Effects of caffeine, theophylline and theobromine on scheduled controlled responding in rats.

1 Rats were trained to respond under a variable interval 30 s (VI 30) schedule of food reinforcement. Caffeine (0.32-32 mg/kg), theophylline (1.0-56 mg/kg) and theobromine (10-320 mg/kg) in general produced dose-related decreases in operant responding. At relatively low doses, caffeine (1.0 mg/kg) and theophylline (3.2 mg/kg) produced slight but nonsignificant increases in VI 30 responding. 3 The rank order of potency for producing decreases in responding was caffeine greater than theophylline greater than theobromine. 4 Daily caffeine injections (32 mg/kg, i.p.) resulted in the development of caffeine tolerance. This tolerance was characterized by a 6 fold shift to the right in the caffeine dose-effect curve. Saline substitution for the 32.0 mg/kg caffeine maintenance dose resulted in a substantial decrease in responding.     

Differential involvement of dopamine in mediating the discriminative stimulus effects of low and high doses of caffeine in rats

The hypothesis that low and high doses of caffeine produce effects that are differentially mediated by dopamine (DA) receptor mechanisms was investigated in rats trained to discriminate either 10 or 56 mg/kg of caffeine from saline. Rats trained to discriminate 56 mg/kg of caffeine acquired the discrimination in an average of 74 sessions, whereas rats trained to discriminate 10 mg/kg of caffeine required an average of 108 sessions. The DA D1 receptor agonist SKF 81297 and the DA D2 receptor agonist R(-)-propylnorapomorphine (NPA) generalized partially (50-75%) in rats trained to discriminate 10 mg/kg of caffeine, but produced predominantly saline-appropriate responding (< 40%) in rats trained to discriminate 56 mg/kg of caffeine. When SKF 81297 and NPA were combined, stimulus generalization was no greater than it was when either agonist was tested alone. The DA uptake inhibitors cocaine and GBR 12909 produced predominantly saline-appropriate responding in both groups of rats. Neither the DA D1 receptors antagonists SCH 23390 and SCH 31966, nor the DA D2 receptor antagonists eticlopride and sulpiride, generalized in rats trained to discriminate 10 or 56 mg/kg of caffeine. When administered in combination with caffeine, both the DA D1 and DA D2 antagonists antagonized completely the discriminative stimulus effects of the low training dose of caffeine, but did not alter the discriminative stimulus effects of the high training dose. These results suggest that the discriminative stimulus effects of 10 mg/kg of caffeine, but not 56 mg/kg of caffeine, are dependent on, but not limited to, DA D1 and D2 receptor mechanisms.     

Triazolam as a discriminative stimulus in humans.

Seven healthy normal male and female volunteers (19-42 years) were trained to discriminate between the benzodiazepine triazolam (0.32 mg/70 kg; e.g. drug A) and placebo (e.g. drug B). During the first four daily sessions, drug A and drug B were administered orally in capsules 60 min prior to the session on alternate days and subjects were informed of the drug label at the time of drug administration. Subsequently, drug A and drug B were administered in a randomized-block fashion and subjects identified the drug code they thought they received. Subjects were informed of the drug code post-session. Once the criterion for discrimination was met (i.e. correct drug code identification on four consecutive sessions), the dose-effect curve for triazolam (0.1-0.75 mg/70 kg) was determined. The discrimination was acquired in all subjects; triazolam (0.32 mg/70 kg) and placebo produced approximately 85-95% correct responding. During the dose-effect curve determination, triazolam produced dose-related increases in triazolam-appropriate responding and self-reported sedation and drug strength. These results indicate that a triazolam-placebo discrimination can be acquired and that the triazolam discriminative stimulus effect is related to dose and to self-reported sedation.     

Triazolam discrimination by humans under a novel response procedure: effects of buspirone and lorazepam

Six healthy human volunteers (ages 18 to 24) acquired a triazolam (0.32mg/70kg) vs placebo discrimination under a standard, two-response drug discrimination procedure. Dose-effect curves were then determined for triazolam (0.1-0.56mg/70kg), lorazepam (0.75-3.0mg/70kg) and buspirone (7.5-30mg/70kg) under a novel response procedure that provided a response alternative for drugs unlike triazolam or placebo (i.e. a novel-appropriate response). Triazolam dose-dependently increased triazolam-appropriate responding but did not occasion any novel-appropriate responding. Lorazepam dose-dependently increased triazolam-appropriate responding in four of six subjects, but at least one dose also occasioned novel-appropriate responding in three subjects. Buspirone dose-dependently increased novel-appropriate responding, although three of six subjects also made triazolam-appropriate responses following some dose(s). All three drugs comparably increased self-reported sedation. Self-reported effects did not differentiate triazolam from lorazepam whereas only buspirone increased "bad" self-reports, and did not increase "liking" and "good" self-reports. The results suggest that the novel response procedure enhanced the pharmacological selectivity of human benzodiazepine discrimination and may help interpret partial generalization under two-choice drug discrimination procedures. The results also add to the evidence of a close relationship between the discriminative stimulus and self-reported effects of drugs.     

Discriminative stimulus effects of self-administered ethanol

The conditions under which a drug is administered often alter the behavioral effects of that drug. The present study examined the effect of changes in response dependence on the discriminative stimulus effects of ethanol. Six Long-Evans rats were trained to discriminate 1000 mg/kg, interperitoneal (i.p.) ethanol from saline. A dose-effect curve was then obtained using i.p. doses of 100, 320, 560, 1000, 1320 and 1560 mg/kg ethanol. Ethanol doses of 1000 mg/kg and greater produced more than 80% ethanol-lever selection. The rats were then trained to orally self-administer 10% weight/volume ethanol and tested to determine if self-administered oral ethanol would substitute for experimenter administered i.p. ethanol. A mean self-administered ethanol intake of 1114 mg/kg (+/-156 mg/kg) produced 83% ethanol-lever responding. Restricted access to 560 mg/kg of self-administered ethanol resulted in 33% i.p. ethanol-lever responding. Doses of 100 and 320 mg/kg ethanol did not substitute for i.p. ethanol. These data show that orally self-administered ethanol can produce discriminative stimulus effects that are similar to i.p. experimenter-administered ethanol and that orally self-administered ethanol produces centrally-mediated discriminative stimulus effects.     

Buspirone is differentiated from diazepam in humans using a three-response drug discrimination procedure

The discriminative stimulus effects of buspirone and diazepam were examined in 12 healthy volunteers using a three-response drug discrimination procedure and a within-subject design. During an initial sampling phase, the training drug conditions (placebo, 15 mg/70 kg buspirone, and 10 mg/70 kg diazepam) were identified to subjects by letter codes before oral drug administration. During a subsequent training phase, subjects earned money for correct drug identifications made two hours after drug administration. Ten out of 12 subjects acquired the three-response discrimination. When lower doses of buspirone (3.75 and 7.5 mg/70 kg) and diazepam (2.5 and 5.0 mg/70 kg) were tested in a subsequent generalization testing phase, both buspirone and diazepam produced dose-related increases in appropriate drug identifications, without significant cross-generalization. Analyses of standardized and unstructured self report questionnaires revealed that buspirone and diazepam produced different profiles of effects, and that buspirone was associated with a number of “negative” subject-rated effects including tension, nausea, and dizziness. These results demonstrate a distinct profile of discriminative stimulus and subjective effects for buspirone relative to diazepam which is consistent with its distinct pharmacological profile, and provide evidence for the sensitivity of the three-response drug discrimination procedure. Received: 7 July 1997/Final version: 18 December 1997     

Further characterization of the discriminative stimulus effects of buspirone using monoamine agonists and antagonists in the pigeon

White Carneau pigeons were trained to discriminate 1.0 mg/kg buspirone from saline when key pecking was maintained under a fixed-ratio 30 schedule of food presentation. Buspirone (0.3-10.0 mg/kg), the serotonin 1A (5-HT(1A)) agonist 8-OH-DPAT (0.1-1mg/kg), the buspirone analog BMY 7378 (3.0-5.6mg/kg), the mixed 5-HT(1A/1B) agonist RU 24969 (3.0-10.0mg/kg) and the 5-HT(1A) agonist spiroxatrine (0.1-1.0mg/kg) occasioned at least 80% buspirone-appropriate responding in all subjects tested. Administration of the 5-HT(1B) agonist (TFMPP 0.1-10.0mg/kg) or the 5-HT(3) antagonist (MDL 72222 (3.0-17.0mg/kg) resulted in primarily saline-key responding. The dopamine receptor antagonist chlorpromazine (1.0-17.0mg/kg), the specific D-2 receptor antagonist eticlopride (0.03-0.56mg/kg), the noradrenergic alpha-2 antagonist yohimbine (0.1-1.0mg/kg), the alpha-2 agonist clonidine (0.003-0.10mg/kg) and (+/-) and (-) propranolol (3.0-30.0mg/kg) all produced primarily saline-appropriate responding. Coadministration of the beta-adrenergic agonist isoproterenol (1.0-5.6mg/kg) or the 5-HT(1A) partial agonist BMY 7378 (0.01-10.0mg/kg) with 1.0mg/kg buspirone did not block the discriminative stimulus effects of buspirone. However, 3.0-10.0mg/kg BMY 7378, in combination with a lower dose of buspirone (0.3mg/kg) decreased drug-key responding to approximately 50%. Results from the present study suggest that (1) the discriminative stimulus effects of buspirone, 8-OH-DPAT, BMY 7378, RU 24969 and spiroxatrine are mediated through the 5-HT(1A) receptor; (2) buspirone's discriminative stimulus effects do not interact with the noradrenergic or dopaminergic system; and 3) under this procedure BMY 7378 was a partial agonist at 5-HT(1A) receptors.     

Methylphenidate enhances the abuse-related behavioral effects of nicotine in rats: intravenous self-administration, drug discrimination, and locomotor cross-sensitization.

Stimulant drugs, including D-amphetamine, cocaine, and methylphenidate, increase cigarette smoking in controlled human laboratory experiments. Although the mechanism(s) underlying this effect are unknown, it is possible that stimulants may enhance directly the abuse-related effects of nicotine. In the present study, we characterized the behavioral pharmacological interactions between methylphenidate and nicotine in the intravenous self-administration, drug discrimination, and locomotor cross-sensitization procedures. Adult male Sprague-Dawley rats were trained to respond for intravenous nicotine (0.01 or 0.03 mg/kg/infusion) or sucrose, and the acute effects of methylphenidate (1.25-10 mg/kg) were determined; in addition, separate groups of rats were treated with methylphenidate (2.5 mg/kg) or saline before 12 consecutive nicotine (0.03 mg/kg/infusion) self-administration sessions. Next, the discriminative stimulus effects of nicotine (0.03-0.3 mg/kg) and methylphenidate (1.25-10 mg/kg), alone and in combination with a low nicotine dose (0.056 mg/kg), were tested in nicotine-trained rats. Finally, the locomotor effect of repeated methylphenidate (2.5 mg/kg) was tested in rats previously treated with nicotine (0.2-0.8 mg/kg). Results indicated that acute methylphenidate increased the rate of nicotine self-administration at doses that reduced sucrose-maintained responding; furthermore, tolerance to this effect was not apparent following repeated methylphenidate. Methylphenidate, while not substituting for nicotine alone, dose-dependently enhanced the discriminative stimulus effect of a low nicotine dose. In addition, repeated nicotine exposure promoted the development of locomotor sensitization to methylphenidate. Taken together with recent clinical findings, these results suggest that methylphenidate may enhance the abuse-related behavioral effects of nicotine, perhaps increasing vulnerability to tobacco dependence.     

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.     

Discriminative stimulus properties of triadimefon: Comparison with methylphenidate

Two groups of rats (N=4 each) were trained to discriminate either triadimefon (40 mg/kg) or methylphenidate (4 mg/kg) from saline in a two-lever, milk-reinforced drug discrimination paradigm. Dose-response functions were determined during 5-min extinction sessions. Both agents produced a dose-related increase in the percentage of responses that occurred on the drug lever. In the substitution phase of the study, rats trained to discriminate triadimefon were tested with methylphenidate and rats trained to discriminate methylphenidate were tested with triadimefon. Triadimefon substituted completely for methylphenidate and methylphenidate substituted completely for triadimefon. These results indicate that triadimefon can function as a discriminative stimulus and that it shares discriminative stimulus properties with methylphenidate.     

Drug discrimination and cross generalization between two methylxanthines

Twenty-one rats were trained to discriminate 32 mg/kg caffeine from saline in a two-lever drug discrimination task (variable ratio) while another ten rats were trained to discriminate 56 mg/kg theophylline from saline. For each group, dose-effect curves (% drug-lever responses and overall response rate) were obtained for both caffeine and theophylline. Significant dose-related generalization of each training drug was found for both the caffeine- and theophylline-trained rats. Concomitant dose-related decreases in overall response rate also were apparent. Similar dose-related effects were seen with cross-generalization tests for various doses of the other xanthine. The nature of the training session preceding the test session was found to have an effect on discrimination performance at intermediate test doses. Drug appropriate responding was higher and overall response rate was lower after saline- than after drug-training days. Such data may suggest the possibility of short-term tolerance to caffeine's cue. That the discriminative cue was specific to the xanthines was shown by the lack of generalization seen after either amphetamine or metrazol.     

Discriminative stimulus properties of d-amphetamine and related compounds in rats

The discriminative stimulus properties of amphetamine were demonstrated in rats trained to discriminate between 0.8 mg/kg of d-amphetamine sulfate and saline. During the discriminative training, animals were shaped on a DRL 15-second schedule to respond to one of two levers for a food reward when they were given d-amphetamine, and to respond to the other lever when they were treated with saline. Tests for the discriminative stimulus properties consisted of 10-min extinction sessions in which the reinforcement delivery was disconnected. Animals receiving low doses (0.2–0.4 mg/kg) of d-amphetamine exhibited mostly saline-like responses, but at a dose of 0.8 mg/kg they produced more than 80% responses on the amphetamine lever. Doses higher than 2.4 mg/kg caused an initial stereotyped behavior and the animals showed a period of latency before responding on the amphetamine lever. In order to elucidate the structural characteristics of d-amphetamine involved in the production of the discriminative stimulus properties, a number of amphetamine derivatives and related compounds were administered to these animals. 1-Amphetamine, ephedrine, norephedrine, 4-methoxyamphetamine and methylphenidate all produced the discriminative stimulus properties similar to d-amphetamine, but doses of 2–10 times greater than d-amphetamine were necessary. Mescaline, STP and DOET did not produce the d-amphetamine-like responses. These results suggest that most psychomotor stimulants, although having different structures, are likely to produce discriminative stimulus properties similar to d-amphetamine.     

Relationship between caffeine discrimination and caffeine plasma levels

Rats, trained to discriminate 32 mg/kg caffeine from saline in a two-lever operant task, were tested for the presence of caffeine-appropriate lever responding at various intervals after the intraperitoneal injection of 32 mg/kg caffeine. Following completion of all behavioral tests, caffeine plasma levels were determined in the same animals at the same intervals after caffeine administration. After injection, both caffeine levels and caffeine-appropriate responding showed rapid increases followed by a differential decline.     

The stimulus effect of 5,6,7,8-tetrahydro-1,3-dioxolo[4,5-g]isoquinoline is similar to that of cocaine but different from that of amphetamine.

5,6,7,8-Tetrahydro-1,3-dioxolo[4,5-g]isoquinoline (TDIQ) is a conformationally restricted phenylalkylamine related in structure to amphetamine and N-methyl-1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA) that does not act as a locomotor stimulant. To further evaluate this agent, a group of six rats was trained to discriminate 5.0 mg/kg of TDIQ from vehicle and tests of stimulus generalization were conducted to define the stimulus. The TDIQ stimulus (ED(50)=0.9 mg/kg) failed to generalize to the central stimulants (+)amphetamine, methylphenidate or (-)ephedrine but, curiously, generalized to cocaine (ED(50)=1.5 mg/kg). When administered to rats (n=5) trained to discriminate 1.0 mg/kg of (+)amphetamine from vehicle, TDIQ produced a maximum of 7% (+)amphetamine-appropriate responding, whereas when administered to rats (n=7) trained to discriminate 4.0 mg/kg of (-)ephedrine from vehicle, TDIQ produced a maximum of 57% drug-appropriate responding. Administration of MDMA to TDIQ-trained animals resulted in 76% TDIQ-appropriate responding. Tests of stimulus generalization were also conducted with fenfluramine, nisoxetine, clenbuterol, imipramine and buspirone, and tests of antagonism were conducted with haloperidol and R(+)SCH-23390 using the TDIQ-trained animals. Results were inconclusive in that these agents either failed to completely substitute for or failed to completely antagonize the TDIQ stimulus. Nevertheless, the generalization seen with cocaine, the partial generalization seen with (-)ephedrine, MDMA, nisoxetine, clenbuterol and buspirone and the partial antagonism seen with haloperidol suggest that TDIQ might be acting through a mixed mechanism that involves adrenergic, dopaminergic and/or serotonergic systems. Given that TDIQ is an agent that seems to differentiate among the stimuli produced by amphetamine, methylphenidate, ephedrine and cocaine, it is proposed that further tests be undertaken, using animal models of cocaine abuse, to evaluate the potential usefulness of TDIQ as pharmacotherapy in cocaine dependence.     

Caffeine-induced stimulus control

Six rats were trained to discriminate the effects of caffeine (60 mg/kg, pretreatment time: 1 hour) and saline in a two-lever choice task using a fixed ratio 10 schedule of water reinforcement. Stimulus control was assumed to be present when 80% or more of the first ten responses were appropriate for the treatment condition on each of five consecutive days. The mean number of sessions prior to the onset of criterion performance was 22 (SE = 3; range = 11?32). In trained subjects, doses of caffeine of 30, 10, and 3 mg/kg were followed by a progressively smaller proportion of responses on the caffeine-appropriate lever. Stimulus control by caffeine began to diminish about four hours after administration and was completely absent after 24 hours. The caffeine cue generalized partially to d-amphetamine and completely to aminophylline. Neither pizotyline nor spiperone antagonized stimulus control induced by caffeine.     

Serotonin involvement in the discriminative stimulus effects of mu and kappa opioids in rats

The role of serotonin (5-HT) in the discriminative stimulus effects of opioids was examined using a two-lever, food-reinforced drug discrimination procedure. The effects of the 5-HT(1A) full agonist 8-OH-DPAT, the 5-HT(1A) partial agonist buspirone and the 5-HT(2) antagonist ketanserin were evaluated in rats trained to discriminate the mu opioid agonist morphine, or the kappa opioid agonist U50, 488 from saline. In rats trained to discriminate 5.6mg/kg of morphine from saline, morphine dose-dependently substituted (produced >/= 80% morphine-appropriate responding) for the morphine stimulus. In contrast, U50,488, 8-OH-DPAT and ketanserin did not substitute for morphine, and buspirone produced only a small degree of substitution (approx. 40% morphine-appropriate responding). When administered in combination with morphine, 8-OH-DPAT, but not buspirone and ketanserin, attenuated the discriminative stimulus effects of higher doses of morphine. In rats trained to discriminate 5.6mg/kg of U50, 488 from saline, U50, 488 dose-dependently substituted for the U50, 488 stimulus. When administered alone, 8-OH-DPAT and buspirone partially substituted (produced between 40% and 79% U50, 488-appropriate responding) for the U50,488 stimulus, whereas morphine and ketanserin did not substitute for U50,488. The opioid antagonist naltrexone failed to antagonize the effects of 8-OH-DPAT and buspirone suggesting that the effects of these drugs in U50,488-trained rats were not mediated by opioid receptors. When administered in combination with U50,488, 8-OH-DPAT, but not buspirone or ketanserin, attenuated the discriminative stimulus effects of the training dose of U50,488. These results suggest that the 5-HT system is involved in the discriminative stimulus effects of both morphine and U50,488, although the exact nature of this 5-HT involvement is not clear.     

Pharmacological specificity of Δ9-tetrahydrocannabinol discrimination in rats

While many previous studies have shown that a variety of cannabinoids substitute and cross-substitute for ⁹-tetrahydrocannabinol (THC) in drug discrimination procedures, few have systematically examined potential THC-like effects of non-cannabinoid compounds. The purpose of the present study was to delineate further the pharmacological specificity of THC discrimination. Rats were trained to discriminate THC (3.0 mg/kg) from vehicle. Following determination of a dose-effect curve with THC, substitution tests with selected compounds from a variety of pharmacological classes, includingl-phenylisopropyl adenosine, dizocilpine, dextromethorphan, clozapine, buspirone, MDL 72222, muscimol, midazolam and chlordiazepoxide, were performed. Whereas THC produced full dose-dependent substitution, substitution tests with non-cannabinoid drugs resulted in less than chance (50%) levels of responding on the THC-appropriate lever, with the exception of (+)-MDMA (2.5 mg/kg, 50%) and diazepam (3.0 mg/kg, 67%). These results are consistent with those of previous studies and suggest that the discriminative stimulus effects of THC exhibit pharmacological specificity.     

GABAergic modulation of the discriminative stimulus effects of methamphetamine

To assess whether gamma-aminobutyric acid (GABA) modulation of dopamine is important in mediation of the discriminative stimulus effects of methamphetamine, the GABA compounds chlordiazepoxide (benzodiazepine site agonist), pentobarbital (barbiturate site agonist), bicuculline and pentylenetetrazol (GABA(A) receptor antagonists) were tested in Sprague-Dawley rats trained to discriminate methamphetamine (1 mg/kg, i.p.) from saline. Each of the compounds produced modest amounts of methamphetamine-appropriate responding (20-35%) when tested alone. When tested in combination with methamphetamine, the antagonists (bicuculline and pentylenetetrazol) failed to shift the methamphetamine dose-effect curve. In contrast, chlordiazepoxide (25 mg/kg, i.p.) reduced methamphetamine-appropriate responding at each dose of methamphetamine tested, and pentobarbital (10 mg/kg, i.p.) dose-dependently decreased the discriminative stimulus effects of 1 mg/kg methamphetamine. In conclusion, GABA(A) antagonists and positive modulators likely do not produce methamphetamine-like stimulus effects. However, activation of GABA(A) receptors can interfere with the discriminative stimulus effects of methamphetamine.     

Effects of ethanol on cocaine discrimination in rats

Ethanol and cocaine are frequently abused in combination, but little is known about how the subjective effects of the two drugs interact. The ability of ethanol and other GABA(A)-active compounds to alter the discriminative stimulus effects of cocaine was tested. Male Sprague-Dawley rats were trained to discriminate cocaine (10 mg/kg ip) from saline using either single- or cumulative-dosing methods. In single-dose testing, ethanol (0.1-0.5 g/kg) dose-dependently decreased cocaine-appropriate responding following the training dose of cocaine. Ethanol (0.5 g/kg) produced a rightward shift in the cocaine cumulative dose-effect curve. Ethanol (0.1-1.0 g/kg) failed to substitute for the discriminative stimulus effects of cocaine and the higher doses (1-2 g/kg) completely suppressed responding. Indirect GABA(A) agonists diazepam (benzodiazepine site) and pentobarbital (barbiturate site) did not block the discriminative stimulus effects of cumulative doses of cocaine. The GABA(A) antagonist pentylenetetrazol (PTZ) (10-40 mg/kg) did not substitute for cocaine. These findings suggest that ethanol can modulate the discriminative stimulus effects of cocaine, and that these effects may not be mediated by the actions of ethanol at the GABA(A) receptor.     

Discriminative stimulus effects of the novel anxiolytic buspirone

Separate groups of Long-Evans rats were trained to discriminate either 0.56 or 1.0mg/kg buspirone i.p. in a two-lever, drug vs no-drug discrimination procedure. Training took twice as long for the lower versus the higher training-dose group. Generalization tests were conducted with buspirone (0.1-1.8mg/kg, i.p., 0.32-10mg/kg, p.o.), pentylenetetrazole (1-18mg/kg, i.p.), meprobamate (3.2-180mg/kg, p.o.), haloperidol (0.01-0.32mg/kg, i.p.), and 8-OH-DPAT (0.01-0.32mg/kg, i.p.). Buspirone p.o. was 0.5-1.0 log(10) units less potent than buspirone i.p. in producing dose-dependent generalization (i.e. > 80% buspirone-lever responding). Dose-effect functions for the 1.0 training-dose group were to the right of those for the 0.56 group. Partial generalization to meprobamate occurred in both groups, representing the first report of overlap of the buspirone discriminative stimulus with that of another anxiolytic. Complete generalization to 8-OH-DPAT occurred, consistent with buspirone's prominent 5HT(1A)-receptor activity and replicating findings in the pigeon. Partial generalization to haloperidol was concluded: every rat generalized to haloperidol, but the gradients did not increase monotonically and drug-lever responding at a given dose was inconsistent within and across rats. The haloperidol results suggest a stronger influence of the dopaminergic component in the buspirone discriminative stimulus in rats than was found with pigeons. Although a previous study found generalization to buspirone from pentylenetetrazole in baboons, there was no generalization to pentylenetetrazole from buspirone in the present study.