Inhibition of Apomorphine-Induced Climbing in Mice by Cholinergic Drugs and Neuroleptics

Abstract Apomorphine (ap) was administered subcutaneously to mice kept in individual cages. Ap elicited an abnormal vertical climbing behaviour. The muscarinomimetics physostigmine and oxotremorine as well as the neuroleptics clozapine and haloperidol inhibited the climbing produced by ap 1 mg/kg. A small inactive dose of physostigmine potentiated the effect of clozapine but not that of haloperidol. The anticholinergic atropine antagonized the effect of physostigmine, oxotremozine, clozapine and haloperidol. The climbing behaviour produced by ap is presumably due to stimulation of dopamine receptors and this effect can be antagonized either by blockade of dopamine receptors or by activation of muscarinic receptors. Some lines of evidence suggest that the ap-inhibitory effect of clozapine may be partly due to a muscarinomimetic effect.     

Inhibition of apomorphine-induced climbing in mice by cholinergic drugs and neuroleptics.

Apomorphine (ap) was administered subcutaneously to mice kept in individual cages. Ap elicited an abnormal vertical climbing behaviour. The muscarinomimetics physostigmine and oxotremorine as well as the neuroleptics clozapine and haloperidol inhibited the climbing produced by ap 1 mg/kg. A small inactive dose of physostigmine potentiated the effect of clozapine but not that of haloperidol. The anticholinergic atropine antagonized the effect of physostigmine, oxotremozine, clozapine and haloperidol. The climbing behaviour produced by ap is presumably due to stimulation of dopamine receptors and this effect can be antagonized either by blockade of dopamine receptors or by activation of muscarinic receptors. Some lines of evidence suggest that the ap-inhibitory effect of clozapine may be partly due to a muscarinomimetic effect.     

Inhibition of mitochondrial complex I by haloperidol: the role of thiol oxidation

We have examined the effects of a variety of classical and atypical neuroleptic drugs on mitochondrial NADH ubiquinone oxido-reductase (complex I) activity. Sagittal slices of mouse brain incubated in vitro with haloperidol (10 nM) showed time- and concentration-dependent inhibition of complex I. Similar concentrations of the pyridinium metabolite of haloperidol (HPP+) failed to inhibit complex I activity in this model; indeed, comparable inhibition was obtained only at a 10000-fold higher concentration of HPP+ (100 microM). Treatment of brain slices with haloperidol resulted in a loss of glutathione (GSH), while pretreatment of slices with GSH and alpha-lipoic acid abolished haloperidol-induced loss of complex I activity. Incubation of mitochondria from haloperidol treated brain slices with the thiol reductant, dithiothreitol, completely regenerated complex I activity demonstrating thiol oxidation as a feasible mechanism of inhibition. In a comparison of different neuroleptic drugs, haloperidol was the most potent inhibitor of complex I, followed by chlorpromazine, fluphenazine and risperidone while the atypical neuroleptic, clozapine (100 microM) did not inhibit complex I activity in mouse brain slices. The present studies support the view that classical neuroleptics such as haloperidol inhibit mitochondrial complex I through oxidative modification of the enzyme complex.     

Effect of ritanserin on the interaction of amfonelic acid and neuroleptic-induced striatal dopamine metabolism.

In the present study we evaluated the interaction of amfonelic acid (AFA) with the typical neuroleptic haloperidol and the atypical antipsychotic clozapine on rat striatal dopamine metabolism in the absence or presence of the 5HT2 receptor antagonist ritanserin. In the absence of ritanserin, AFA significantly enhanced haloperidol stimulated 3,4- dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) accumulation by 36% and 37% respectively above that produced by haloperidol alone. This effect is believed to be due to AFA's ability to facilitate dopamine release produced by the potent haloperidol-induced increase in nigrostriatal impulse flow. In contrast, AFA did not potentiate the ability of clozapine to stimulate DOPAC or HVA. This lack of potentiation could be explained by clozapine's known potent 5HT2 receptor blocking activity attenuating its stimulatory effects on impulse flow. To test this, we combined ritanserin with haloperidol and again studied the interaction with AFA on dopamine metabolism. In the presence of ritanserin, AFA failed to potentiate the effects of haloperidol on DOPAC or HVA accumulation; an effect similar to that seen with clozapine. This result extends the idea that 5HT2 receptor blockade modulates nigrostriatal dopaminergic neurotransmission.     

A comparison of the effects of neuroleptics on phencyclidine-induced behaviors in the rat

The dose-response effects of neuroleptic pretreatment on phencyclidine (PCP; 3 or 5 mg/kg)-induced locomotor activity, stereotyped behaviors and ataxia were quantified in groups of male rats using rating scales recently developed in this laboratory. Three butyrophenone neuroleptics consistently produced dose-dependent antagonism of the behavioral effects of PCP administration. Fluphenazine antagonized the behavioral effects produced by 3 mg/kg PCP but not those produced by 5 mg/kg PCP. Each of the other neuroleptics examined (chlorpromazine, thioridazine, mesoridazine, triflupromazine, cis-flupenthixol) had no consistent antagonistic effect or actually enhanced one or more of the behavioral effects of PCP. Some neuroleptics slightly reduced PCP locomotion or stereotypies at high doses, but these effects were probably a non-specific consequence of the synergistic ataxia-producing properties of these drugs. In a second set of experiments, atropine sulfate pretreatment increased PCP-induced locomotor activity and stereotyped behaviors but had no effect on ataxia; pretreatment with physostigmine produced opposite effects. Combined pretreatment with haloperidol and atropine sulfate significantly reduced only haloperidol antagonism of PCP-induced ataxia, thus suggesting that non-dopoaminergic effects of neuroleptics may interfere with their ability to antagonize PCP.     

Neuroleptics and conditional discrimination tasks: cholinergic mediation of the accuracy- and response rate-altering effects of chlorpromazine and clozapine but not haloperidol

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.     

Differential effects of haloperidol and clozapine on the reinforcing efficacy of food reward in an alleyway reacquisition paradigm

Using the alleyway reacquisition procedure developed by Horvitz and Ettenberg, the present study compared the effects of a typical neuroleptic haloperidol (0.15 and 0.30 mg/kg) to those of an atypical neuroleptic clozapine (5.0 and 10 mg/kg) on running times 24 hours after a single food-rewarded trial administered during an extinction regimen. Rats that received food reward plus an injection of vehicle or 0.15 mg/kg haloperidol ran faster on the subsequent test day than did nonrewarded rats. The 0.30 mg/kg dose of haloperidol blocked this reacquisition effect, yielding results consistent with the anhedonia hypothesis. Clozapine (5.0 and 10 mg/kg), however, failed to block the reacquisition of alleyway running. Thus, unlike haloperidol, clozapine did not produce anhedonic effects in this reacquisition paradigm. These results suggest that neither motor nor anhedonic properties of neuroleptics appear to be crucial to the clinical efficacy of neuroleptics.     

Alterations in the effects of atropine on the behavior of pigeons following chronic administration

The acute effects of atropine (0.01-1.0 mg/kg) on pigeons' key-pecking maintained under a variable-interval (VI) 60-sec schedule of food reinforcement were determined. Atropine decreased key-peck rates in a dose-dependent manner. A rate-decreasing dose of physostigmine, an acetylcholinesterase inhibitor, was studied in combination with the range of atropine doses. The rate reduction produced by physostigmine was attenuated by some doses of atropine. An atropine dose which decreased key-peck rates was then administered to the pigeons every day after their experimental sessions (chronic post-session phase). During this regimen, the dose-effect curves for atropine and the combination of atropine and physostigmine were redetermined. Atropine was then given chronically prior to experimental sessions (chronic pre-session phase), and the dose-effect curves for atropine and the combinations of atropine and physostigmine were determined again. The pigeons became tolerant to the rate-reducing effects of atropine following chronic post-session administration. Physostigmine's effect alone was unchanged following chronic atropine administration for two pigeons, and was slightly greater for a third. The rate reduction caused by physostigmine was attenuated across a wider range of atropine doses in the two pigeons for which the effect of physostigmine alone was unchanged. The atropine/physostigmine interaction curve for the third pigeon was shifted to the right following chronic post-session atropine administration. No further changes in effects of either atropine alone or in combination with physostigmine were seen following chronic pre-session atropine administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Chronic treatment with clozapine, unlike haloperidol, does not induce changes in striatal D-2 receptor function in the rat

Comparison has been made of the effects on brain dopamine function of chronic administration of haloperidol or clozapine to rats for up to 12 months. In rats treated for 1-12 months with haloperidol (1.4-1.6 mg/kg/day), purposeless chewing jaw movements emerged. These movements were only observed after 12 months' treatment with clozapine (24-27 mg/kg/day). Apomorphine-induced (0.125-0.25 mg/kg) stereotyped behaviour was inhibited during 12 months treatment with haloperidol. Clozapine treatment was without effect. After 12 months, stereotypy induced by higher doses of apomorphine (0.5-1.0 mg/kg) was enhanced in haloperidol, but not clozapine, treated rats. Bmax for striatal 3H-spiperone binding was elevated throughout 12 months of haloperidol administration, but was not altered by clozapine treatment. Bmax for striatal 3H-NPA binding was only elevated after 12 months of haloperidol treatment; clozapine treatment was without effect. Bmax for 3H-piflutixol binding was not altered by haloperidol treatment, but was increased after 9 and 12 months of clozapine treatment. Dopamine (50 microM)-stimulated adenylate cyclase activity was inhibited after 1 month's haloperidol treatment but normal thereafter. Adenylate cyclase activity was not altered by chronic clozapine treatment. Striatal acetylcholine content was increased after 3 and 12 months of haloperidol or clozapine intake. These findings indicate that the chronic administration of the atypical neuroleptic clozapine does not produce changes in brain dopamine function which mirror those of the typical neuroleptic haloperidol. In particular, chronic administration of clozapine, unlike haloperidol, does not appear to induce striatal D-2 receptor supersensitivity. Unexpectedly, clozapine treatment, unlike haloperidol, altered D-1 receptor function.     

Behavioral effects of sertindole,risperidone, clozapine and haloperidol inCebus monkeys

Extrapyramidal side effects (EPS) are major limitations to neuroleptic treatment of psychoses. To evaluate further the behavioral characteristics of the novel antipsychotic agents, a wide range of single intramuscular doses of sertindole (0.1–2.5 mg/kg IM), risperidone (0.01–0.25 mg/kg IM), clozapine (1.0–25.0 mg/kg IM), and haloperidol (0.01–0.25 mg/kg IM) were blindly evaluated at weekly intervals inCebus monkeys previously sensitized to neuroleptics. All drugs except clozapine produced dystonia and parkinsonian symptoms, but haloperidol and risperidone were 50–100 times more potent than sertindole in producing EPS. Sertindole, risperidone and haloperidol had no significant sedative effects, whereas clozapine produced dose related sedation. Risperidone, clozapine and haloperidol but not sertindole decreased locomotor activity. Sertindole, risperidone and clozapine had a calming effect at doses below the EPS threshold, unlike haloperidol. Sertindole has many behavioral effects in nonhuman primates that are similar to those seen with the new antipsychotics, risperidone and clozapine, which suggests a favorable antipsychotic benefit/risk ratio in the clinic, especially regarding EPS.     

Differential effects of iloperidone,clozapine, and haloperidol on working memory of rats in the delayed non-matching-to-position paradigm

Rationale Because cognitive function, particularly working memory (WM), is severely impaired in schizophrenia, evaluation of neuroleptic medication should include investigation of possible effects on cognition. Iloperidone is a promising, novel atypical neuroleptic drug (NL), for which no cognitive data is presently available.Objective To investigate whether the novel atypical NL iloperidone would affect performance of rats on a WM test, using a delayed non-matching-to-position (DNMTP) paradigm, and compare its effects with those of the atypical NL clozapine and the typical NL haloperidol.Methods Male Lister Hooded rats trained to criterion in an operant DNMTP task (0–64 s delay intervals) were administered vehicle, iloperidone (0.03, 0.1 mg/kg, i.p.), clozapine (0.1, 0.3 mg/kg, s.c.), haloperidol (0.003, 0.01, 0.03 mg/kg, s.c.), or scopolamine (0.05 mg/kg, s.c.). Together with choice accuracy, the motor performance of the task was measured.Results It was found that: (1) iloperidone significantly improved choice accuracy delay-dependently while impairing task performance; (2) the atypical NL clozapine had no effect on choice accuracy and parameters related to motor function, but significantly increased the number of uncompleted trials; (3) haloperidol did not affect choice accuracy except at the longest delay with the highest dose, but in contrast to clozapine it significantly impaired task performance.Conclusion In accordance with their different pharmacological profiles, the three NLs iloperidone, clozapine, and haloperidol have different effects in this preclinical cognitive task. These results might provide important information for the development of NLs with beneficial effects on cognition.     

Subchronic effects of clozapine and haloperidol on rats’ forelimb force and duration during a press-while-licking task

 In order to compare and contrast the behavioral effects of the typical neuroleptic haloperidol with the atypical neuroleptic clozapine, ten daily doses of these drugs were administered to separate groups of rats trained to extend the forelimb through a rectangular hole and to exert downward pressure on a force transducer to gain access to water. Doses were individually titrated daily for each rat in an attempt to achieve a 50% reduction in time on task (analogous to response rate) during 8-min daily sessions. Clozapine-treated rats exhibited dramatic tolerance to the drug’s suppressive effect on time on task. In contrast, haloperidol rats displayed little tolerance on this measure. Despite the tolerance reflected by time on task, no tolerance was seen in clozapine’s marked slowing of the dominant frequency of oscillations in forelimb force as measured by Fourier analysis of the force-time recordings. Haloperidol did not slow the dominant frequency. No tolerance was seen for clozapine’s effects on forelimb force or tremor measures. Haloperidol did not significantly affect forelimb force. Both haloperidol and clozapine produced increases in the duration of long-duration forelimb responses, and no tolerance was seen for either drug on this measure of behavior. For clozapine, the dissociation between the tendency to respond (time on task) and the observed slowing of the dominant frequency may reflect effects peculiar to atypical neuroleptics, while the lengthening of long-duration responses by both drugs may reflect a more general behavioral effect that is characteristic of both typical and atypical antipsychotic drugs. Received: 27 June 1996 / Final version: 12 November 1996     

Multiunit activity from the A9 and A10 areas in rats following chronic treatment with different neuroleptic drugs

Effects of repeated twice daily i.p. administration of haloperidol (0.5 mg/kg), clozapine (3.0 mg/kg) and prothipendyl (1.0 mg/kg) on spontaneous A9 and A10 cell activity were studied using extracellular multiunit recording in rats, which offers relatively rapid access to neural activity in a large number of cells. Two cell types were identified, which probably represent the putative dopaminergic and non-dopaminergic neurons. Repeated neuroleptic treatment reduced the number of spontaneously active type 1 A10 cells per track. The effect of haloperidol was more pronounced than that of clozapine or prothipendyl. A9 cells were affected by haloperidol only. The frequency and amplitude of A9 and A10 active cells remained quite stable, except for a clozapine-induced increase of their values for type 1 A10 cells. Stability of spontaneously active type 1 A10 cells was significantly reduced by the chronic neuroleptic treatment. Collectively the activity of type 2 cells was not altered. Prothipendyl was classified as an atypical neuroleptic drug with potency comparable to clozapine.     

Parkinsonism by haloperidol and piribedil

Three groups of schizophrenic patients were treated with haloperidol, with a low dose of piribedil (a dopamine agonist), and with a combination of the two treatments, respectively. After a few days, all 7 patients treated with the drug combination showed marked rigidity and akinesia, while patients treated with haloperidol alone (4) and piribedil alone (4) showed either mild or no symptoms of parkinsonism. The drug combination induced mainly an akinetic-hypertonic syndrome, while tremors were absent or mild. The results suggest that low doses of the DA-agonist potentiate the extrapyramidal side effects of haloperidol by acting on self-inhibitory DA receptors, thereby blocking the compensatory increase in dopaminergic firing elicited by the neuroleptic agent.     

Oral dyskinesia in rats following brain lesions and neuroleptic drug administration

After 10–12 weeks of chronic haloperidol administration rats with frontal cortex ablations or lesions induced by intracerebroventricular injection of 6-hydroxydopamine developed vacuous chewing behavior at a fairly stable frequency (bifrontal ablations had 15–20, 6-hydroxy-dopamine lesioned rats 7–12 chewing movements/min). This behavior persisted for 10 weeks after the last injection of haloperidol decanoate. However, rats with frontal cortex lesions developed a low rate of vacuous chewings (4–8 chewings/min) even without haloperidol administration. Bilateral intrastriatal injections of kainic acid in combination with chronic haloperidol administration did not cause chewing movements in excess of unlesioned haloperidol-treated controls.Pharmacological tests of this animal model for tardive dyskinesia (TD) revealed similarities to human TD, but also differences. Dopamine agonists (apomorphine) and antagonists (haloperidol) both lowered chewing behavior analogous to reported effects on TD and so did gabaculine. The cholinergic drugs physostigmine and pilocarpine, however, increased chewing in rats, while anticholinergics (atropine) reduced it, in contrast to reported effects on human TD.     

Phencyclidine-induced stereotyped behaviour and social isolation in rats: a possible animal model of schizophrenia

Phencyclidine (PCP) can induce a model psychosis in humans that mimics the positive and negative symptoms of schizophrenia. The purpose of the present study was to determine whether PCP can induce similar behavioural effects in rats and whether these effects can be alleviated by neuroleptic drug treatment. Rats were tested in the social interaction test, and their behaviour was quantified by an automated video-tracking system and manual scorings of stereotyped behaviour and ataxia. The behavioural effects of different dose- and administration regimes of PCP were initially determined, and it was found that PCP dose-dependently induced stereotyped behaviour and social isolation in the rats. Comparison to clinical studies suggests that these behaviours correspond to certain aspects of the positive and negative symptoms, respectively, of a PCP psychosis in humans. Subsequently, the effects of 3 or 21 days of administration of the antipsychotic drugs haloperidol or clozapine on the behaviour of either vehicle- or PCP-treated rats were determined. Haloperidol did not produce a selective antagonism of PCP, whereas chronic clozapine selectively inhibited the PCP-induced stereotyped behaviour and social isolation. These effects of haloperidol and clozapine suggest that this animal model can determine the effects of neuroleptic drugs on positive and negative symptoms, onset of action, and side-effect profile, including effects on the motor system. Together these data suggest that this may be a possible animal model of the positive and negative symptoms of schizophrenia.     

Chronic clozapine versus chronic haloperidol treatment: differential effects on electrically evoked dopamine efflux in the rat caudate putamen, but not in the nucleus accumbens

Fast cyclic voltammetry at carbon-fibre microelectrodes was used to investigate the effects of chronic clozapine or haloperidol administration on electrically evoked dopamine efflux in the nucleus accumbens and caudate putamen of the anaesthetized rat. Stimulation trains were delivered to the median forebrain bundle (60 pulses, 350 s duration) every 5 min, and the evoked dopamine efflux measured as a function of a) the applied stimulus intensity (range 0.2 mA-1.0 mA), and b) the applied stimulus frequency (range 10 Hz-250 Hz). Chronic administration of either clozapine (20 mg/kg × 21 days, p.o.) or haloperidol (1 mg/kg × 21 days, p.o.) significantly reduced electrically evoked dopamine efflux in the nucleus accumbens over the range of stimulus intensities and frequencies tested. The reduction in evoked dopamine efflux observed in the nucleus accumbens of clozapine- and haloperidol-treated rats showed no statistically significant difference. In contrast, only chronic haloperidol treatment significantly reduced evoked dopamine efflux in the caudate putamen. These findings demonstrate that chronic treatment with either the atypical neuroleptic, clozapine, or the typical neuroleptic, haloperidol, produce long-term changes in mesolimbic dopamine function; actions which may underlie their antipsychotic efficacy. They also provide further evidence that the sparing action of clozapine on nigrostriatal dopamine activity may underlie the lower incidence of extrapyramidal side effects associated with its long-term administration.     

Clozapine enhances neurocognition and clinical symptomatology more than standard neuroleptics

Neurocognition and clinical symptomatology were evaluated in 27 patients with schizophrenia during a double-blind, placebo-controlled, cross-over study involving clozapine, an atypical antipsychotic agent, and haloperidol, a conventional neuroleptic. Patients were assessed 5 to 6 weeks after initiation of each phase. Clinical symptomatology, based on Brief Psychiatric Rating Scale and Scale for the Assessment of Negative Symptoms ratings, markedly improved after treatment with both haloperidol and clozapine. The beneficial effects of clozapine were statistically significantly greater than the effects from the haloperidol treatment. Regarding neurocognition, both agents proved efficacious in improving performance on nearly all measures compared with placebo. In addition, as compared with haloperidol, clozapine significantly improved performance on Trails B, Verbal Fluency, and measures of delayed verbal memory, and it tended to increase performance on most measures. Additional analyses indicated that the improvement on neurocognitive measures was not because of symptom amelioration; rather, neurocognitive deficits seem to be an intrinsic enduring feature of schizophrenia. The superiority of clozapine over haloperidol may be related to clozapine's unique psychopharmacologic profile.     

Repeated treatment with ascorbate or haloperidol,but not clozapine,elevates extracellular ascorbate in the neostriatum of freely moving rats

Acute administration of neuroleptic drugs alters the extracellular level of ascorbate in the neostriatum, and increasing evidence suggests a role for this vitamin in the behavioral, and possibly therapeutic, effects of these drugs. To shed further light on this issue, extracellular ascorbate was recorded in the neostriatum and nucleus accumbens of awake, behaving rats following chronic treatment with either classical (haloperidol) or atypical (clozapine) neuroleptics or ascorbate itself. Electrochemically modified, carbon-fiber microelectrodes were lowered in place the day after the last of 21 daily injections of either haloperidol (0.5 mg/kg, SC), clozapine (20 mg/kg, IP), sodium ascorbate (500 mg/kg, IP) or vehicle. Voltammetric measurements were obtained during quiet rest and following administration ofd-amphetamine (2.5 mg/kg). Repeated treatment with either haloperidol or ascorbate elevated basal extracellular ascorbate and potentiated the amphetamine-induced increase in ascorbate release in neostriatum but not nucleus accumbens. Both treatment groups also showed a significant increase in amphetamine-induced sniffing and repetitive head movements compared to vehicle-treated animals. In contrast, repeated clozapine had no effect on extracellular ascorbate in either neostriatum or nucleus accumbens, but increased the locomotor response to an amphetamine challenge. Thus, to the extent that increases in neostriatal ascorbate exert neuroleptic-like effects, such effects are likely to parallel haloperidol rather than clozapine.     

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.