Effects of buspirone on fixed interval responding in rats

Buspirone is a novel anxiolytic which does not share the muscle relaxant, anticonvulsant and sedative properties of classical anxiolytics such as the benzodiazepines. Its effects in different animal models of anxiety are also variable. The present experiments investigated the effects of buspirone on a fixed interval 60 s schedule of reinforcement (FI). In experiment 1, four doses of buspirone (10, 3.3, 1.1 and 0.3 mg/kg, i.p.) and two doses of chlordiazepoxide (5 and 20 mg/kg, i.p.) were administered to separate groups of rats throughout acquisition of the FI task. In experiment 2, four doses of buspirone (1.1, 0.3, 0.1 and 0.03 mg/kg, i.p.) and a single dose of chlordiazepoxide (5 mg/kg, i.p.) were used. Chlordiazepoxide generally released responding. At higher doses (1.1 mg/kg and above) buspirone suppressed responding in the later parts of the FI interval. The effects of lower doses were variable but included some response release in the later parts of the FI interval. At no dose did buspirone release responding at the beginning of the FI interval. The experiments show that buspirone differs qualitatively as well as quantitatively from chlordiazepoxide and that current animal models based on behavioural inhibition may need to be used with considerable care if detection of novel anxiolytics is to be ensured.     

Similar effects of buspirone and chlordiazepoxide on a fixed interval schedule with long-term, low-dose administration

Buspirone is a novel anxiolytic which does not share the muscle relaxant, anticonvulsant and sedative properties of classical anxiolytics such as the benzodiazepines. Its effects on behavioural tests of anxiolytic action generally match those of classical anxiolytics provided a low dose is used. However, in a previous experiment, buspirone appeared to affect fixed interval responding in a way which differed qualitatively as well as quantitatively from the classical anxiolytic chlordiazepoxide. It takes as much as 2 weeks for the clinical effects of anxiolytics to develop, during which time the side effects of benzodiazepines undergo tolerance. We, therefore, decided to compare long-term pre-administration (60 days, three injections/day) of buspirone and chlordiazepoxide on learning of a fixed interval 60-s schedule. The doses were based on previous acute dose-response tests of hippocampal theta rhythm in freely moving animals. Buspirone (0.1 mg/ kg i.p.) and chlordiazepoxide (0.4 mg/kg i.p.) produced similar increases in responding, especially in the middle of acquisition of the fixed interval schedule. Consistent with our acute electrophysiological tests, the effects of 0.4 mg/kg chlordiazepoxide were somewhat larger than those of 0.1 mg/kg buspirone. These results suggest that the acute effects of buspirone, but probably not chlordiazepoxide, on fixed interval responding are contaminated by side effects which do not seriously affect the results with long-term administration. The effects of both novel and classical anxiolytics on control of hippocampal theta rhythm appear to predict the magnitude of their common anxiolytic effects and to be unrelated to their different side effects.     

Comparison of the effects of buspirone and chlordiazepoxide on successive discrimination

Buspirone is a novel anxiolytic which does not share the muscle relaxant, anticonvulsant and sedative properties of classical anxiolytics such as the benzodiazepines. It has variable effects in conflict tasks based on shock which normally show consistent effects with classical anxiolytics. The present experiment investigated the effects of buspirone on successive discrimination, a conflict task employing omission of reward rather than shock. Buspirone (3.3, 1.1 and 0.3 mg/kg, IP) and chlordiazepoxide (5 and 20 mg/kg, IP) were administered to separate groups of rats throughout acquisition of a visual successive discrimination. Chlordiazepoxide released nonrewarded responding in a dose-related fashion. The effects of buspirone were qualitatively similar in releasing response suppression but were both less in magnitude and less clearly related to dose. The experiment shows that the action of buspirone in successive discrimination tasks does not depend on the use of shock but, rather, appears to be a genuine failure to fully release behavioural inhibition.     

Effects of long-term administration of anxiolytics on reticular-elicited hippocampal rhythmical slow activity.

Buspirone is effective in treating clinical anxiety but, unlike classical anxiolytics, does not have anti-convulsant, sedative or muscle relaxant side-effects and does not interact with GABA. Buspirone may also differ from classical anxiolytics in requiring a period of 2 weeks or more to achieve its full therapeutic action. It has previously been shown that all anxiolytic drugs, including buspirone, reduce the frequency of reticular-elicited hippocampal rhythmical slow activity (RSA). The present experiments tested whether the time course of the effect of buspirone on rhythmical slow activity differed from that of the anxiolytic benzodiazepine chlordiazepoxide. Rats, implanted with reticular stimulation electrodes and subicular recording electrodes, received three intraperitoneal injections per day of buspirone (2.5 mg/kg), chlordizepoxide (5 mg/kg) or saline for 45 days. Both buspirone and chlordiazepoxide reduced the frequency of rhythmical slow activity on the first day of testing and Ro15-1788 (10 mg/kg) blocked the effects of chlordiazepoxide but not buspirone. There was no increase in the effect of buspirone with time. These results showed that, if the effect of anxiolytic drugs on rhythmical slow activity provides any basis for their clinical action, then some additional factors are required to explain both the delayed action of buspirone and the immediate action of classical anxiolytic drugs.     

Dose-response analysis of the effects of buspirone on rearing in rats

The effects of buspirone were tested on rearing in an open field. Six different doses of buspirone (10, 3.3, 1.1, 0.3, 0.1 and 0.04 mg/kg) and a single dose of chlordiazepoxide (5 mg/kg) were administered i.p. to separate groups of rats. Buspirone produced a dose-dependent decrease in rearing in the range 0.04-10 mg/kg, whereas only the higher doses (10 and 3.3 mg/kg) decreased ambulation significantly. Chlordiazepoxide reduced rearing to an extent equivalent to 1 mg/kg of buspirone. Together with data in the literature, the results suggest that 5-HT1A agonists affect rearing at lower doses than ambulation; that the effects of buspirone in the open field are similar to classical anxiolytics; and that changes in rearing may be more closely related to anxiolytic than muscle relaxant, anti-convulsant and other GABA-mediated effects of the classical anxiolytics.     

Minimal changes with long-term administration of anxiolytics on septal driving of hippocampal rhythmical slow activity

In free-moving male rats, the function relating frequency to the threshold current required to drive hippocampal rhythmical slow activity (RSA; theta) with septal stimulation has a minimum at 7.7 Hz. Classical anxiolytics all increase thresholds in the region of 7.7 Hz, and so does the novel anxiolytic buspirone. However, unlike classical anxiolytics, 2 or 3 weeks are normally required for the onset of the clinical effects of buspirone. This study tested the effects of long-term administration of chlordiazepoxide and buspirone on septal driving of RSA. Separate groups of naive rats received three IP injections per day of chlordiazepoxide (0.4 mg/kg), buspirone (0.1 mg/kg) or saline for 50 days. Both chlordiazepoxide and buspirone increased thresholds at 7.7 Hz, as expected. These acute effects were not significantly changed with chronic administration. Buspirone and chlordiazepoxide produced similar, statistically significant, but small cumulative reductions in thresholds at 6.9 Hz. The present experiments suggest that if the effects of anxiolytic drugs on septally driven RSA provide any basis for their clinical action, then classical anxiolytics may have two actions: an immediate effect on euphoria and tension and a delayed effect on anxiety proper — with buspirone sharing only the latter effect.     

Neurochemically dissimilar anxiolytic drugs have common effects on hippocampal rhythmic slow activity.

Previous experiments have shown that anxiolytic drugs reduce the frequency of hippocampal rhythmic slow activity, induced by high frequency stimulation of the reticular formation and flatten the function relating threshold septal stimulation to the frequency of driven rhythmic slow activity. All of the drugs involved are known to augment GABAergic transmission. The present experiments investigated the effects of the novel anxiolytic compound buspirone which, unlike conventional anxiolytics, does not interact with GABA, yet is a clinically effective anxiolytic. Buspirone (0.156-40 mg/kg, i.p.) was found to reduce the frequency of reticular-elicited rhythmic slow activity, in a similar manner to chlordiazepoxide (0.019-20 mg/kg, i.p.). Buspirone did not change the linearity of the voltage-frequency function. Buspirone (10 mg/kg, i.p.) also altered the threshold for septal driving of rhythmic slow activity, in a similar manner to classical anxiolytics. The combination of chlordiazepoxide (5 mg/kg, i.p.) with corticosterone (0.2 mg, s.c.) removed the minor differences between buspirone and chlordiazepoxide in both the septal and reticular tests. These results show that buspirone altered the control of rhythmic slow activity in the hippocampus, in a manner which appeared functionally equivalent to other anxiolytics but which depends on mechanisms which are likely to be neurally and pharmacologically distinct from those of other anxiolytic drugs.     

Conditioned defensive burying as a model for identifying anxiolytics

Rats exposed to a presumably aversive stimulus such as electric shock respond by heaping litter on the source, a behavior known as conditioned defensive burying (CDB). Because some anxiolytics suppress this behavior, CDB has been proposed as a screening method for anxiolytics. We tested the effects of the conventional anxiolytics chlordiazepoxide (4-32 mg/kg) and meprobamate (75-125 mg/kg), the novel anxiolytic buspirone (8-64 mg/kg), the antidepressant imipramine (4-16 mg/kg), the opiate analgesic morphine (2-8 mg/kg), and the antipsychotic chlorpromazine (1-16 mg/kg) on CDB. Chlordiazepoxide, meprobamate, imipramine, and morphine significantly suppressed CDB, but chlordiazepoxide did so only at a dose that reduced general activity. Buspirone and chlorpromazine did not suppress CDB at doses that reduced activity. There were some methodological differences from previous studies. We conclude that the test as constituted in this study lacks drug-class specificity. The necessity of distinguishing between specific reduction of burying and general reduction of activity is emphasized.     

The interaction of serotonin depletion with anxiolytics and antidepressants on reticular-elicited hippocampal RSA

Hippocampal rhythmical slow activity (RSA) can be elicited by stimulation of the midbrain reticular formation. Buspirone, chlordiazepoxide and imipramine are all anxiolytic and have all been shown to decrease the frequency of RSA. All these compounds have been suggested to affect, directly or indirectly, 5-HT metabolism and function. The present experiments tested the possibility that buspirone, chlordiazepoxide and imipramine reduce RSA frequency via 5-HT1A autoreceptors. Rats received buspirone (10 mg/kg), chlordiazepoxide (5 mg/kg) and imipramine (30 mg/kg) after 5-HT depletion with p-chlorophenylalanine (PCPA, 100 mg/kg/day for 3 days or 350 mg/kg/day for 2 days) or after pretreatment with 5-HTP (40 mg/kg, to replete 5-HT) as well as pCPA. The frequency-reducing effects produced by buspirone and chlordiazepoxide were unchanged by either dose of pCPA, whereas the frequency-reducing effect of imipramine was completely eliminated by the high dose of pCPA. Pindolol, but not beta-blockers (a combination of metoprolol and ICI118 551), was able to block the effect of imipramine on RSA frequency. Pindolol has been reported to block the effects of buspirone but not chlordiazepoxide. These data suggest that: (1) buspirone obtains its frequency-reducing effects via pre- or post-synaptic 5-HT1A receptors rather than 5-HT1A autoreceptors; (2) chlordiazepoxide obtains its frequency-reducing effect via benzodiazepine receptors and GABA with no direct or indirect involvement of 5-HT systems; and (3) imipramine obtains its frequency-reducing effect by increasing the availability of 5-HT at 5-HT1A receptors which are not autoreceptors.     

Naloxone and chlordiazepoxide: effects on acquisition of DRL and signalled DRL

The ability of the opiate antagonist, naloxone, to block the anti-conflict effects of the benzodiazepines suggests endogenous opioid involvement in the mechanism of action of these drugs. However naloxone's ability to attenuate the effects of the benzodiazepines in animal conflict paradigms appears to be schedule specific. It is effective in acquisition of a differential reinforcement of low rates of response (DRL) schedule but not in acquisition of a non-reward successive discrimination schedule. We tested the effects of naloxone and chlordiazepoxide on acquisition of DRL and on acquisition of a version of the same schedule (signalled DRL) which was like successive discrimination in having an explicit visual signal of non-reward. Chlordiazepoxide (5 mg/kg i.p.) impaired DRL responding by increasing burst responding and premature responding close to the criterion interval. Naloxone (3 mg/kg i.p.) alone decreased burst and premature responding, it also blocked the effects of chlordiazepoxide. The signalled DRL schedule produced essentially similar drug effects. Clearly the critical schedule parameter determining whether naloxone will attenuate the anxiolytic actions of the benzodiazepines is not the presence or absence of an explicit signal of conflict.     

Disinhibitory effects of buspirone and low doses of sulpiride and haloperidol in two experimental anxiety models in rats: Possible role of dopamine

Low doses of buspirone, haloperidol and sulpiride were compared with diazepam in two experimental models of anxiety in rats. In a conflict test, 0.6 and 1.2 mg/kg buspirone, 0.05 and 0.10 mg/kg haloperidol and 0.5 mg/kg sulpiride significantly increased punished responding. Buspirone 1.2 and 2.5 mg/kg significantly reduced the number of unpunished responses while haloperidol and sulpiride at the doses tested had no effect. Effects on punished responding were seen in a narrow dose range and were less pronounced with these drugs than with diazepam. Similar results were obtained with rats', activity in the two-compartment exploratory test. At doses causing no change in the locomotion of rats in photocell activity cages, buspirone (0.1 mg/kg), haloperidol (0.025–0.100 mg/kg) and sulpiride (0.5–1.0 mg/kg) significantly increased the number of crossings between the two compartments. Again, the peak effects were small when compared with the effect of diazepam and the active dose range was very narrow. Apomorphine 0.2 mg/kg SC significantly counteracted the effect of 0.1 mg buspirone and 1.0 mg/kg sulpiride in the two-compartment exploratory test with no effect on 2.5 mg/kg diazepam.The data show that buspirone, in a narrow dose range, shows disinhibitory effects in experimental models of anxiety. Similar effects are shown by low doses of haloperidol and sulpiride. It is suggested that buspirone and sulpiride produce these disinhibitory effects by blocking particular dopamine receptors in the brain, possibly those located in the nerve terminals, but it is likely that other mechanisms, particularly serotonin, are involved in the effects of buspirone in anxious states.     

Antagonism by CGS 8216 and Ro 15-1788, benzodiazepines antagonists, of the action of chlordiazepoxide on a timing behavior in rats

Rats were trained to respond under a differential reinforcement of low rate (DRL) schedule of reinforcement. Pretreatment with relatively low doses of chlordiazepoxide (1-10 mg/kg) produced increases in total DRL responses and decreases in the numbers of reinforced responses. Chlordiazepoxide produced a shift in the interresponse time (IRT) distribution of DRL responses. Low doses of chlordiazepoxide shifted the IRT distribution of DRL responses. Low doses of chlordiazepoxide shifted the IRT distribution from the reinforced to the non-reinforced bins. In addition there was marked increase in the number of responses that occurred in the earliest IRT bin (0-3.75 sec). The highest dose of chlordiazepoxide (32 mg/kg) produced a decrease in total DRL responses and resulted in an even IRT distribution of responses. Both CGS 8216 and Ro 15-1788 had minimal effect on DRL responding when given alone. Ro 15-1788 had no effect at either 10 or 32 mg/kg, while CGS 8216 produced decreases in DRL responding at 32 and 100 mg/kg. Both Ro 15-1788 and CGS 8216 antagonized the effects of high and low chlordiazepoxide doses on total DRL responding and on the IRT distribution of responding.     

Ethological evaluation of the effects of acute and chronic buspirone treatment in the murine elevated plus-maze test: comparison with haloperidol

Buspirone is renowned for its highly inconsistent effects in animal models of anxiety. In the present study, the effects of acute (0.63–5.0 mg/kg) and chronic (1.25–5.0 mg/kg, daily, 15 days) buspirone treatment on the behaviour of mice in the elevated plus-maze test were assessed using a recently developed ethological scoring method. On acute administration, a selective reduction in risk assessment behaviours was observed at 1.25 mg/kg; these mild anxiolytic-like effects were maintained at higher doses (2.5–5.0 mg/kg) which also reduced measures of general activity. Similar, though more potent, effects were observed with chronic administration; the lowest dose tested (1.25 mg/kg) reduced open arm entries and total stretch attend postures while higher doses profoundly reduced all major indices of anxiety (traditional and novel) and, concomitantly, suppressed total entries and rearing. Acute administration of haloperidol (0.0125–0.1 mg/kg) appeared to mimic the behavioural suppressant effects of buspirone without selectively affecting anxiety-related measures at any dose. It is suggested that the anti-anxiety and behavioural suppressant profile of buspirone may reflect combined action at 5-HT_1A and D₂ receptors, respectively. Results are discussed in relation to the utility of risk assessment as a sensitive index of anxiety in models based upon unconditioned behaviour.     

Effects of buspirone and ipsapirone on schedule induced polydipsia: comparison with 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and raclopride

In the present experiments, the effects of the azapirone anxiolytics, buspirone and ipsapirone, on excessive drinking induced by a FT-60 schedule of food delivery (schedule induced polydipsia, SIP) were investigated. Because buspirone is known to block dopamine receptors and both buspirone and ipsapirone act as agonists at the 5-HT_1A receptor, their effects on polydipsia were compared to raclopride, an antagonist at D₂ receptors, and 8-OH-DPAT, an agonist at the 5-HT_1A receptor, thus providing information about the relative importance of the serotonergic and/or dopaminergic systems for the maintenance of polydipsia. The effects of all four drugs were investigated both acutely, and following repeated treatment. The doses employed were as follows: buspirone, 1.0, 3.0, and 10.0 mg/kg; raclopride, 0.05, 0.15, and 0.5 mg/kg; 8-OH-DPAT, 0.1, and 1.0 mg/kg and ipsapirone, 1.0, 3.0, 10.0 mg/kg. Administered acutely, the lowest doses of buspirone and raclopride did not alter drinking, whilst the low dose of 8-OH-DPAT significantly reduced polydipsia. These effects were reversed following repeated treatment over 16 successive days. Buspirone 1.0 mg/kg and 0.05 mg/kg raclopride reduced drinking, whilst tolerance developed to the effects of 0.1 mg/kg 8-OH-DPAT. Ipsapirone, at low doses, was without effect on drinking. At high doses, all four drugs reduced drinking both acutely and chronically. Repeated treatment with buspirone (3.0, and 10.0 mg/kg) reduced licking and panel entries, but induced aselective decrease in licking at the low dose (1.0 mg/kg). Similar effects were seen following raclopride treatment, although the effects were less selective. 8-OH-DPAT and ipsapirone, in contrast, reduced licking only at the highest dose, and both drugs increased panel entries as testing continued. The effects of buspirone resembled those of raclopride whereas the effects of ipsapirone resembled those of 8-OH-DPAT. Buspirone appears to act as a dopamine antagonist in this test. The effects of the drugs suggest that SIP depends upon motivational and performance factors which may be more sensitive to drug manipulation than potential underlying psychological factors such as anxiety or stress.     

Buspirone effects in an animal conflict procedure: comparison with diazepam and phenobarbital

Buspirone has been introduced as a novel non-benzodiazepine anti-anxiety agent. The Conditioned Suppression of Drinking (CSD) paradigm is an "animal model" for anxiety which provides information on both the relative potency and relative efficacy of anti-conflict agents. The present study compared the anti-conflict effects of buspirone to those of more "classical" anti-anxiety agents, diazepam and phenobarbital. In daily 10-minute sessions, water-deprived rats were trained to drink from a tube which was occasionally electrified (0.5 mA), electrification being signalled by a tone. Within 2-3 weeks control CSD responding had stabilized (approximately 15-20 shocks/session and 10-15 ml water/session); drug tests were conducted at weekly intervals. Diazepam and phenobarbital markedly (400-500%) increased the number of shocks received at doses which did not depress background responding (i.e., water intake). A number of agents, most notably morphine and ethanol, did not reliably affect punished responding in the CSD. Administered IP, low doses (0.25-1 mg/kg) of buspirone increased punished responding only slightly (less than 100% increase); higher doses (2, 4 mg/kg) depressed background responding. Administered SC, buspirone (0.125-1.0 mg/kg) had more potent effects on both punished and unpunished responding; again, anti-conflict efficacy was only marginal. These results suggest that buspirone might be less effective than the benzodiazepines in the management of anxiety.     

Anxiolytic-like action of melatonin on acquisition but not performance of DRL

The behavioural effects of melatonin have been attributed to a general reduction in motor activity; interference with memory fixation; a decrease in emotionality; or an anxiolytic action. The present experiments compared the effects of melatonin with an anxiolytic benzodiazepine, chlordiazepoxide (Librium), on a schedule of differential reinforcement of low rates of response (DRL) increasing 'burst' responding and premature responding. No doses of melatonin tested (0.03-8.1 mg/kg, IP) affected performance of well-learned DRL. Both low (0.03 mg/kg) and high (1.0 mg/kg) doses of melatonin impaired acquisition of DRL in a similar manner to chlordiazepoxide (5.0 mg/kg) and to much the same extent. Chlordiazepoxide had its usual effects on both acquisition and performance of DRL. These results show that melatonin shares a subset of the effects of chlordiazepoxide. The nature of the effects favours an 'anxiolytic' hypothesis of melatonin action rather than the other hypotheses so far proposed.     

Buspirone produces a dose-related impairment in spatial navigation.

Classical anxiolytic drugs and hippocampal lesions have common behavioural effects that include loss of place navigation in the water maze. The novel anxiolytic drug buspirone, unlike classical anxiolytic drugs, does not interact with GABA and is not muscle relaxant, sedative, hypnotic, anticonvulsant, or addictive. Buspirone affects hippocampal electrophysiology in a similar fashion to classical anxiolytics and so we predicted it would have similar effects on spatial navigation. Rats injected with buspirone (0.1-10.0 mg/kg, IP) showed a loss of acquisition of spatial navigation in the water maze that has a similar dose dependence to that reported for the effects of buspirone on the hippocampus. This finding demonstrates that the effects of anxiolytics on spatial navigation are not due to their side effects and supports the view that changes in hippocampal function may underlie some components of clinical anxiolytic action.     

Buspirone, a novel nonbenzodiazepine anxiolytic

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, dosage, administration, and availability of buspirone hydrochloride, a novel nonbenzodiazepine anxiolytic, are reviewed. Buspirone hydrochloride is an azaspirodecanedione anxiolytic. The exact mechanism of its anxiolytic action is unknown. It does not appear to influence the benzodiazepine-gamma-aminobutyric acid-chloride ionophore complex as the benzodiazepines do. It antagonizes striatal-dopamine autoreceptors, and it may act as a midbrain modulator exerting selective anxiolytic activity. Buspirone is rapidly absorbed after oral administration. Administration with food appears to slow the rate of drug absorption and increase the amount of unchanged drug reaching the systemic circulation. Buspirone's elimination half-life is 2.5-3 hours. It is extensively metabolized, with less than 1% of an administered dose excreted as unchanged drug. The contribution of its metabolites to its anxiolytic effects is unknown. Buspirone has been shown to be as effective as diazepam and clorazepate and more effective than placebo in the treatment of generalized anxiety. Buspirone lacks the sedative, muscle relaxant, and anticonvulsive effects of the benzodiazepines. Its adverse effects are minimal, with dizziness, nervousness, and headaches as the most common side effects. Buspirone does not impair driving skills, interact with alcohol or concomitant medications, or produce physiologic dependence. It appears to have little potential for abuse. The average daily adult dose is 15-20 mg. Buspirone hydrochloride is an effective drug in the treatment of generalized anxiety disorder that is comparable with the conventional benzodiazepine anxiolytics.     

Behavioral effects of acute and chronic buspirone

The effects of buspirone were studied in squirrel monkeys trained to lever-press under a fixed-interval schedule involving suppressed responding. Buspirone (0.01-0.1 mg/kg) generally did not increase rates of suppressed responding. Buspirone (0.01-0.1 mg/kg) generally did not increase rates of suppressed responding; 0.3 mg/kg of buspirone decreased rate. In comparison, diazepam (0.1-1.0 mg/kg) and CL 218872 (0.3-3.0 mg/kg) increased responding. Additionally, the effects of buspirone (0.01-0.3 mg/kg) were unchanged over a 12-day period of daily administration. The results show that buspirone has effects on schedule-controlled behavior of squirrel monkeys that differ from those of typical anxiolytic drugs.     

Effects of buspirone in the geller-seifter conflict test with incremental shock

The novel anxiolytic buspirone has weak or inconsistent activity in most of the animal models commonly used to identify anxiolytics. Among the six published studies of the effects of buspirone on punished level-pressing in the rat, only one reported a clear effect (at two doses), and the peak effect was half that of diazepam. In the present study, in which rats responded for food in Geller-Seifter conflict procedure with incremental shock, five factors were examined for influence on the effects of buspirone upon punished lever-pressing: (1) fixed-ratio 10 vs. fixed ratio 1 in the punishment portion of the multiple schedule, (2) drug-naive vs. drug-experienced rats, (3) albino vs. hooded rats, (4) SC vs. PO injection, and (5) time course up to 2 hr. The benzodiazepine chlordiazepoxide robustly increased responding punished by foot-shock, but under none of the conditions did buspirone produce more than a small, inconsistent increase. Punished level-pressing in the rat appears not to be an adequate method for identifying buspirone-like anxiolytics.