The effects of the beta-carboline FG 7142, on intracranial self-stimulation in the rat

The effects of FG 7142 were examined, alone and in combination with chlordiazepoxide, on self-stimulation of the mid-lateral hypothalamus. Rewarding stimuli were delivered according to a 10-sec variable-interval schedule of reinforcement. FG 7142 (1-20 mg/kg) produced a dose-related depression in responding, and chlordiazepoxide (5 mg/kg) enhanced it. When these two drugs were given together, response rates did not differ significantly from control rates.     

Interaction of d-amphetamine with pentobarbital and chlordiazepoxide: Effects on punished and unpunished behavior of pigeons

Key pecking of two pigeons was maintained under a multiple schedule of food presentation. In the presence of one keylight stimulus responding produced food according to a fixed-interval 5-min schedule. Additionally, during this component, each 50th response produced electric shock. When a different keylight stimulus was present, key pecking resulted in food delivery under a variable-interval 3-min schedule. Responding was suppressed by schock presentation (punishment) but was still positively accelerated throughout each fixed-interval cycle; steady response rates occurred during the alternate component when only the variable-interval schedule was in effect. Overall rates of punished responding were largely unchanged with d-amphetamine (0.1–3.0 mg/kg); unpunished responding was generally either increased slightly or was decreased. Pentobarbital and chlordiazepoxide (1.0–17.0 mg/kg) administered alone increased both punished and unpunished responding at most doses. Combinations of d-amphetamine with either pentobarbital or chlordiazepoxide produced increases in punished responding that exceed those obtained with either of these drugs alone. The combined effects of d-amphetamine and either pentobarbital or chlordiazepoxide on unpunished responding depended on the individual dose combinations. Combinations of d-amphetamine with pentobarbital or chlordiazepoxide produced effects on both punished and unpunished responding that differed substantially from those obtained when any of these drugs were administered separately.     

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.     

d-Amphetamine and phencyclidine alone and in combination: Effects on fixed-ratio and interresponse-time-greater-than-t responding of rats

The effects of three doses of d-amphetamine (0.5, 1.0, and 2.0 mg/kg) and phencylidine (0.5, 1.0, and 2.0 mg/kg), alone and in combination, were assessed in rats performing under fixed-ratio 30 and interresponse-time-greater-than-15-sec food reinforcement schedules. When given alone, phencyclidine and d-amphetamine produced similar increases in responding under the interresponse-time-greater-than-t schedule, and decreases in responding under the fixed-ration 30 schedule. Each drug decreased the number of reinforcers (food pellets) earned relative to control values under both schedules. The effects of the two drugs in combination were nearly always less than additive. That is, the effects of a given dose of phencyclidine and d-amphetamine together were less than an arithmetic summation of the effects of the drugs given alone.     

Behavioral effects of the isomers of pentobarbital and secobarbital in mice and rats

To determine what stereoselective differences there may be in the behavioral effects of the isomers of pentobarbital and secobarbital, the effect of each isomer was determined on the spontaneous motor activity (SMA) and multiple fixed-ratio 30, fixed-interval 600-sec (mult FR30 FI600) responding of mice, and on the variable-interval 60-sec (VI60) responding of rats. The S-(-) isomers of pentobarbital and secobarbital decreased SMA at lower doses than those required for the R-(+) isomers. At moderate to high doses of R-(+)-pentobarbital (30-42.5 mg/kg) and low to moderate doses of S-(-)-secobarbital (5.6-17.5 mg/kg) SMA was increased. An increase in SMA following R-(+)-secobarbital was only observed at 30 mg/kg, and no increases were observed with S-(-)-pentobarbital. No potency differences were observed between the isomers of pentobarbital and secobarbital on the responding of mice under the mult FR30 FI600 schedule over a dose range of 1-30 mg/kg. Increases in FI600 responding were only observed following moderate doses of the S-(-) isomer of pentobarbital (5.6-17.5 mg/kg). In rats responding under the VI60 schedule of food presentation, no qualitative stereoselective differences were observed in the behavioral effects of the isomers of pentobarbital (1-13 mg/kg) and secobarbital (1-13 mg/kg), but small differences in potency were observed. Thus, differences in the effects of the isomers were usually restricted to differences in potency, but in some cases differences in efficacy were observed.     

Effects of mephenytoin on schedule-controlled responding in the pigeon

Acute and chronic effects of mephenytoin (30-360 mg/kg) were examined in pigeons responding under a multiple fixed-ratio 50 fixed-interval 90-sec schedule of food delivery. The highest dose administered acutely (240 mg/kg) produced substantial reductions in rate of responding under both components of the multiple schedule; the effects of other doses were small and inconsistent. With chronic exposure tolerance appeared to develop to the rate-decreasing effects of the drug.     

Effects of the group II metabotropic glutamate receptor agonist, LY354740 on schedule-controlled behaviour in rats

The present study examined the effect of the novel, systemically active Group II metabotropic glutamate (mGlu) receptor agonist, LY354740, on schedule-controlled behaviour in rats. Responding for food reward was maintained by three different operant procedures; the first, a three-component conflict schedule; the second, a multiple fixed-interval 60 s/fixed-ratio 10 (FI60/FR10) schedule and the third, a differential reinforcement of low rates of responding 10 s (DRL10) schedule. In the first procedure, rats were trained to respond for food on a schedule comprising of variable-interval 30 s (food, VI30) and fixed-ratio 10 (food + shock, FR10) components separated by time-out (TO). LY354740 (1.25-5 mg/kg, i.p.) produced a dose-related reduction in responding during the VI component and increased responding during the TO component, while having no effect on responding during the punished FR10 phase. In the FI60/FR10 schedule, LY354740 produced a dose-related reduction in the high rates of responding observed during the FR10 component of the schedule. Although LY354740 (0.6-10 mg/kg, i.p.) had no effect on the overall response rates produced by the FI60 component, there was a shift in the temporal distribution of responding as measured by the quarter-life. LY354740 (10 mg/kg, i.p.) increased the low rates towards the start of the interval, while decreasing the rates of responding towards the end of the FI60 period. In the DRL10 s schedule, LY354740 (5-20 mg/kg, i.p.) had no effect on the total number of responses but produced a significant reduction in the total number of rewards, suggesting that the temporal control of responding had been disrupted. The changes in operant responding occurred at doses that decreased exploratory behaviour. In summary, LY354740 modified responding maintained by all three operant schedules at doses which suppressed spontaneous activity. These data demonstrate that stimulation of Group II mGlu receptors can produce changes in responding which are dependent on the base-line rate of responding, suggesting that mGlu 2/3 receptors may be involved in the stimulus and temporal control of behaviour.     

Effects of phencyclidine, atropine and physostigmine, alone and in combination, on variable-interval performance in the squirrel monkey.

The role played by cholinergic activity in the effects of phencyclidine (PCP) on schedule-controlled responding was studied in three squirrel monkeys trained to respond on a variable-interval (VI) 100 sec schedule of food presentation. A low dose of PCP (0.08 mg/kg IM) produced small increases in rates of responding. Higher doses (0.16--0.64 mg/kg) produced dose-dependent decreases in rates of responding. Atropine (0.05--3.2 mg/kg IM) and physostigmine (0.025--0.20 mg/kg IM) caused only decreases in response rates, the dose-response curve for atropine being particularly flat over a wide range of doses. When atropine was combined with PCP, no significant interaction was obtained. When physostigmine was combined with PCP, a complex interaction was observed. Evidence fo partial antagonism of PCP by physostigmine was obtained only at the highest PCP dose tested. Atropine-physostigmine combinations resulted in response rates suggestive of antagonism.     

d-Amphetamine,operant history,and variable-interval performance

The effects of d-amphetamine on the bar-pressing of rats maintained under a variable-interval schedule of water reinforcement were examined as a function of the operant history of the subjects. One group of rats initially received 51 sessions of exposure to a fixed-ratio 20 schedule, while a second group received equivalent exposure to an interresponse-time-greater-than-12-sec schedule. Mean group response rate when stable was over ten times as high under the fixed-ratio schedule as under the interresponse-time-greater-than-12-sec schedule. Response rates of the two groups largely converged across 47 sessions of exposure to a variable-interval 60-second schedule, at which time response rates for both groups appeared stable. Acute administrations of d-amphetamine sulfate similarly affected mean response rates of both groups: A 0.25 mg/kg dose did not obviously affect rate, while doses of 0.5, 1.0, and 2.0 mg/kg produced dose-dependent rate decreases. These results indicate that the efficacy of operant history as a determinant of drug effects may be limited to circumstances where current contingencies do not exercise powerful and direct control over behavior.     

Effects of olanzapine and other antipsychotic agents on responding maintained by a conflict schedule

The effects of the "atypical" antipsychotic olanzapine and several other antipsychotics were examined using a conflict schedule. Rats were trained to respond for food on a three-component schedule, comprising variable-interval 30s (food, VI30) and fixed-ratio 10s (food + shock, FR10) components separated by time-out (TO). Olanzapine (0.3125-1.25mg/kg), clozapine (1.25-5mg/kg) and chlordiazepoxide (2.5-5mg/kg) decreased or had no effect on VI30 responding, whereas responding in the FR10 component increased. Chlordiazepoxide (5mg/kg) also increased TO responding. The antipsychotic agents haloperidol (0.125 and 0.25mg/kg), trifluoperazine (0.0625-0.25mg/kg), remoxipride (1.25-5mg/kg) and risperidone (0.0625-0.5mg/kg) decreased V130 responding and either had no effect, or decreased TO and FR10 rates. The anticholinergic agent scopolamine (0.03125-0.25mg/kg) decreased VI30 responding. The 5-HT(2) antagonist ritanserin (2.5 and 5mg/kg) and the anticholinergic agent trihexyphenidyl (2.5 and 5mg/kg) had no effect on responding. Flumezanil (10mg/kg) reduced the anticonflict effect of chlordiazepoxide but not olanzapine. These results further emphasize the unusual profile of olanzapine.     

Effects of methylphenidate on responding under extinction in the presence and absence of conditioned reinforcement

Pigeons pecked a key during sessions that began with a variable number of reinforcers under a second-order schedule of food presentation. Every 30sec, on the average, a key peck was followed immediately by one of two consequences: (a) food presentation, accompanied by a stimulus complex that consisted of houselight off, key color change, tone presentation, and hopper-light illumination, or (b) the stimulus complex alone. Following the last food presentation, 20min of one of two types of extinction began. The two types of extinction were: (a) standard extinction (key pecks had no consequence) and (b) key pecks produced, on a variable-interval schedule, the stimulus complex previously paired with food. Consequently, it was possible to study performance under extinction during which responses either did or did not result in occasional presentation of a food-paired stimulus complex. Methylphenidate (5, 10 and 20mg/kg) occasionally was administered before sessions containing each type of extinction. At moderate doses methylphenidate produced higher response rates during extinction when the stimulus complex was presented than when it was not. These results support previous findings with rats that stimulant drugs can enhance responding during extinction when responding produces conditioned reinforcers, and illustrate this effect in a novel, within-subject design.     

The effects of scopolamine on three different types of suppressed behavior of rats

Twelve albino rats were trained to lever press on a variable-interval one min schedule for sweetened condensed milk reinforcement. While responding on this schedule a two minute tone was presented. For one group it signalled a response contingent shock (Punishment), for another group it signalled the delivery of an unavoidable non-contingent shock at its termination (CER) and for a third group, reinforcement was witheld during the tone (Extinction). In the first experiment scopolamine in doses of 0.8 to 12.8 mg/kg did not alter response rates during the tone for any group. In a second experiment 16 hooded rats were tested with 6.4 mg/kg of scopolamine using a similar procedure, but with different shock levels, apparatus, reinforcement and session duration. For all three groups the drug depressed responding during the tone. It was concluded that when all other aspects of the situation are equated scopolamine will produce the same effect on behavior suppressed by punishment, CER and extinction.     

Chronic administration of S-(-)-pentobarbital in pigeons and rats: tolerance development

The development of tolerance to pentobarbital and cross-tolerance to other barbiturates has been documented in both laboratory animals and man. This study was undertaken to determine the extent of tolerance development to S-(-)-pentobarbital in rats and pigeons receiving 10 mg/kg/day S-(-)-pentobarbital, PO. In addition, the extent of cross-tolerance was determined to R-(+)-pentobarbital and both isomers of secobarbital. Rats were trained to respond under a variable-interval 60-sec (V160) schedule of food presentation while pigeons were trained to respond under a multiple fixed-ratio 30, fixed-interval 600-sec schedule of food presentation. After responding had stabilized, dose-response curves were determined for R-(+)-pentobarbital, S-(-)-pentobarbital, R-(+)-secobarbital, and S-(-)-secobarbital in both species. Upon the completion of the acute dose-response curves, both rats and pigeons were given 10 mg/kg/day S-(-)-pentobarbital, PO for 30 consecutive days prior to the redetermination of all four dose-response curves. Upon the completion of this second determination of each curve, the daily administration of the S-(-)-pentobarbital was discontinued, and the rats and pigeons remained drug free for 30 days. Following this 30-day drug free period, dose-response curves for the isomers of both pentobarbital and secobarbital were redetermined for a third time.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of nikethamide, picrotoxin and strychnine on 'amphetamine-state'

Rats were trained to discriminate between d-amphetamine sulfate (0.8 mg/kg) or saline by selectively pressing two levers programmed on differential response at low rate 15-sec schedule for food reinforcement. Nikethamide (25–75 mg/kg), strychnine (0.5 and 10 mg/kg) and picrotoxin (1.0 and 2.0 mg/kg) did not produce d-amphetamine-like responding in the animals. Results indicated that in order for drugs to produce similar discriminative cue they should possess a specific pharmacological property in common.     

Stimulus properties of ring-methyl amphetamine analogs

There are three possible ring-substituted methyl amphetamines (or tolylaminopropanes; TAPs): oTAP, mTAP and pTAP. These agents are positional isomers of methamphetamine. Although all three isomers have been previously reported to possess amphetamine-like character, few studies have examined all three agents in comparison with (+)amphetamine. Using rats trained to discriminate 1 mg/kg of (+)amphetamine from saline under a variable-interval 15-sec schedule of reinforcement, tests of stimulus generalization were conducted with the three positional isomers. Only oTAP (ED50 dose = 4.1 mg/kg) completely substituted for (+)amphetamine. mTAP and pTAP resulted only in partial (ca. 50% amphetamine-appropriate responding) generalization. It is concluded that oTAP is capable of producing amphetamine-like stimulus effects and that it is approximately one-tenth as potent as (+)amphetamine; however, because the partial generalization produced by mTAP and pTAP was followed by disruption of behavior at slightly higher doses, it cannot be reliably stated that these latter two isomers lack amphetamine-like character.     

Some effects of d-amphetamine, caffeine, nicotine and cocaine on schedule-controlled responding of the mouse

The effects of d-amphetamine (0.03-10.0 mg/kg), caffeine (0.3-100.0 mg/kg), nicotine (0.003-10.0 mg/kg) and cocaine (0.03-56.0 mg/kg) were compared on responding maintained under three different schedules of food presentation in mice. Cumulative doses of d-amphetamine, nicotine and cocaine only decreased responding maintained under fixed-ratio 30 response, fixed-interval 60-sec and fixed-interval 60-sec schedules with a punishment contingency (suppressed responding). In most cases there was an inverse relationship between the ED50 (dose which decreased responding by 50%) for the drug and the rate of responding maintained under each schedule. The exceptions were, with both d-amphetamine and cocaine the ED50 for suppressed responding was smaller than that for non-suppressed fixed-interval responding, and with nicotine the ED50 for fixed-ratio responding was smaller than that for fixed-interval responding. In contrast, intermediate doses of caffeine increased suppressed responding, had little effect on fixed-interval responding and decreased fixed-ratio responding. This difference in profile of effect over the range of conditions studied, suggests that the behavioral effects of psychomotor stimulants can be used to examine potential differences in the mechanisms of action of each drug. Such findings may aid in the understanding of the relationships between the neuropharmacological and behavioral effects of psychomotor stimulant drugs.     

Effects of RO 15-4513 and FG 7142 alone and in combination with ethanol on avoidance in the rat

Rats were trained on a complex avoidance schedule in which responses on one lever postponed shock and responses on another lever occasionally (variable-interval 45 sec schedule) produced 2 min periods of timeout from avoidance. As shown in previous experiments, ethanol (1.5 or 2.0 g/kg) produced an increase in timeout responding relative to avoidance lever rates. These effects were attenuated in five of the six rats by 6 mg/kg RO 15-4513, a dose that did not produce consistent intrinsic effects. In contrast, FG 7142 (10 mg/kg) reliably reversed ethanol effects in only one of the six rats tested. These results support the notion that RO 15-4513 possesses specific ethanol antagonist properties.     

Effects of valproic acid and ethosuximide on the responding of pigeons maintained under a multiple fixed-ratio fixed-interval schedule of food delivery

The effects of valproic acid and ethosuximide were examined in pigeons responding under a multiple Fixed-Ratio 50 Fixed-Interval 90-sec schedule of food delivery. When given acutely 30 min prior to behavioral testing, both valproic acid (40, 60, 80, 100, and 120 mg/kg) and ethosuximide (40, 60, 80, 100, and 120 mg/kg) produced generally dose-dependent decreases in responding under both the Fixed-Ratio and Fixed-Interval components. Detailed analysis of drug effects on the temporal distribution of responding under the Fixed-Interval failed to reveal rate-dependent effects for either drug. Varying the presession injection interval from 15 to 120 min indicated that both valproic acid and ethosuximide reduced responding to the greatest extent when given 30 or 60 min before behavioral testing. These results indicate that the anticonvulsants valproic acid and ethosuximide similarly affect schedule-controlled responding, although previous studies have revealed the drugs to have different effects under other procedures.     

Schedule-dependent differences among anti-anxiety drugs

Five anti-anxiety drugs were administered to rats on either a variable-interval (VI 1-min) schedule, a chained 10-sec differential reinforcement of other behavior (DRO), fixed-ratio (FR 25) procedure, or an FR 15-satiation schedule. Two dose levels, free of effects on behavior not related to lever pressing, for each anxiolytic were selected for testing. On the VI schedule, the anti-anxiety drugs uniformly increased response rates. On the DRO-FR procedure all the anxiolytics increased responding during the DRO component, but produced dissimilar biphasic increases or decreases in FR response rates. The anti-anxiety drugs also produced dissimilar effects on the FR-satiation schedule: chlordiazepoxide, phenobarbital, and meprbamate disrupted satiation (increased responding), diazepam did not affect satiation (no change in responding), and oxazepam facilitated satiation (decreased responding). None of the anxiolytics altered FR response rates in the FR-satiation schedule. The discrepancies recorded suggest that schedule-dependent differences exist between the anti-anxiety drugs studied.     

Effects of methsuximide on schedule-controlled responding in the pigeon

Acute and chronic effects of methsuximide (25, 50, 75, and 100 mg/kg), a succinimide with anticonvulsant properties, were examined in pigeons responding under a multiple fixed-ratio 50 fixed-interval 90-sec schedule of food delivery. The clearest acute effect of methsuximide was a substantial reduction in response rates under both components of the multiple schedule when the drug was administered at 100 mg/kg. Detailed analysis of the temporal distribution of responding under the fixed-interval failed to reveal rate-dependent drug effects. Tolerance appeared to develop to the effects of methsuximide when the drug was administered chronically.