Further investigation of the stimulus properties of chlordiazepoxide and zolpidem. Agonism and antagonism by two novel benzodiazepines

The effects of Ro 16-6028 and Ro 17-1812, two novel benzodiazepines with mixed agonist and antagonist properties, were studied in rats trained to discriminate either chlordiazepoxide or the benzodiazepine receptor ligand zolpidem. In rats discriminating 5 mg/kg chlordiazepoxide from saline both Ro 16-6028 and Ro 17-1812 produced responding on the drug lever. At a dose of 10 mg/kg both compounds gave rise to 100% responding on the lever associated with chlordiazepoxide. The dose-response curve produced by Ro 16-6028 was flatter than that for Ro 17-1812, however. The discriminative cue produced by 2 mg/kg zolpidem did not generalise to either Ro 16-6028 or Ro 17-1812. In contrast, both of those compounds antagonised the zolpidem cue and also antagonised the reduction in response rates produced by zolpidem. These results are consistent with previous findings that Ro 16-6028 and Ro 17-1812 may exert anxiolytic-like effects typical of benzodiazepines while antagonising the depressant actions of benzodiazepine receptor ligands. The results are also consistent with the suggestion that the discriminative cues produced by chlordiazepoxide and zolpidem may be mediated, at least partially, by activity at different sub-types of benzodiazepine receptors.     

Discriminative stimulus properties of chlordiazepoxide and zolpidem. Agonist and antagonist effects of CGS 9896 and ZK 91296

In previous studies the effects of CGS 9896, a pyrazoloquinoline ligand at benzodiazepine receptors, in rats trained to discriminate benzodiazepines from vehicle, have been variable. The present experiment confirmed that this compound produced responding on the drug-lever in rats trained to discriminate 5 mg/kg of chlordiazepoxide from saline, and showed that CGS 9896 did not antagonise the effect of chlordiazepoxide in this test. In contrast, CGS 9896 antagonised the stimulus properties of zolpidem (2 mg/kg), a non-benzodiazepine hypnotic, which displaces benzodiazepines from their binding sites. The drug CGS 9896 also antagonised responding on the drug-lever produced by chlordiazepoxide in rats trained with zolpidem. The beta-carboline, ZK 91296, produced effects similar to those of CGS 9896, giving rise to responding on the drug-lever in rats trained with chlordiazepoxide and antagonising the zolpidem cue. These results demonstrate the mixed agonist-antagonist effects of CGS 9896 and ZK 91296 and suggest that the stimulus properties of chlordiazepoxide and zolpidem may be mediated by different sub-types of benzodiazepine receptors.     

Discriminative stimulus effects of alpidem,a new imidazopyridine anxiolytic

Alpidem in an imidazopyridine derivative which binds selectively to the ₁(BZ₁) receptor subtype. It is active in some, but not all, behavioural tests sensitive to benzodiazepine anxiolytics and has clinical anti-anxiety effects. However, in a previous study, it was shown that alpidem did not substitute for chlordiazepoxide in rats trained to discriminate this benzodiazepine. The present experiments were carried out to investigate the discriminative stimulus properties of alpidem in greater detail. In the first experiment rats learned to discriminate a dose of 10 mg/kg alpidem from saline. Acquisition of the discrimination was long and performance unstable. Chlordiazepoxide, clorazepate and zolpidem substituted only partially for alpidem but the effects of the training dose of alpidem were blocked by 10 mg/kg flumazenil. The second experiment established stimulus control more rapidly to a dose of 30 mg/kg alpidem. Alpidem induced dose-related stimulus control, and dose-related and complete substitution for alpidem was produced by zolpidem, abecarnil, CL 218,872, triazolam and suriclone. Partial substitution occurred with chlordiazepoxide, clorazepate and pentobarbital. In most cases, high levels of substitution were produced only by doses which greatly reduced response rates even though the training dose of alpidem produced only modest decreases in rates. Ethanol, buspirone and bretazenil produced very little substitution for alpidem and both flumazenil and bretazenil antagonised the effects of alpidem. In two further experiments alpidem was found to substitute for the stimulus produced by zolpidem (2 mg/kg) but not for that produced by ethanol (1.5 g/kg). In the latter case the benzodiazepines chlordiazepoxide and triazolam did substitute for the ethanol cue. These results confirm that the discriminative stimulus effects of alpidem differ from those produced by benzodiazepines. The effects of alpidem are most similar to those of the other imidazopyridine derivative, zolpidem, and may be related to the selectivity of these drugs of the ₁(BZ₁) receptor subtype.     

Further behavioural evidence for the selective sedative action of zolpidem

Small doses of benzodiazepines stimulate behavioural output in experimental animals in a variety of situations. Zolpidem, which displaces benzodiazepines from their binding sites, however, has been shown to exert preferential sedative activity. In order to investigate whether small doses of zolpidem would also have stimulant effects, the actions of zolpidem and chlordiazepoxide were compared in three procedures which are sensitive to the behavioural-facilitating effects of benzodiazepines in rats. A small dose of chlordiazepoxide (3.0 mg/kg) increased locomotion in an open field whereas a large dose (30 mg/kg) suppressed this behaviour. Zolpidem (0.3-3.0 mg/kg) only decreased locomotion. The effects of both chlordiazepoxide and zolpidem were antagonised by flumazenil. Chlordiazepoxide (2.5-10 mg/kg) increased the intake of food in rats habituated to a daily feeding schedule but similar doses of zolpidem neither increased nor decreased the intake of food. Rates of punished operant responding were increased by chlordiazepoxide (3.0-30 mg/kg) but zolpidem (1.0-4.0 mg/kg) produced no such anti-punishment effect and suppressed responding at the large dose. These results show that zolpidem does not increase behavioural output in situations which are sensitive to the stimulant effects of benzodiazepines and further emphasize the selective sedative activity of this drug.     

Effects of alprazolam, caffeine, and zolpidem in humans trained to discriminate triazolam from placebo

This study compared the discriminative stimulus effects of zolpidem, a nonbenzodiazepine hypnotic, to benzodiazepines. Eight participants learned to discriminate triazolam (0.35 mg/70 kg) from placebo. The discriminative stimulus effects, self-reported subjective effects, and performance effects of triazolam (0.05-0.35 mg/70 kg), alprazolam (0.25-1.75 mg/70 kg), zolpidem (2.5-35 mg/70 kg) and caffeine (75-525 mg/70 kg) were assessed under two-response and novel-response drug discrimination procedures. Under the two-response procedure, triazolam, alprazolam and zolpidem fully substituted for triazolam and caffeine did not. Under the novel-response procedure, triazolam and alprazolam substituted for triazolam and zolpidem partially substituted for triazolam. Zolpidem, but not triazolam or alprazolam, also produced some novel responding. Caffeine produced both placebo-appropriate and novel responding. The self-reported effects of triazolam, alprazolam and zolpidem were similar. Overall, zolpidem produced similar, but not identical, effects as the benzodiazepines.     

Behavioural effects of novel benzodiazepine (omega) receptor agonists and partial agonists: increases in punished responding and antagonism of the pentylenetetrazole cue

In recent years a number of novel compounds have been described with affinity and specificity for BZ (omega) receptors. While some of these agents appear to act, like benzodiazepines themselves, as full agonists at different receptor subtypes (e.g. suriclone), several non-selective partial agonists (e.g. bretazenil) have been described, as have a number of BZ(1) (omega(1)) selective drugs (e.g. zolpidem). Previous work has reported a number of differences between the behavioural effects of some of these drugs and those of benzodiazepines; however, very few studies have attempted systematic comparisons of a large number of drugs in different procedures. In the present study a wide range of BZ (omega) receptor ligands was studied using two behavioural methods in rats: unpunished and punished food-reinforced operant responding and the discriminative stimulus effects of pentylenetetrazole. Punished operant responding showed increases with the benzodiazepines, chlordiazepoxide and clorazepate, the non-benzodiazepines, saripidem, CL 273,547 and F 2692 (limited effect at a single dose) and the partial agonists bretazenil and Ro 19-8022, but the BZ(1) selective agents, alpidem, abecarnil and CL 284,846, did not increase rates of punished operant responding. Rates of unpunished responding were decreased by higher doses of all drugs except bretazenil and Ro 19-8022. Dose-related antagonism of the pentylenetetrazole (18mg/kg) discriminative stimulus was produced by several benzodiazepines, by the partial agonists bretazenil, Ro 19-8022 and divaplon, and by suriclone, saripidem and CL 273,547. The BZ(1) (omega(1)) selective drugs abecarnil, CL 284,846, zolpidem, CL 218,872 and alpidem were also active in blocking pentylenetetrazole but produced only partial antagonism which was not clearly dose-related. The results show that novel BZ (omega) receptor ligands do not always produce a behavioural profile identical to that shown by benzodiazepines. In particular, BZ(1) (omega(1)) selective drugs do not give rise to clear increases in punished operant responding and have only limited efficacy in blocking the pentylenetetrazole cue. These effects may be due to the marked propensity of BZ(1) (omega(1)) selective drugs to decrease operant response rates.     

Phenytoin: Similarity to tricyclic antidepressants

Rats were trained to discriminate between the stimulus properties of intraperitoneal injections of 10 mg/kg phenytoin and its pH-adjusted vehicle in a two-lever, food-motivated operant task. Once trained, rats showed a dose-related decrease in discriminative performance with lower phenytoin doses. Administration of pentobarbital and chlordiazepoxide produced vehicle-appropriate responding, whereas injection of imipramine and amitriptyline produced intermediate results. Desipramine, at an intraperitoneal dose of 10 mg/kg, produced a pattern of responding similar to that observed after the training dose of phenytoin. These results demonstrate, for the first time, the ability of a non-disruptive dose of phenytoin to act as a behavioral discriminative stimulus in the rat and suggest the possibility of a common interoceptive cue property with tricyclic antidepressants.     

Pharmacological characterization of the discriminative stimulus properties of the dopamine D1 agonist, SKF 81297

A range of selective dopamine D1 and D2 receptor agonists and antagonists was used to characterize to the discriminative stimuli produced by d-amphetamine (0.5mg/kg) and the D1 agonists SKF 81297 (0.1mg/kg). In rats trained to discriminate d-amphetamine (0.5mg/kg) from saline, d-amphetamine produced a dose-related increase in per cent drug lever responding, and SKF 81297 did not show any d-amphetamine-like discriminative stimulus effects; neither did SKF 81297 potentiate nor antagonize the d-amphetamine discriminative stimulus. In rats trained to discriminate SKF 81297 (0.1mg/kg) from saline, SKF 81297 produced a dose-related increase in per cent drug lever responding, and SKF 38393 and SKF 83565 elicited full SKF 81297-like effects despite the fact that these compounds have widely differing efficacies for stimulating adenylate cyclase. SKF 81297 had a 25-fold greater potency than SKF 38393 in this assay. The D2 agonists, PHNO and ropinirole, did not display any SKF 81297-like discriminative stimulus effects. The SKF 81297 discriminative stimulus was completely blocked by the D1 antagonist SCH 23390 but was not blocked by the D2 antagonist BRL 34778.     

Effect of dopamine agonists and fenfluramine on discriminative behavior in obese and lean Zucker rats

Dopamine agonists and fenfluramine were used as pharmacological probes to investigate the possible difference in sensitivity and time course of drug action in genetically obese Zucker rats and their lean littermates. All rats were trained to discriminate between the stimulus properties of 0.6 mg/kg d-amphetamine and its vehicle in a two-lever, food-motivated operant task. Once trained, both groups of rats showed a dose-related decrease in discriminative performance with lower amphetamine doses. Analysis of the dose-response curves indicated an ED50 for the obese rats of 0.17 mg/kg and for the lean group of 0.14 mg/kg. Administration of 0.3-1.2 mg/kg l-amphetamine and 2.5-10.0 mg/kg cocaine produced a pattern of responding similar to that observed with d-amphetamine. In contrast, 0.08-mg/kg apomorphine produced saline-appropriate responding and 1.5-2.5 mg/kg fenfluramine produced intermediate results in both groups. Time-course experiments indicated that the lean rats maintain errorless discriminative performance through 90 min post-injection, whereas the obese rats discriminate d-amphetamine significantly less at that post-administration time. The results suggest a similar sensitivity to d-amphetamine and other dopaminergic agonists in obese and lean rats with a difference in the time-course of d-amphetamine's action between these two groups.     

Discriminative stimulus properties of pentylenetetrazol and bemegride: Some generalization and antagonism tests

In an operant procedure of lever pressing on a FR 10 schedule of food reinforcement, male hooded rats were trained to respond with a lever on one side of a food cup following a drug injection, and to respond with a lever on the alternate side following a 1ml/kg saline injection. All of 14 subjects learned to discriminate reliably between the effects of 20 mg/kg pentylene-tetrazol (PTZ) and saline. Seven of eight rats learned to discriminate between the effects of bemegride (5 mg/kg) and saline. None of 14 rats learned to discriminate between 5 mg/kg PTZ and saline. The bemegride discriminative stimulus generalized to PTZ (20 mg/kg) and was antagonized by chlordiazepoxide (10 mg/kg). Chlordiazepoxide, diazepam, flurazepam, clobazam, and meprobamate were all effective antagonists of PTZ in a dose-dependent manner. Bemegride and cocaine generalized to the PTZ discriminative stimulus in a dose-dependent manner, but d-amphetamine, methylphenidate, and nicotine did not. Since bemegride and PTZ are convulsants at higher doses, the discriminative stimulus properties of these drugs might be based on a subtle convulsive brain state. The anxiolytic properties of benzodiazepines and meprobamate suggest that the discriminative stimulus produced by these convulsants is related to an anxiety-inducing action.     

Discriminative stimulus properties of benzodiazepines, barbiturates and pharmacologically related drugs; relation to some intrinsic and anticonvulsant effects.

Using a food-reinforced two-lever operant method, rats (n = 12) were trained to discriminate chlordiazepoxide (5 mg/kg, p.o.) from solvent (p.o.). With rats trained thus as subjects, generalization experiments were done with various benzodiazepines, barbiturates and related compounds, and with two neuroleptic drugs. The ability of these drugs to induce a discriminative stimulus complex similar to that induced by chlordiazepoxide, was then compared with some intrinsic and anticonvulsant effects of the same drugs. It was found that the discriminative stimulus properties of benzodiazepines, barbiturates, and related compounds correlate with the ability of these drugs to induce ataxia, as well as with part of their anticonvulsant activity. However, the stimulus properties of these drugs, as defined by the procedure described, are based neither on their ataxia-inducing effect, nor on their general depressant or sedative action. It is concluded that these properties constitute a pharmacologically highly specific phenomenon.     

Midazolam cue in rats: Generalization tests with anxiolytic and other drugs

Some characteristics of the discriminative stimulus (cue) effects of midazolam, a short-acting benzodiazepine, have been determined in rats. A standard two-bar operant conditioning procedure with food reinforcers delivered on a tandem schedule was used. The 0.4 mg/kg dose of midazolam used for training was well discriminated, typically yielding at least 95% correct responding. Other benzodiazepines increased the percentage of drug-appropriate responding in a dose-related manner and were generalized at doses which had little effect on the overall rate of responding. Doses of pentobarbitone which greatly reduced the overall rate of responding were also generalized with midazolam. Amphetamine, oxotremorine, picrotoxin, morphine, nicotine, quipazine and Ro 15-1788 were not generalized, even at doses which severely suppressed overall response rates. The midazolam cue possesses a considerable degree of specificity and provides a potentially useful assay for drug action at the benzodiazepine receptor complex.     

Discriminative stimulus properties of alprazolam

Rationale: The triazolobenzodiazepine alprazolam has a unique clinical profile compared to most other benzodiazepines (e.g. diazepam, chlordiazepoxide), in that it is used to treat panic disorder and is effective in depression, two disorders that are usually treated with anti-depressants. Previous drug discrimination studies suggested that alprazolam has stimulus properties in common with antidepressants. Objective: In the present study, the discriminative stimulus properties of alprazolam were investigated to test more conclusively the role of benzodiazepine receptors and whether alprazolam has stimulus properties in common with antidepressants. Methods: Male Wistar rats (n=12) were trained to discriminate between alprazolam (2.0 mg/kg, PO) and vehicle in an operant two-lever drug discrimination procedure under a tandem VI40”-FR10 schedule of reinforcement. Generalization and antagonism tests were carried out under 2 min extinction. Results: In generalization tests, a number of benzodiazepines (alprazolam, chlordiazepoxide, midazolam, lorazepam) and the barbiturate pentobarbital substituted completely, while zolpidem and abecarnil substituted partially for alprazolam. In contrast, no significant degree of generalization to the antidepressants imipramine and fluvoxamine and the putative antidepressants buspirone and flesinoxan was found. In antagonism studies alprazolam could be antagonized (almost) completely by flumazenil, partially by pentylenetetrazole, but not by methyl 6,7-dimethoxy-4-ethyl-β-carboline-3-carboxylate (DMCM), N-methyl-β-carboline-3-carboxamide (FG-7142) and picrotoxin. Conclusions: These results show that the discriminative stimulus properties of alprazolam are mediated by benzodiazepine receptors and that the finding that antidepressants share discriminative stimulus effects with alprazolam may have limited generality. Received: 7 March 1999 / Final version: 22 June 1999     

Amfonelic acid: similarity to other dopamine agonists

Rats were trained to discriminate between the stimulus properties of intraperitoneally administered 0.8 mg/kg amfonelic acid and its vehicle in a two-lever, food-motivated operant task. Once trained, rats showed a dose-related decrease in discriminative performance with lower amfonelic acid doses and analysis of the dose-response curve indicated an ED50 of 0.11 mg/kg. Administration of 0.08-0.6 mg/kg d-amphetamine produced a pattern of responding similar to that observed with amfonelic acid, with an ED50 of 0.10 mg/kg and a non-parallel dose-response curve. Likewise, the discriminative stimulus properties of amfonelic acid were shown to generalize to both d,l-cathinone and cocaine but not to apomorphine. The results suggest that amfonelic acid, as well as other non-amphetamine stimulants, acts by a different mechanism of action than does amphetamine and biochemical studies are reviewed to further evidence this observation.     

Comparing the discriminative stimuli produced by either the neuroactive steroid pregnanolone or the benzodiazepine midazolam in rats

Rationale

Neuroactive steroids might be therapeutic alternatives for benzodiazepines because they have similar anxiolytic, sedative, and anticonvulsant effects, and their actions at different modulatory sites on ??-aminobutyric acid_A (GABA_A) receptors might confer differences in adverse effects.

Objectives

This study used drug discrimination to compare discriminative stimuli produced by positive GABA_A modulators that vary in their site of action on GABA_A receptors.

Methods

Two groups of rats discriminated either 3.2?mg/kg of pregnanolone or 0.56?mg/kg of midazolam from vehicle while responding under a fixed ratio 10 schedule of food presentation.

Results

Pregnanolone, midazolam, and flunitrazepam produced ??80% drug-lever responding in both groups; each drug was more potent in rats discriminating pregnanolone. Pentobarbital produced ??80% drug-lever responding in all rats discriminating pregnanolone, and in 1/3 of the rats discriminating midazolam with larger doses decreasing response rates to <20% of control. Morphine and ketamine produced predominantly saline-lever responding in both groups. Flumazenil antagonized midazolam and flunitrazepam in both groups; slopes of Schild plots were not different from unity, and pA ₂ values for flumazenil ranged from 5.86 to 6.09. Flumazenil did not attenuate the discriminative stimulus effects of pregnanolone.

Conclusions

The midazolam and pregnanolone discriminative stimuli were qualitatively similar, although the effects of pentobarbital were not identical in the two groups. Although acute effects of midazolam and pregnanolone are similar, suggesting that neuroactive steroids might retain the therapeutic effects of benzodiazepines, differences emerge during chronic treatment, indicating that neuroactive steroids might produce fewer adverse effects than benzodiazepines.     

Behavioral analysis of zopiclone on the basis of their discriminative stimulus properties in the rat

Zopiclone is a new cyclopyrrolone derivative which exerts pharmacological activities similar to those of benzodiazepines in behavioral and biochemical studies. In order to clarify the discriminative stimulus properties of zopiclone, 8 rats were trained to discriminate the interoceptive stimulus induced by zopiclone (3.2 mg/kg, i.p.) from those of saline. Following discrimination acquisition, administration of zopiclone resulted in drug-appropriate responding with an ED50 of 1.3 (1.0-1.8) mg/kg. The zopiclone discriminative stimulus generalized to the benzodiazepines diazepam (1.8 mg/kg), nitrazepam (10 mg/kg) and alprazolam (10 mg/kg). A non-benzodiazepine, suriclone, at 3.2 mg/kg, generalized to the zopiclone stimulus in 5 out of 7 rats, but meprobamate, hydroxyzine, tracazolate and muscimol did not. The benzodiazepine antagonist Ro 15-1788 (1 mg/kg) completely blocked zopiclone stimulus. In contrast, however, bicuculline and pentetrazol failed to antagonize it. The serotonin antagonist cinanserin and ritanserin neither generalized to the zopiclone stimulus nor did they exhibit antagonism. These results suggest that the zopiclone discriminative stimulus is mediated by binding to benzodiazepine receptors and appears not to be related to GABAergic or serotonergic system.     

Asymmetric generalization between the discriminative stimulus effects of nicotine and cocaine

The discriminative stimulus effects of nicotine and cocaine were studied, alone and in combination, in rats. Two sets of rats were trained to press one lever when injected intraperitoneally (i.p.) with either nicotine (0.1 mg/kg = 0.6 micromol/kg, Set 1) or cocaine (8.9 mg/kg base = 29.4 micromol/kg, Set 2), and another lever when injected with saline. Rats learned to discriminate drug from saline, and maintained discriminative control throughout the study (at > 85% drug-appropriate responding). In accordance with most previous findings, cocaine only partially substituted for nicotine (maximum = 41% nicotine-lever responding). The nicotinic agonist, nornicotine, produced dose-related, near-full substitution for nicotine (maximum = 76% nicotine-lever responding), whereas the peripherally acting nicotinic agonist, methylcarbamylcholine, did not substitute for nicotine. The muscarinic receptor agonist pilocarpine also failed to substitute for nicotine. However, in the cocaine-trained rats, nicotine substituted fully for cocaine in a dose-dependent manner, demonstrating that cross-generalization between the two drugs is not symmetrical. Finally, administration of each drug as a pre-treatment to the other yielded inconsistent increases in each drug's discriminative stimulus effects. The results are congruent with the view that the discriminative stimulus effects of nicotine and cocaine share common features, but the asymmetric pattern of cross-generalization and the interactions revealed in the combination tests also suggest that there are important differences between them.     

Discriminative stimulus effects of drugs acting at GABA(A) receptors: differential profiles and receptor selectivity.

The GABA(A) receptor complex contains a number of binding sites at which a variety of psychotropic drugs, including benzodiazepines, barbiturates, and some neurosteroids, act to potentiate or inhibit the effect of the transmitter. Many studies have reported that these drugs can produce discriminative stimulus actions, but the cueing effects of compounds acting at different sites to enhance the effects of GABA are not identical. The discriminative stimulus effects of benzodiazepines have been analyzed in detail, and there is also a great deal of information available on the effects of nonbenzodiazepine compounds acting at BZ(omega) recognition sites, which form part of the GABA(A) receptor complex. Of particular interest are compounds with selectivity for the BZ1(omega1) receptor subtype including zolpidem, zaleplon, and CI 218,872. BZ1(omega1)-selective drugs substitute for the discriminative stimulus produced by chlordiazepoxide only partially and at sedative doses. This is consistent with the view that sedative effects of BZ(omega) receptor agonists are mediated by the BZ1(omega1) receptor subtype, whereas the discriminative stimulus produced by chlordiazepoxide may be produced by activity at the BZ2(omega2) subtype. Analysis of this hypothesis is complicated by the variety of levels of intrinsic activity shown by different drugs.     

Comparison of behavioral effects of cathinone, amphetamine and apomorphine

Rats were trained to discriminate between the stimulus properties of 0.6 mg/kg +/- -cathinone and its vehicle in a two-lever, food-motivated operant task. Once trained, rats showed a dose-related decrease in discriminative performance with lower cathinone doses and analysis of the dose-response curve indicated an ED50 of 0.24 mg/kg. Administration of 0.2-0.8 mg/kg d-amphetamine produced a pattern of responding similar to that observed with cathinone. The dose-response curve after d-amphetamine was shown to be parallel to that of cathinone and the ED50 generated was 0.21 mg/kg. Thus, cathinone was equi-potent to d-amphetamine in this behavioral paradigm. In contrast, administration of 0.16-0.32 mg/kg apomorphine produced intermediate results. The results suggest a common site and/or mechanism for action of +/- -cathinone and d-amphetamine.     

Effects of selective dopamine receptor agonists in rats trained to discriminate apomorphine from saline

Rats (N = 12) were trained to discriminate apomorphine (0.25 mg/kg, IP) from saline in a two-lever, food-reinforced (FR 30) drug discrimination paradigm. When the discrimination was acquired, various doses of apomorphine as well as several other dopamine receptor agonists were injected before test sessions. Apomorphine (0.03-0.25 mg/kg, IP) produced a dose-related increase in the percent of responses that occurred on the drug lever during test sessions. The selective DA2 receptor agonist piribedil (0.25-8.0 mg/kg, IP) produced a dose-related increase in drug lever responding that was similar to that seen with apomorphine. On the other hand, administration of the selective DA1 receptor agonist SKF 38393 (1.0-32 mg/kg, IP) resulted in principally saline lever responding, even at doses that substantially reduced the rate of responding. Administration of dopamine (1.0-8.0 mg/kg, IP), which does not readily cross the blood-brain barrier, also resulted in principally saline lever responding. These results suggest that the discriminative stimulus properties of apomorphine are based on its action at a receptor that is similar to the DA2 receptor that has been characterized in the periphery and that this receptor is centrally located.