparison, Ro 64-6198 interactions were also examined with the kappa-opioid receptor agonist nalfurafine. Each opioid ligand was examined alone and following fixed-dose Ro 64-6198 pretreatments in assays of thermal nociception (n = 3–4) and schedule-controlled responding (n = 3). Ro 64-6198 alone failed to produce significant antinociception up to doses (0.32 mg/kg, IM) that significantly decreased rates of responding. All opioid ligands, except NAQ and nalfurafine, produced dose- and thermal intensity-dependent antinociception. Ro 64-6198 enhanced the antinociceptive potency of buprenorphine, nalbuphine, methadone, and nalfurafine. Ro 64-6198 enhancement of nalbuphine antinociception was NOP antagonist SB-612111 reversible and occurred under a narrow range of dose and time conditions. All opioid ligands, except NAQ and buprenorphine, produced dose-dependent decreases in rates of responding. Ro 64-6198 did not significantly alter mu-opioid ligand rate-decreasing effects. Although these results suggest that NOP agonists may selectively enhance the antinociceptive vs. rate-suppressant effects of some mu-opioid agonists, this small enhancement occurred under a narrow range of conditions dampening enthusiasm for NOP agonists as candidate “opioid-sparing” adjuncts.

Effects of chronic oral acrylamide exposure on incremental repeated acquisition (learning) task performance in Fischer 344 rats

Acrylamide (ACR) is a relatively potent neurotoxicant. The ingestion of carbohydrate-containing foods cooked at high temperature exposes humans to low levels of ACR virtually daily. At relatively high levels of exposure (i.e., sub-chronic through chronic levels of exposure of ≥20mg/kg body weight/day), ACR has been shown in both rats and humans to produce a variety of effects on the nervous system. The possibility that chronic dietary exposure to ACR might produce brain toxicity which could impede the development of learning skills is a question of current concern. This research evaluated the effects of ACR on learning task performance in Fischer 344 rats exposed daily beginning prenatally and continuing throughout the lifespan. Dams were gavaged with ACR since implantation [gestation day (GD) 6] with 0, 0.1, 0.3, 1.0 or 5.0mg/kg/day through parturition. Gavaging continued at the same doses to pups through weaning on post-natal day (PND) 22 after which dosing continued via their drinking water. One male and one female per litter (8–9 per treatment group) were tested. Using an incremental repeated acquisition (IRA) task to assess learning ability, ACR-exposed Fischer 344 rats exhibited altered performance by 4months of age. From approximately 1–8months of age (through ~PND 240), over 52 testing sessions, a significant treatment effect was found on percent task completed (PTC), with Tukey's post-hoc test (P<0.05) indicating a significantly lower PTC for the 5.0mg/kg/day group compared to controls. While there was no treatment effect on accuracy (P=0.53), a significant decrease in response rate was seen at 5.0mg/kg/day, suggesting that the noted decrease in PTC was due to a decrease in rate of responding, not to an effect on accuracy of task solution. Previous findings in these same animals performing a progressive ratio task for the assessment of motivation, as well as a range of tests of motoric function, suggest that this decreased response rate could be due to subtle motoric effects, or possibly due to decreases in psychomotor speed, but is most likely due to motivational effects.

Rate Decreasing Effects of Morphine and Cocaine in NR1 Knockdown Mice in an Assay of Schedule‐Controlled Responding

The present study examined the rate decreasing effects of morphine and cocaine in an assay of schedule-controlled responding in mice in which the NR1 subunit of the NMDA receptor had been reduced to approximately 5% (NR1 KD mice). Wild-type littermates (NR1 WT) served as controls. Mice were initially trained on a fixed-ratio 3 schedule of Ensure® presentation. Once criteria were met, mice were exposed to a multiple schedule of reinforcement with each cycle consisting of a 5 min timeout period followed by a 5 min response period. During the timeout period, stimulus lights were not illuminated and responding had no scheduled consequences. During the response period, stimulus lights were illuminated and mice could earn up to 10 reinforcers, at which point stimulus lights were turned off and responding had no scheduled consequences. The time it took to extinguish responding during the timeout period was measured. Extinction was defined as a decrease in response rates during the timeout period over 5 consecutive sessions below 0.1 responses/sec. Responding was extinguished in 8 days in NR1 WT mice; whereas responding was extinguished in 17 days in NR1 KD mice. After 20 sessions of multiple cycle training, the timeout period was increased to 10 min and drug testing began. Both morphine (0.32–10.0 mg/kg, i.p.) and cocaine (3.2–56.0 mg/kg, i.p.) produced dose-dependent decreases in rates of responding. A dose of 1.0 mg/kg morphine decreased rates of responding by 56% in the NR1 KO mice and increased rates of responding by 50% in the NR1 WT controls. Cocaine reduced rates of responding in a similar manner in both groups. These results suggest that the rate decreasing effects of morphine are different in NR1 KD mice and NR1 WT controls; however the rate decreasing effects of cocaine are similar in both groups.

Behavioral effects of nicotine, amphetamine and cocaine under a fixed-interval schedule of food reinforcement in rats chronically exposed to caffeine.

Epidemiological surveys demonstrate that caffeine, the main psychoactive ingredient of coffee, is a positive correlate in drug abuse. To characterize the behavioral nature of caffeine interactions with other psychomotor stimulants, we examined the effects of chronic caffeine exposure on the behavioral responses to nicotine, amphetamine, cocaine, the selective D1 agonist SKF-82958 and the selective D2 receptor agonist NPA, in rats responding under a fixed interval (FI) schedule of food reinforcement. Following stabilization of rates and temporal patterns of responding (mathematically expressed as quarter-life values, QL), twenty-one Sprague-Dawley rats responding under a 5-min FI schedule of food reinforcement were divided into two groups; one (twelve rats) maintained on tap water (control) and the other (nine rats) on caffeine (3 mg/ml added to the drinking water). Following the substitution of caffeine solution for tap water, behavior was temporarily disrupted as evidenced by decreases in responding and QL values which reached a maximum after 72 h (rate 60% and QL 30% below baseline levels). Rats developed complete tolerance to these effects of caffeine over 5 days of caffeine exposure. After response rate and QL values stabilized, effects of drugs were evaluated. Nicotine (0.01-1.0 mg/kg; SC), amphetamine (0.1-5.6; IP), and cocaine (1.0-17; IP) each produced biphasic dose-dependent changes in response rate with maximum increases in response rate following intermediate doses and decreases in response rates following higher doses. The increase in rates of responding produced by amphetamine or cocaine (but not nicotine) were greater (P<0.05) in caffeine-drinking than in water-drinking rats. Both SKF-82958 (0.001-0.3 mg/kg; IP) and NPA (0.0001-0.1; IP) produced only dose-dependent decreases in rates of responding. Caffeine-drinking rats were less sensitive to the rate-depressant effects of SKF-82958 (P<0.05) than water-drinking rats. However, similar changes (P>0.05) were produced by NPA in both groups. Except for amphetamine, the remaining drugs produced similar (P>0.05) dose-dependent decreases in QL values in water- and caffeine-drinking rats. Amphetamine produced smaller decreases in QL values in caffeine-drinking rats than in water-drinking rats (P<0.05). Chronic exposure to caffeine produced complete insurmountable tolerance to the response-rate increasing (stimulant) effects of acute caffeine (3.0-17 mg/kg; IP) in caffeine-drinking rats. In conclusion, our study revealed that chronic caffeine exposure potentiates the behavioral response to amphetamine and cocaine but not to that of nicotine in rats responding under a FI schedule of food reinforcement. Thus, it is likely that these effects are mediated through different pharmacological mechanisms.

Effects of cocaine on fixed-ratio responding of rats: Modulation by required response force

The effects of acute cocaine administrations (5.6–32 mg/kg) were determined in rats responding under a multiple fixed-ratio 15 (FR 15) FR 15 schedule of food delivery. The minimum response effort required in one schedule component was 25 g, whereas in the other component it was 200 g. Cocaine produced generally dose-dependent decreases in rate of responding and increases in preratio pause time under each component. There was, however, a significant interaction between force and drug dose, and drug effects were larger in the component requiring 200 g for lever operation. Although a number of other parameters have been shown previously to modulate the effects of cocaine on schedule-controlled responding, the present data constitite the first demonstration that minimum response effort does so.

Δ9-Tetrahydrocannabinol interactions with phencyclidine and ethanol: Effects on accuracy and rate of responding

The effects of Δ 9-tetrahydrocannabinol ( Δ 9-THC) in combination with phencyclidine (PCP) or ethanol were examined in rats responding under a fixed-consecutive-number schedule of food presentation. Under this schedule, a minimum of 13 consecutive responses on one lever followed by one response on another lever produced food. When administered alone, PCP (0.1–10.0 mg/kg) and Δ 9-THC (0.1–5.6 mg/kg), but not ethanol (0.3–1.7 g/kg), decreased accuracy. PCP, Δ 9-THC, and ethanol alone all produced dose-dependent decreases in rate of responding. A dose-effect curve for PCP or ethanol was then redetermined in combination with selected doses of Δ 9-THC (0.125–1.75 mg/kg) and the data were analyzed according to the effect-addition and dose-addition models of additivity. When administered in combination, Δ 9-THC produced dose-dependent leftward shifts in the PCP dose-effect curves for both accuracy and rate of responding. The interactions for PCP + Δ 9-THC combinations were effect-additive for accuracy. In contrast, the type of interaction obtained for PCP + Δ 9-THC combinations on rate of responding depended upon the particular doses combined, as well as on the model used to analyze the interactions. According to the effect-addition model, these interactions were additive at low doses of Δ 9-THC and supraadditive at the highest dose. However, according to the dose-addition model the interactions at the higher doses of Δ 9-THC were infraadditive. Δ 9-THC also shifted the ethanol dose-effect curve for rate of responding to the left but did not alter the ethanol dose-effect curve for accuracy. The interactions for ethanol + Δ 9-THC combinations were effect-additive for accuracy and both effect- and dose-additive for rate of responding. The present investigation clearly illustrates the importance of examining an extensive range of dose combinations on different behavioral measures, as well as the use of appropriate analyses in studies designed to evaluate the interactions between drugs.

Differential cross-tolerance to mu and kappa opioid agonists in morphine-tolerant rats responding under a schedule of food presentation

If different populations of opioid receptors mediate the actions of mu and kappa opioid agonists, then tolerance induced by the chronic administration of a mu agonist should confer cross-tolerance to other mu agonists but not necessarily to those compounds whose effects are mediated by the kappa receptor. This hypothesis was evaluated in the present investigation by examining the effects of the mu agonists morphine, l-methadone and fentanyl, the kappa agonists U50,488 and bremazocine, and the mixed kappa/mu agonist ethylketocyclazocine in rats responding under a fixed-ratio 30 schedule of food presentation before, during and after exposure to a regimen of chronic morphine administration. For comparison, naloxone was evaluated as a representative mu antagonist and the phenothiazine chlorpromazine as a control drug. During all phases of the experiment, each of these compounds produced dose-related decreases in rate of responding. During the daily administration of 40 mg/kg morphine, tolerance developed to the rate-decreasing effects of morphine, l-methadone and fentanyl, and an enhanced sensitivity to the effects of naloxone. In contrast to the effects obtained with these mu opioids, there was no evidence that chronic morphine administration produced tolerance or enhanced sensitivity to the rate-decreasing effects of U50,488, bremazocine, ethylketocyclazocine and chlorpromazine. The present findings demonstrate that the chronic administration of morphine results in the selective development of tolerance to other mu agonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Discriminative stimulus effects of intravenous l-nicotine and nicotine analogs or metabolites in squirrel monkeys

Squirrel monkeys were trained to emit one response after IV administration of l-nicotine (0.4 or 0.2 mumol/kg) and a different response after IV administration of saline. After stable discriminative performances were established, subjects were tested with cumulative doses of l-nicotine (0.02-2.2 mumol/kg), d-nicotine (0.02-19.7 mumol/kg), l-nornicotine (0.2-12.0 mumol/kg), l-cotinine (56.8-567.5 mumol/kg), and dl-anabasine (0.6-19.7 mumol/kg). All of the drugs produced dose-related increases in the percentage of drug-appropriate responses emitted, from predominantly saline-appropriate responses after low doses, to predominantly drug-appropriate responses at the highest doses studied. Relative potency comparisons indicated that l-nicotine was 28 times more potent than d-nicotine, 29 times more potent than l-nornicotine, and approximately 2000 times more potent than l-cotinine. Each of the drugs also produced decreases in rates of responding, with potency order similar to that obtained for the discriminative effects. The effects of l-cotinine may be attributed to trace amounts of l-nicotine, which existed within the l-cotinine. The effects of dl-anabasine were lethal in one subject and were consequently not studied in the other subjects.

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.

Neuroleptics and conditional discrimination tasks

The effects of the neuroleptic compounds clozapine, chlorpromazine and haloperidol were examined alone and in combination with the muscarinic cholinergic agonist oxotremorine in pigeons responding under a fixed-consecutive-number schedule. Under this procedure, nine or more consecutive responses on one response key followed by a single response on a second response key produced 3sec access to grain. In one component of this schedule (FCN 9-SD), an external discriminative stimulus was presented following the completion of the response requirement on the first response key, whereas no stimulus change was programmed in the other component (FCN 9). When administered alone, clozapine (0.1-5.6mg/kg) and chlorpromazine (3.0-170mg/kg) decreased accuracy (i.e. increased the mean number of response runs per reinforcer) under the FCN 9 at doses that had no effect under the FCN 9-SD. In contrast, haloperidol (0.03-1.7mg/kg) and oxotremorine (0.001-0.1mg/kg) had no effect on accuracy under either variant of the FCN schedule. Under both variants of the FCN schedule, clozapine, chlorpromazine, haloperidol and oxotremorine produced dose-related decreases in rates of responding. When administered in combination, oxotremorine (0.01 and 0.03mg/kg) antagonized the accuracy- and response rate-decreasing effects of both clozapine and chlorpromazine. Although neither haloperidol or oxotremorine decreased accuracy when administered alone, these drugs produced large decreases in accuracy when administered in combination. In most instances, the magnitude of these decreases in accuracy was larger than those obtained following the administration of clozapine or chlorpromazine. The effects of the co-administration of oxotremorine and haloperidol on rate of responding were generally additive. These findings indicate that both the accuracy- and response rate-decreasing effects of clozapine and chlorpromazine are, in part, mediated by their antagonist actions at muscarinic cholinergic receptors. In addition, the finding that the co-administration of haloperidol and oxotremorine decreased accuracy provides support at the behavioral level for an interaction of the dopaminergic and cholinergic systems.

Evaluation of a procedure to measure the time course of a drug's behavioral action

The utility of a novel procedure to examine a drug's time course of behavioral action was evaluated. Time- and dose-effect relations for the antiepilepsy drug methsuximide were determined in pigeons during 12-hr overnight sessions through the use of a multiple variable-interval 60-sec extinction (mult VI EXT) schedule of food delivery. The VI 60-sec components were programmed for the first 10 min of each hour and were followed by 50-min EXT components. Methsuximide produced dose-dependent decreases in rate of responding; the higher the dose, the longer the duration of effect. The present procedure appears to be useful for determining effective presession injection intervals and time-effect relations.

Diprenorphine and naloxone in squirrel monkeys with enhanced sensitivity to opioid antagonists.

The effects of diprenorphine and naloxone were examined in squirrel monkeys responding under a multiple fixed-ratio 30, fixed-interval 5-min schedule of food presentation. Dose-response curves for diprenorphine and naloxone were determined prior to and following chronic administration of 10.0 mg/kg naloxone once daily for at least 21 days. Prior to the chronic regimen, naloxone (0.1-10.0 mg/kg) had little effect on performance. At the highest dose examined, rates of responding were decreased only slightly. Diprenorphine (0.003-0.1 mg/kg) produced dose-dependent decreases in rates of responding under both components of the multiple schedule. Subsequent to the chronic naloxone regimen, doses of both naloxone and diprenorphine produced greater decreases in rates of responding. This suggests that frequent exposure to naloxone enhances its own rate-decreasing effects as well as those of diprenorphine.

Use of A Multiple Schedule to Evaluate Long-Acting Drugs: Results with Mephenytoin

The utility of a novel procedure to examine a drug’s time course of behavioral action was evaluated. Time- and dose-effect relations for the antiepilepsy drug mephenytoin were examined in pigeons during 12-hr sessions through the use of a multiple variable-interval 60-sec extinction (mult VI EXT) schedule of food delivery. The VI 60-sec components were programmed for the first 10 min of each hr and were followed by 50-min EXT components. Mephenytoin produced dose-dependent decreases in rate of responding; the higher the dose the longer the duration of effect. Peak effects of mephenytoin were observed 2 hr after injection (during the third VI component). At the higher doses drug effects were still evident at the end of the session (i.e., 12 hr after injection). The orderliness of results suggests that, although session length was too short to profile fully the time course of high mephenytoin doses, the present procedure merits further attention by behavioral pharmacologists.

Effects of adenosine analogs alone and in combination with caffeine in the squirrel monkey

Effects of the adenosine analogs R-N 6-phenylisopropyl-adenosine (R-PIA) and 5′-N-ethylcarboxamidoadenosine (NECA), alone and in combination with caffeine, were studied in squirrel monkeys trained to respond under multiple fixed-interval fixed-ratio schedules of reinforcement. Both drugs produced dose-related decreases in rates of responding, with little difference between effects in the two components. NECA was about ten times more potent than R-PIA in producing these effects, the order of potency suggests that these effects may be mediated by actions at A 2-adenosine receptors. Effects of either drug were antagonized by caffeine. Caffeine when administered alone increased rates of responding. The increases in response rates produced by caffeine were altered by R-PIA only at doses of R-PIA that alone decreased response rates. Effects of caffeine were either enhanced or attenuated by doses of NECA that were inactive when administered alone. These results do not support the notion that increases in rates of behavior, e.g., psychomotor-stimulant effects, produced by caffeine are due to its antagonist actions at adenosine receptors.

Effects of methsuximide and mephenytoin on the behavior of pigeons under a repeated acquisition procedure

Learning impairment is a potentially serious side effect of antiepilepsy medications. The present study investigated the effects of methsuximide and mephenytoin on learning in pigeons performing under a repeated acquisition procedure. Given acutely, methsuximide (25, 50, 75, and 100 mg/kg) and mephenytoin (60, 120, and 240 mg/kg) produced generally dose-dependent decreases in rates of responding. High doses of each drug increased overall errors; a within-session analysis of error distributions also indicated learning impairment.

Effects of clonazepam and ethosuximide on the responding of pigeons under a fixed-consecutive-number schedule with and without an external discriminative stimulus

The effects of the anticonvulsant drugs clonazepam and ethosuximide were examined in pigeons performing under a fixed-consecutive-number schedule with and without an added external discriminative stimulus. Under these schedules, food was delivered whenever subjects responded between and 8 and 12 times on one response key (work key), and then responded once on a second response key (reinforcement key). For one group, an external discriminative stimulus signalled completion of the response requirement on the work key, while no stimulus change was programmed for the other group. Clonazepam (0.06-0.75 mg/kg) produced dose-dependent decreases in percentage of reinforced runs and rate of responding for both groups. The magnitude of the accuracy-decreasing effect was generally greater in the group without the external discriminative stimulus. For this group, the higher doses of clonazepam produced pronounced increases in switching to the reinforcement key before completing the minimum requirement of eight consecutive responses on the work key. No consistent patterns of errors were evident for the subjects with the added external discriminative stimulus. Although ethosuximide (20-160 mg/kg) produced dose-dependent decreases in rate of responding, it had little effect on the percentage of reinforced runs or the run length distributions. These findings are consistent with previous reports indicating that clonazepam, but not ethosuximide, substantially disrupts performance under operant tasks requiring conditional discriminations. These data also suggest that the addition of an external discrimination stimulus attenuates the disruptive behavioral effects of clonazepam.

The effects of acute and repeated clonidine administration on fixed-interval performance in rhesus monkeys

The effects of clonidine before, during and after 95 days of chronic administration of 100 μg/kg/day clonidine were investigated in five rhesus monkeys which had been trained to lever press under a fixed interval 5-min schedule of food presentation. The effects of clonidine (3–100 μg/kg) were generally to cause dose-related decreases in rates of responding and quarter-life, and increases in the line slopes of rate-dependency plots. Before chronic treatment, 200 μg/kg of clonidine caused somewhat less response rate suppression than 100 μg/kg. During chronic treatment, one monkey showed some development of tolerance to the rate-suppressant effects and another showed tolerance to the quarter-life effects, but the group as a whole did not show evidence of tolerance development to these effects of clonidine. Following cessation of chronic treatment, no overt signs of dependence were observed, however, some subjects did show disruption of schedule-controlled performance during the first week. In general, however, no consistent evidence for the development of tolerance or dependence to clonidine were observed under these dosing conditions.

Discriminative stimulus properties and brain distribution of phencyclidine in rats following administration by injection and smoke inhalation

Four male Sprague-Dawley rats were trained to discriminate IP injections of 3.0 mg/kg phencyclidine (PCP) from saline under a 2-lever fixed-ratio 32 schedule of food presentation. After reliable discriminative control of lever choice was established, other doses of injected PCP were tested resulting in dose-dependent increases in PCP-lever selection and dose-dependent decreases in rates of responding. When doses of PCP were administered by exposure to smoke from cigarettes containing PCP, a dose-dependent increase in PCP-lever responding was also observed Δ 9-Tetrahydrocannabinol administered via smoke exposure, up to doses which markedly suppressed response rates, did not result in PCP-appropriae responding, demonstrating the specificity of the PCP stimulus by the inhalation route. Brain levels and distribution of 3H-PCP were determined in rats administered doses calculated to result in 50% generalization by the IP injection or smoke inhalation routes. By both routes of administration roughly equivalent brain levels were attained and the distribution was relatively even across the seven brain areas analyzed. These results demonstrate the validity of using the injection route of administration when studying PCP experimentally, in spite of the fact that PCP is abused primarily by smoking.

Effects of pimozide on accuracy of performance and distribution of correct responding on a simultaneous discrimination task in the rat.

After training rats in a simultaneous discrimination problem, pimozide, a dopamine receptor blocker, was administered to determine whether accuracy of performance would be disrupted. Each animal received five doses of pimozide (vehicle, 0.05, 0.10, 0.30, and 0.60 mg/kg) delivered in a Latin Square sequence with five non-drug days between injections. Pimozide did not disrupt well established discrimination behavior at any of the doses even though a decrease in rate of responding was observed at the two higher doses. These results provide additional evidence that DA neutrons are not essential in the mediation of previously learned associations.

Effects of phencyclidine, atropine and physostigmine, alone and in combination, on variable-interval performance in the squirrel monkey

The role played by cholinergic activity in the effects of phencyclidine (PCP) on schedule-controlled responding was studied in three squirrel monkeys trained to respond on a variable-interval (VI) 100 sec schedule of food presentation. A low dose of PCP (0.08 mg/kg IM) produced small increases in rates of responding. Higher doses (0.16–0.64 mg/kg) produced dose-dependent decreases in rates of responding. Atropine (0.05–3.2 mg/kg IM) and physostigmine (0.025–0.20 mg/kg IM) caused only decreases in response rates, the dose-response curve for atropine being particularly flat over a wide range of doses. When atropine was combined with PCP, no significant interaction was obtained. When physostigmine was combined with PCP, a complex interaction was observed. Evidence for partial antagonism of PCP by physostigmine was obtained only at the highest PCP dose tested. Atropine-physostigmine combinations resulted in response rates suggestive of antagonism.