The effects of acute administration of gepirone in rats trained on conflict schedules having different degrees of predictability

The anticonflict activity of gepirone, a putative anxiolytic and antidepressant, was examined on three schedules which conditioned the suppression of licking. The novel schedules differed in the degree to which they predicted (signalled) the presentation of a conflict-inducing electric shock. Three doses of gepirone (1.25, 2.5, and 5 mg/kg SC) were evaluated on a predictable, a moderately predictable, and an unpredictable schedule of shock presentation. Gepirone induced a nondose-dependent increase from baseline in punished licking on the predictable schedule on the last two days of a five-day test period. The lowest dose (1.25 mg/kg) of gepirone induced a significant increase in punished licking on the moderately predictable schedule on the last two days of testing. The highest dose (5 mg/kg) induced initial decreases in overall responding on this schedule. However, responding returned to baseline over the course of the four days of testing. When administered to rats trained on an unpredictable schedule of shock presentation, all doses of gepirone induced an initial decrease from baseline. The lowest dose group returned to baseline control response levels over the next four days, whereas the suppressive effects of the higher doses persisted. The initial decrease in responding observed on all schedules may be due to the effects of gepirone on motor functioning. However, the 2.5-mg/kg dose induced a proconflict or anxiogenic effect on the last test day (decreased punished responding alone) on the unpredictable schedule, while inducing an anticonflict effect on the predictable one. The unpredictable schedule is sensitive to detecting decreases as well as increases in punished responding and as such may be a unique conflict model for evaluating novel anxiolytics. The results indicate that the pharmacological effects of gepirone vary depending on the schedule of shock presentation as well as the dose and frequency of administration.     

Effects of drugs on the temporal distribution of schedule-induced polydipsia in rats.

Drinking was induced in food-deprived rats by a fixed-time 1-min schedule of food presentation. With three rats, d-amphetamine (0.25, 0.5, 1.0, and 2.0 mg/kg) led to a dose-related increase in licking early in the interfood intervals, the peak of the temporal distribution of licking being shifted to earlier values. These effects were seen even when d-amphetamine had no effect on overall rates of licking and drinking. With another three rats, however, diazepam (0.5, 1.0, 2.0, and 4.0 mg/kg) did not shift the peak of the temporal distribution of licks in interfood intervals, even at doses that produced small increases in overall rates of licking and drinking. However, diazepam did reduce the peak of the distributions of licks at doses that did not decrease water intake and licks per minute.     

Different types of GABA(A) receptors may mediate the anticonflict and response rate-decreasing effects of zaleplon, zolpidem, and midazolam in squirrel monkeys

RATIONALE: The role of different types of GABA(A) receptors in mediating anticonflict and response rate-decreasing effects of benzodiazepines in primate species is not known. OBJECTIVE: To examine the behavioral effects of the benzodiazepine-site, GABA(A) agonists zolpidem, zaleplon, and midazolam in the presence of two antagonists, flumazenil and beta-carboline-3-carboxylate-t-butyl ester (beta-CCt) in squirrel monkeys. METHODS: Two schedules of operant responding were used: (1) a multiple fixed-ratio (FR) schedule of food presentation involving punished and nonpunished behavior, and (2) an FR schedule of stimulus shock-termination. RESULTS: Midazolam (0.03-1.0 mg/kg), zolpidem (0.1-3.0 mg/kg), and zaleplon (0.1-3.0 mg/kg) increased rates of punished responding and decreased rates of nonpunished responding under the multiple schedule. Pretreatment with flumazenil (0.3-1.0 mg/kg) antagonized the anticonflict and response rate-decreasing effects of all three agonists. Pretreatment with beta-CCt (3-10 mg/kg) antagonized the anticonflict and rate-decreasing effects of midazolam, as well as the rate-decreasing effects of zolpidem and zaleplon. However, beta-CCt did not antagonize the anticonflict effects of zolpidem and zaleplon; instead, these effects of zolpidem and zaleplon were apparently enhanced in the presence of beta-CCt. Under the schedule of stimulus shock-termination, both flumazenil and beta-CCt antagonized zolpidem and zaleplon; however, the effects of beta-CCt were less consistent than the effects of flumazenil. CONCLUSION: In nonhuman primates, different types of GABAA receptors may mediate the anticonflict and the response rate-decreasing effects of the nonselective GABAA agonist midazolam and the selective GABAA1 agonists zolpidem and zaleplon.     

Effects of diazepam on conflict behaviour and on plasma corticosterone levels in male and female rats

The anxiolytic properties of diazepam and its effects on plasma corticosterone levels were compared in male and female, water deprived rats exposed to the punished (0.8 mA) drinking procedure. The effects of diazepam on unpunished licking, tested under familiar or unfamiliar conditions, and on the lick latency were also studied and a comparison between the two sexes was made. Both punished and unpunished drinking were less in females than in males. In both sexes, a clear anticonflict effect, i.e. a much greater effect on punished than on unpunished drinking, was obtained with 2 and 4 mg/kg, but not with I mg/kg, of diazepam i.p. Plasma corticosterone levels were higher in water deprived females than in males. Following the punished and unpunished drinking procedure, plasma corticosterone levels were found to have decreased more in female than in male rats, especially after administration of 1 mg/kg of diazepam. Diazepam had similar anticonflict effects in rats of both sexes but had a greater suppressive effect on the plasma corticosterone levels in female rats. There was no correlation between the anxiolytic effects of diazepam and its effect on the plasma corticosterone levels. When testing was done under unfamiliar conditions, the latency to licking was greater in female than in male rats and diazepam (1, 2 and 4 mg/kg) increased this latency in both sexes. The results suggest sex differences in the neuroendocrine, but not in the anxiolytic, effects of diazepam.     

Effects of d-amphetamine, diazepam and buspirone on schedule-induced polydipsia suppressed by response-dependent and response-independent shock

Food deprived Wistar rats were exposed to a fixed time 60 s food schedule until they developed schedule-induced polydipsia. Rats were matched in pairs according to their licking rate, being designated experimental or yoked control at random. Every fifth lick by experimental rats was then followed by an electric shock (0.05, 0.1, or 0.2 mA) while the food schedule continued in operation. Yoked-control rats received the same shocks as experimental rats, but independently of their own licking. Drugs were then tested on the suppressed rates of licking. Diazepam (0.5-2.0 mg/kg) increased punished schedule-induced polydipsia, a result not observed in yoked controls. No increases in the licks per minute of experimental or control animals were found after d-amphetamine (0.25-4.0 mg/kg) or buspirone (0.5-8.0 mg/kg). In comparison with previous results it is concluded that the antipunishment effects of drugs on schedule-induced behaviour depend on the type of punishment contingency.     

Effects of l-methyl-5-(O-fluorophenyl)-7-chloro-1,3-dihydro-2H-1,4-benzodiazepin-2-One (ID-540) on operant behavior in rats]

Effects of ID-540, a new benzodiazepine derivative, on operant behavior were studied and compared with those of diazepam in rats for the purpose of determining the characteristics on behavioral pharmacology. Four schedules used were as follows: Fixed interval (FI-60sec) of food reinforcement and differential food reinforcement of low rate (DRL20sec) for positively reinforced behavior, Sidman-type avoidance response for negatively reinforced behavior and conflict behavior induced by simultaneously rewarding with food and punishing with electric shock. In the experiments on FI-60sec schedule, the responses at the early stage (0 approximately 30 min after administration of the drug) were increased by both ID-540 and diazepam at lower doses (0.5 approximately 4 mg/kg p.o.), but inhibited at higher doses (8 approximately 32 mg/kg p.o.). The effect of ID-540 lasted longer than that of diazepam. In the experiments on DRL20sec schedule, neither drug accelerated the responses, but decreased the lever-press response and total number of reinforcements at higher doses (4 mg/kg or more) showing the disturbance of discrimination on time. In Sidman-type avoidance responses, ID-540 did not show any inhibitory effect, thus a neuroleptic-like effect of ID-540 was not demonstrated. In experiments on FI-60sec and Sidman-type avoidance schedules, the effect of ID-540 was not changed by a consecutive administration for 10 days. Conflict behavior is considered to resemble the anxiety states in humans, and in related experiments, ID-540 increased the lever-press response which delivered a food-pellet and an electric shock simultaneously at a dose of 0.0625 mg/kg (i.p.). Change in other behavior was not observed at this dose level. Maximum effect of ID-540 was observed at a dose of 0.5 mg/kg (i.p.). Maximum effect of diazepam on conflict behavior was seen at a dose of 4 mg/kg (i.p.). The potency of ID-540 on conflict behavior was estimated to be about 8 times that of diazepam.     

The benzodiazepine antagonist CGS 8216 decreases both shocked and unshocked drinking in rats

Previous studies of the benzodiazepine antagonist CGS 8216 have reported that this compound may enhance the punishment-induced suppression of behaviour. In order to investigate this phenomenon further, water-deprived rats were trained to drink from a water spout during a multiple schedule with shocked and unshocked components. During the shocked components a very mild electric footshock was presented after every 20th lick. The shock slightly reduced the rate of licking during these components below that which occurred during periods without shock, although this effect decreased during the experiment. CGS 8216 (0.3–10 mg/kg) produced a dose-related reduction in licking during both schedule components. The overall volumes of water consumed were reduced by CGS 8216 as was the number of licks during the first, unshocked schedule component, before shock was applied, showing that the effect on unshocked licking was not due to a generalisation of suppression between periods with or without shock. In contrast to CGS 8216, a dose of 10 mg/kg pentylenetetrazol selectively reduced shocked licking. In a second group of rats which drank under identical conditions but without shock, CGS 8216 again reduced water intake. These results show that CGS 8216 can reduce water intake in rats regardless of whether drinking results in shock presentation.     

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.     

Interactions between naloxone and narcotic analgesics under three schedules that induce polydipsia

A pattern of schedule-induced polydipsia was maintained in rats by a fixed-time schedule where food pellets were presented every 90 sec, a fixed-interval schedule where licking the drinking tube produced pellets every 90 sec, or a fixed-interval schedule where lever presses produced pellets every 90 sec. Under all 3 schedules, injections of morphine, methadone, etonitazene and meperidine generally decreased licking rates and amounts of water consumed, as well as rates of lever-pressing under the schedules where lever presses were required. Naloxone (1 mg/kg) almost completely blocked the effects of morphine and etonitazene, but the effects of methadone sometimes were blocked to a lesser degree. Small increases in the rate of licking and amount of water consumed after the lowest dose of meperidine under the schedule requiring lever-presses were blocked by naloxone, but the higher doses of meperidine that decreased licking, lever-pressing and amount of water consumed under the three schedules were not blocked by naloxone. These data suggest that there are important differences in the ability of naloxone to antagonize the behavioral effects of different narcotic analgesics.     

Anticonflict effects of buspirone and chlordiazepoxide in pigeons under a concurrent schedule with punishment and a changeover response

A procedure was developed with pigeons to extend the experimental analysis of punished behavior and the effects of anxiolytic drugs. Under this procedure the completion of a fixed-ratio requirement on a changeover key switched between two variable-interval schedules of reinforcement that were programmed on a second response key. Under one schedule, correlated with a green keylight, key pecks produced only food; under the second schedule, correlated with a red keylight, key pecks produced both food and electric shock. Pigeons were switched into the component with shock if they did not enter that component within 5 min. Parameter values of the variable-interval schedules were manipulated systematically and the effects of two clinically active anxiolytic drugs, buspirone and chlordiazepoxide, were examined. Responding was suppressed during the component with shock (punishment) and, under non-drug conditions, pigeons infrequently switched into the punishment component; changeover responses occurred rapidly when switched into the punishment component. Both buspirone (0.1–3.0 mg/kg) and chlordiazepoxide (3.0–30 mg/kg) increased punished responding at doses that had little effect on unpunished responding;d-amphetamine (0.3–5.6 mg/kg), which was studied only under one parameter of the variable-interval schedule, produced greater decreases in rates of punished responding than in unpunished responding. Changeover responses were increased only moderately by the anxiolytic drugs when the punishment schedule was added to a 3-min variable-interval schedule and the alternate schedule was a 1-min variable-interval schedule without punishment; the amount of time spent in the punishment component, however, increased two-fold at the higher doses of chlordiazepoxide. When these conditions were reversed and punishment was added to the variable-interval 1-min schedule, time spent in the punishment component increased and changeover responses out of the punishment component decreased, particularly following chlordiazepoxide. Anxiolytic drugs appear to attenuate the aversiveness of stimuli correlated with punishment, but the degree of attenuation is controlled by other conditions prevailing in the presence of those stimuli.     

Second-order schedules of intravenous drug self-administration in rhesus monkeys.

Lever-pressing behavior was generated and maintained in 3 rhesus monkeys by intravenous infusions of morphine or cocaine under a second-order schedule of reinforcement. Under this schedule, every tenth lever-press response (FR 10) during a fixed interval of time produced a 2 sec stimulus light. The first FR 10 completed after a 60 min interval had elapsed produced the stimulus light and an intravenous infusion of morphine or cocaine. The stimulus light remained on for the duration of the drug infusion (50-60 sec). Sessions of morphine or cocaine presentation, each with distinct stimulus light conditions, alternated on a daily basis. Under this schedule, single doses of morphine from 0.125 to 1.0 mg/kg maintained high overall response rates (maximum of 40 Rs/min) in the pattern characteristic of fixed interval (FI) schedules of reinforcement. There was no functional relationship between the response-rates and the doses of morphine tested. The simultaneous infusion of naloxone (0.125 mg/kg/) with morphine (0.25 mg/kg) markedly decreased response rates. However, the infusion of the same dose of naloxone five min after the presentation of morphine failed to suppress self-administration behavior. Naloxone had no effects on cocaine-reinforced responding.     

Effects of buspirone differ from those of gepirone and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on unpunished responding of pigeons

Under several behavioral procedures, such as punished responding and drug discrimination, the effects of the atypical anxiolytic buspirone are similar to those of its analogue gepirone, and to those of the 5-HT1A receptor agonist 8-OH-DPAT. Similarities in the effects of these compounds occur despite the fact that buspirone produces strong dopaminergic actions, whereas both gepirone and 8-OH-DPAT effects mainly appear to be serotonergically mediated. When keypeck responding of pigeons was maintained under a multiple 3-min fixed-interval, 30-response fixed ratio schedule of food presentation, responding under both the fixed-interval and fixed-ratio schedules was decreased over a range of buspirone doses (0.3-5.6 mg/kg). As has been reported with many antipsychotic compounds, performance under the fixed-interval schedule was more sensitive to the rate-decreasing effects of buspirone. In contrast, both gepirone (0.03-3.0 mg/kg) and 8-OH-DPAT (0.03-1.0 mg/kg) increased responding under the two schedules. Differences in the effects of buspirone from the other compounds in this study, compared to the similar effects of these drugs obtained using other procedures, emphasize the importance of the specific behavior as a determinant of drug action. The multiple fixed-interval, fixed-ratio schedule may be useful for delineating the relative balance of dopaminergic and serotonergic effects produced by drugs that are less apparent using other behavioral procedures.(ABSTRACT TRUNCATED AT 250 WORDS)     

Behavioral effects of plant-derived essential oils in the geller type conflict test in mice

The present study was conducted to further explore plant-derived essential oils that possess an anticonflict effect using the Geller type conflict test in ICR mice. The benzodiazepine anxiolytic diazepam increased the response (lever pressing) rate during the alarm period (i.e., an anticonflict effect), but the 5-HT1A partial agonist buspirone did not. Oils of juniper, cypress, geranium and jasmine did not produce any effect in this test. Frankincense oil decreased the response rate during the safe period at 1600 mg/kg, but did not exhibit any effect on the response rate during the alarm period. In contrast, lavender oil increased the response rate during the alarm period in a dose-dependent manner in the same manner as diazepam. These results indicate that not only rose oil but also lavender oil possess an anticonflict effect in mice.     

Pharmacological analysis of the effects of benzodiazepines on punished schedule-induced polydipsia in rats

Food-deprived Wistar rats were exposed to a fixed-time 60-s food delivery schedule until they developed schedule-induced polydipsia. Every fifth lick was then followed by an electric shock during two, signalled, 5-min periods, which ran concurrently with the food delivery schedule. Shock intensities were adjusted to reduce licking to 60-70% of the unpunished licking rates. The benzodiazepine full agonists, diazepam (0.3-3.0 mg/kg), chlordiazepoxide (0.3-10.0 mg/kg), oxazepam (0.3-3.0 mg/kg) and the benzodiazepine partial agonist, RU-32698 (3.0-17.0 mg/kg), led to increases in punished responding at intermediate doses and decreases at the highest doses tested. All benzodiazepine agonists brought about dose-dependent decreases in unpunished schedule-induced polydipsia, with doses required to reduce drinking proving higher than doses required to increase punished schedule-induced polydipsia. The antipunishment effect of 0.3 mg/kg of diazepam was dose-dependently antagonized by flumazenil and the benzodiazepine inverse agonist, RU-34000. Flumazenil effects, however, could reflect actions of flumazenil as a partial inverse agonist at GABAA receptors. RU-32698 at 10.0 mg/kg further facilitated the rate-increasing effect of 0.3 mg/kg of diazepam, but at 17.0 mg/kg partially blocked such antipunishment effect. Overall, the present results extend the similarities of the effects of benzodiazepine compounds on adjunctive and operant patterns of behaviour by showing similar interactions within the benzodiazepine receptor complex.     

Antipsychotic drug effects on the behavior of squirrel monkeys differentially controlled by noxious stimuli

The effects of several antipsychotic compounds were examined on two types of behavioral performances of squirrel monkeys. Both behaviors occurred simultaneously and were maintained separately by different schedules using noxious stimuli. Steady rates of responding were maintained when a chain pulling response postponed electric shock delivery (avoidance schedule). Concurrently, positively accelerated rates of responding were maintained on a lever where the first response after 3 min produced electric shock (fixed-interval 3-min schedule). The effects of the different drugs depended both upon whether the behavior postponed or presented shock and on the particular drug. Chlorpromazine (0.001–0.03 mg/kg), haloperidol (0.001–0.01 mg/kg), molindone (0.001–0.03 mg/kg) and thiothixene (0.001–0.03 mg/kg) increased slightly or had no effect on responding under the shock-postponement schedule at doses that decreased responding maintained by shock presentation. The effects of clozapine, a clinically effective antipsychotic compound, differed markedly from the other antipsychotic drugs. Clozapine (0.01–1.0 mg/kg) increased responding maintained by the presentation of shock at doses that decreased responding under the shock-postponement schedule. Higher doses of these drugs decreased responding under both schedules and, with the exception of clozapine, resulted in increased frequency of shocks under the postponement schedule.     

Antipunishment effects of diazepam on two levels of suppression of schedule-induced drinking in rats

Food-deprived Wistar rats were exposed to a fixed-time (FT) 60-s food delivery schedule until they developed schedule-induced drinking. Rats were matched in pairs according to their licking rates and were designated master or yoked at random. Every fifth lick by master rats was followed by an electric shock during two signalled 5-min periods, which ran concurrently with the food delivery schedule. For the master rats, shock intensities were adjusted to reduce licking to 5-30% (low suppression) or 50-75% (high suppression) of the unpunished licking rates. Yoked rats received the same shocks as master rats, but independently of their own licking. The drinking by yoked animals was not decreased by the presentation of these lick-independent shocks. Diazepam (0.3-10.0 mg/kg) was studied for its effects on punished and nonpunished schedule-induced drinking. Intermediate doses of the drug increased the punished behavior of master rats, but only when schedule-induced drinking was highly suppressed. Diazepam dose dependently decreased licking rates in all other conditions. The antipunishment effects of benzodiazepines may depend on the level of suppression of schedule-induced drinking, and this is in keeping with the results of other experimental preparations where behavior was under aversive control.     

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.     

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.     

Behavioral pharmacological and electroencephalographic effects of the 5-HT1A partial agonist ipsapirone]

The behavioral and EEG effects of the 5-HT1A partial agonist ipsapirone were investigated to determine its pharmacological characteristics as an anxiolytic drug in rats, mice and rabbits, as compared with those of buspirone and diazepam. 1) The anticonflict effect of ipsapirone was almost equipotent as that of buspirone and less potent than that of diazepam in rats. Ro15-1788 antagonized the anticonflict effect of diazepam, but did not that of ipsapirone. 2) Muricide in midbrain raphe-lesioned and olfactory bulbectomized rats was inhibited by ipsapirone. However, the inhibition of muricide by ipsapirone was attenuated by its repeated administration. 3) The muscle relaxant effects of ipsapirone and buspirone on rotarod performance were less potent than that of diazepam. Ethanol-induced muscle relaxation was markedly potentiated by diazepam, but less potently by ipsapirone and buspirone. 4) The pentetrazol-induced convulsion was dose-dependently antagonized by diazepam, while it was weakly potentiated by ipsapirone and buspirone. 5) The limbic afterdischarges induced by either hippocampal or amygdaloid stimulation in rabbits were markedly inhibited by diazepam. Conversely, ipsapirone and buspirone slightly potentiated afterdischarges. In conclusion, it is suggested that ipsapirone has anxiolytic activities similar to that of buspirone and moderate antimuricidal action. In addition, ipsapirone, like buspirone, is also characterized by its less potent muscle relaxant, alcohol-potentiating and anticonvulsant actions.     

GABAergic drugs and conflict behavior in the rat: Lack of similarities with the actions of benzodiazepines

Summary Effecs of drugs which enhance or reduce GABAergic neurotransmission upon conflict behavior were evaluated with a modified Vogel procedure which was shown to be insensitive to variations in motivation to drink and to the analgesic effects of morphine. In addition, the effects of these drugs on ambulatory activity and motor execution were quantified. For comparison, the benzodiazepines diazepam and chlordiazepoxide were used. Anticonflict actions of diazepam were obtained with a shock current of 0.25 mA but not with 0.05 or 0.5 mA, whereas the proconflict effect of FG7142 was obtained with 0.05 mA but not with higher currents. Diazepam and chlordiazepoxide had anxiolytic effect in a dose similar to that required to reduce ambulatory activity, but below that needed to affect motor execution. At doses high enough to impair motor execution, anticonflict effects were considerable. The GABA-A receptor agonist THIP and the GABA-B receptor agonist baclofen lacked effect on conflict behavior in moderate doses, which reduced ambulatory activity. In doses which produced motor deficiencies these drugs reduced licking both in the conflict test and when tested without shock administration. The effects of the GABA transaminase inhibitors 7-acetylen GABA and sodium valproate were similar to those of the receptor agonists. The GABA reuptake inhibitor SKF 100330A produced anticonflict effect in a dose below that needed to reduce ambulatory activity, but lacked effect on conflict behavior in higher doses. The GABA antagonist picrotoxin, and the GABA synthesis inhibitors 4-deoxypyridoxine and isoniazide, reduced licking both in the absence and presence of shock, and affected motor functions in the same doses. Bicuculline, at the doses used, had no behavioral effects. The different behavioral profiles of GABAergic agents and benzodiazepines, and the lack of consistent effects of the former on conflict behavior, seem to suggest that GABA receptors are not involved in conflict reduction. Further evidence for this hypothesis was obtained in experiments where it was found that the GABA antagonists bicuculline and picrotoxin did not block the effects of the benzodiazepines. No evidence was found for a tonic anticonflict action of GABAergic systems. It thus appears that anticonflict actions of benzodiazepines may be independent of GABAergic mechanisms.