Fixed-interval Schedule Of Food Presentation Research Articles

Modulation of the Discriminative Stimulus and Rate-Altering Effects of Cocaine by Competitive and Noncompetitive N-Methyl-d-Aspartate Antagonists

The purpose of this study was to determine the extent to which N-methyl- d-aspartic acid (NMDA) antagonists modified the discriminative stimulus effects of cocaine in rats trained to discriminate 5 mg/kg cocaine from vehicle on a fixed-ratio schedule of food presentation as well as the rate-altering effects of cocaine in rats maintained on a fixed-interval schedule of food presentation. NMDA-associated ion channel blockers (dizocilpine, phencyclidine, and magnesium chloride) and competitive NMDA antagonists (NPC 17742 and CGP 37849) displayed similar behavioral effects when administered alone: each drug engendered intermediate levels of cocaine-appropriate responses and rate-dependent effects on food-reinforced operant responding. Selected doses of dizocilpine, magnesium chloride, and phencyclidine given in combination with 1 mg/kg cocaine produced more cocaine-appropriate responses than this dose of cocaine alone. In addition, dizocilpine and magnesium chloride each attenuated the discriminative stimulus effects of higher doses of cocaine. The competitive NMDA antagonists did not appreciably modify the discriminative stimulus effects of any dose of cocaine. Under the fixed-interval schedule, each NMDA antagonist attenuated the effects of 3 mg/kg cocaine, which normally produced maximal increases in response rate. Attenuation of the rate-decreasing effects of the highest dose of cocaine (30 mg/kg) also were observed after pretreatment with dizocilpine and magnesium chloride. These findings demonstrated differences in the way that NMDA-associated ion channel blockers and competitive NMDA antagonists interact with cocaine, and suggest that some NMDA-associated ion channel blockers may either enhance or antagonize the effects of cocaine, depending on the dose and type of behavioral procedure.

Pentobarbital discrimination and generalization to other drugs under multiple fixed-ratio fixed-interval schedules

Pigeons were trained to discriminate 5mg/kg pentobarbital from saline under several multiple fixed-ratio fixed-interval schedules of food presentation. The following schedules were studied: multiple fixed-ratio 40 fixed-interval 18s (mult FR40 FI18), mult FR10 FI18s, mult FR10 FI180s and mult FR90 FI10s. After responding stabilized under each multiple schedule, generalization curves were determined for pentobarbital, amobarbital, diazepam, phencyclidine and d-amphetamine. Pentobarbital generated dose-dependent increases in responding under all schedule components; however, there was more responding on the drug key after low doses of pentobarbital under FI components than under FR components, except for the FR90 component of the mult FR90 FI10 schedule. This tendency for more responding on the drug key after low doses of pentobarbital under FI components than under FR components generally was observed for low doses of all of the drugs. Examination of data from individual subjects revealed that there was a greater tendency for birds to distribute responding on both keys (mixed responding) under FI components than under FR components, where responding after each dose was confined largely to one of the two response keys. Analysis of local rates of responding within the FI component of the schedules showed that responding under the FI components developed the typical FI scallop at all FI-component durations. These data suggest that FI schedules with values between 10 and 180s generate similar dose-effect curves with higher rates of responding on the drug key after low doses of drugs than under FR schedules with low response requirements; however, under schedules with higher FR requirements, the dose-effect curves for some drugs begin to look more like those under FI schedules.

Evaluation of neuroprotection and behavioral recovery by the kappa-opioid, PD117302 following transient forebrain ischemia

The effects of the selective kappa-opioid, PD117302 ((±)-trans- N-methyl- N-[2-(1-pyrrolidinyl) cyclohexyl] benzo[b]thiophene-4-acetamide), on transient (15 min) global forebrain ischemia, induced by four-vessel occlusion, was evaluated using a multiple fixed-ratio, fixed-interval schedule of food presentation in rats. The schedule produced distinctive patterns of responding in the fixed-ratio and fixed-interval components. Ischemia produced CA1 hippocampal necrosis and prolonged suppression of responding under both schedule components. When responding resumed, the pattern of responding rapidly returned. Response disruption and CA1 hippocampal necrosis were minimal or nonexistent in sham-occluded rats. Behavioral recovery time under both components of the schedule of reinforcement correlated with CA1 necrosis. On average, CA1 necrosis was less, and behavioral recovery time was shorter, in rats treated with PD117302 postocclusion as compared with vehicle-treated rats. The difference, however, did not reach statistical significance. These results demonstrate the utility of schedule-controlled responding for evaluating potentially therapeutic compounds for the treatment of ischemie injury. These results also further characterize the neuroprotective actions of kappa opioids.

Evaluation of transient forebrain ischemia induced by four vessel occlusion using schedule-controlled behavior

Transient (5-min) global forebrain ischemia, induced by four- vessel occlusion, was assessed using a multiple fixed-ratio, fixed-interval schedule of food presentation in five rats. Under control conditions, the schedule produced distinctive response rates in each schedule component. Initially, ischemia disrupted responding under both schedule components, and to approximately the same degree. In general, total session responses returned to pre-occlusion levels during the course of 45 post-occlusion days, however, response rates under the fixed-interval component showed slightly less recovery than those under the fixed-ratio component. Histological assessment revealed considerable variability in hippocampal damage between rats. Severe damage in the CA1, CA2, and CA3 formations was observed in a single rat, and that rat also showed the greatest degree of response disruption. These results suggest that schedule-controlled responding may be a valuable method for assessing the effects of ischemic injury, and thus, putative neuroprotective compounds, on complex behavior.

Effects of cocaine and ethylcocaine on schedule-controlled responding in rats

The effects of cocaine and benzoylecognine ethyl ester (ethylcocaine), its metabolite found only in simultaneous users of cocaine and ethanol, were studied in rats responding for food under a multiple fixed-ratio fixed-interval schedule of food presentation. Both cocaine and ethylcocaine increased rates of responding under the fixed-interval component and decreased the quarter life. Both drugs only decreased rates of responding under the fixed-ratio component. Cocaine was approximately equipotent to ethylcocaine. Ethylcocaine may contribute to interactions between cocaine and ethanol by exerting cocaine-like effects not seen with other cocaine metabolites.

Effects of d-amphetamine, WIN 35,428, pentobarbital and morphine on schedule-controlled responding in two inbred rat strains that differ in locomotor stimulatory effects of cocaine

Behavioral effects of d-amphetamine, the cocaine analog, WIN 35,428, morphine, and pentobarbital were compared in NBR/NIH and F344CR1BR rats. Either nose-poke or lever-press responding was maintained under 3-min fixed-interval schedules of food presentation. The effects of morphine, WIN 35,428 and pentobarbital depended upon the rat strain studied: morphine increased nose-poke responding in NBR but not F344 rats; significant strain x dose interactions were observed with WIN 35,428; and pentobarbital was more potent in decreasing nose-poke responding in NBR than in F344 rats. No strain differences were observed in the behavioral effects of d-amphetamine. There were also prominent differences in the effects of drugs that were related to the nature of the response requirement. In both rat strains, nose-poke responding was affected differently than lever-press responding by morphine, d-amphetamine, and WIN 35,428. Pentobarbital produced effects that were independent of the specified response topography. A global underlying difference in these rat strains cannot be identified at present to account for the diversity of findings. The behavioral effects of these drugs appear to be influenced by a host of interactive factors including the drug, strain of animal, the baseline response rate and physical dimensions of the response.

Associative influences on tolerance to decreased fixed-interval responding by clonidine

Responding of rats was maintained under a 5-min fixed-interval schedule of food presentation. One group of animals (n = 5) received the alpha-2-agonist clonidine (0.1 mg/kg/day) before experimental sessions for 16 weeks. Additional animals (n=5) also received 0.1 mg/kg/day for 16 weeks but experience drug administration after sessions for 4 weeks, before sessions for 4 weeks, after sessions for 4 weeks, and then finally, before sessions for 4 weeks. Animals receiving clonidine before daily experimental sessions for the entire period developed tolerance to decreased responding within 3 weeks, and their responding remained near control levels except when clonidine was occasionally preceded by the alpha-2-antagonist yohimbine. Animals receiving clonidine after sessions did not develop tolerance, and responding was markedly suppressed during the first exposure to pression clonidine. When these animals subsequently received clonidine again after sessions, responding was disrupted (increased) in spite of continued drug administration as if animals were “dependent” on clonidine in specific circumstances. When these animals again received clonidine before sessions, responding was partially suppressed in spite of uninterrupted drug administration as if animals had “lost” tolerance in specific circumstances. Tolerance to the behavioral effects of clonidine on fixed-interval responding was not determined by the presence of drug alone, but by the associative influence of drug-related effects in the presence of specific environmental stimuli.

Effects of corticotropin-releasing factor (CRF), tuftsin and dermorphin on behavior of squirrel monkeys maintained by different events

The effects of intracerebroventricular (ICV) administration of ovine CRF (0.1–30.0 μg/kg), dermorphin (0.3–30.0 μg/kg) and tuftsin (10–3000 μg/kg) were examined in squirrel monkeys trained to respond under a multiple 3-min fixed-interval schedule of food presentation and either shock presentation or stimulus-shock termination. Initial administration of the 41-amino acid polypeptide CRF increased food-maintained responding by 150–200% in 2 of 3 subjects. However, no other doses tested affected response rates, a result that may have been due to the rapid development of tolerance. The tetrapeptide tuftsin selectively increased responding maintained by food presentation at doses that decreased shock-maintained responding. The heptapeptide dermorphin selectively increased food-maintained responding when responding in the other component of the multiple schedule was maintained by shock presentation. When responding was maintained by a multiple food, stimulus-shock termination schedule, dermorphin decreased response rates in both components. Dermorphin's rate increases were blocked by the opiate antagonist naloxone, indicating that dermorphin's actions were mediated through the opiate receptor. These results indicate that the behavioral effects of tuftsin, dermorphin, and perhaps CRF, depend on the manner in which responding is controlled by its consequences. While the actions of tuftsin and dermorphin are believed to be mediated through the opiate system, the behavioral effects observed in primates appear different from the effects of morphine under similar schedule conditions.

Behavioral effects of benzodiazepine antagonists in chlordiazepoxide tolerant and non-tolerant rats

Rats were trained to respond under 3-min fixed-interval schedules of food presentation, and effects of the benzodiazepine-receptor ligands, flumazenil, 2-(4-methoxy-phenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one (CGS 9895), 3-carbo-t-butoxy-β-carboline (β-CCtB), and β-carboline-3-carboxylic acid ethyl ester (β-CCE) were assessed before and after the induction of tolerance to chlordiazepoxide. Before daily administration of chlordiazepoxide, none of the antagonists produced appreciable effects on rates of responding up to doses of 32.0 mg/kg i .p. β-CCE was the only antagonist studied at a higher dose (100.0 mg/kg i .p.), which decreased response rates. After 23 days of daily chlordiazepoxide administration (oral doses started at 10 and increased to 100 mg/kg/day by the 17th day), dose-effect curves for chlordiazepoxide were shifted to the right by about one-half log unit. Subjects were also more sensitive to the flumazenil, CGS 9895, and β-CCtB, however, since these drugs produced only small effects in non-tolerant subjects, precise estimates of the degree of the shift in dose-effect curves could not be estimated. However, there were differences in the changes in the dose-effect curves induced by chlordiazepoxide tolerance. These results suggest differences in mechanism of action of antagonists in tolerant and non-tolerant subjects, and further that the sensitivity that is induced to antagonists in tolerant subjects is not conferred equally to all drugs having benzodiazepine antagonist activity.

Tolerance to effects of cocaine on schedule-controlled behavior: effects of fixed-interval schedule parameter.

Tolerance to the effects of cocaine on key pecking by pigeons, maintained by differently valued fixed-interval schedules of food presentation, was studied. Key pecking was established on a multiple fixed-interval 5-sec fixed-interval 30-sec fixed-interval 120-sec schedule. Cocaine (1.0-10.0 mg/kg) was administered acutely and then chronically (i.e., before each session) in 5.6 mg/kg doses. Acute cocaine administration produced dose-related decreases in response rates under all three schedules. When cocaine was administered chronically, response rates either recovered fully, or increased to the extent that no reinforcers were missed during the sessions. The development of tolerance was not systematically related to the schedule value. Considered in relation to previous research, these results indicate that different control rates of reinforcement, within the schedules and parameters studied, do not contribute to tolerance to cocaine's behavioral effects.

Effects of the novel benzodiazepine agonist quazepam on suppressed behavior of monkeys

Behavioral effects of the benzodiazepine agonist quazepam were compared with those of lorazepam in squirrel monkeys responding under a fixed-interval schedule of food presentation with a superimposed fixed-ratio schedule of response-produced shock. Low and intermediate i.v. doses of quazepam (0.1–1.0 mg/kg) and lorazepam (0.03–0.3 mg/kg) increased rates of suppressed responding, yet the maximal increases in rate were less after quazepam than after lorazepam. Higher doses of both drugs tended to increase responding less or decrease it and, with quazepam, frequent sleep was observed for 2–3 days afterwards. The dose-response curves for quazepam and lorazepam were shifted to the right following i.v. pretreatment with the benzodiazepine antagonists Ro 15-1788 (0.18–3.0 mg/kg) or AHR-11797 (1.0–5.6 mg/kg); in this regard, AHR-11797 was less potent than Ro 15-1788. Although the effects of quazepam on suppressed responding are likely due to actions at benzodiazepine receptors, these effects may be influenced by or reflect a more prominent sleep-promoting action of the drug.

Effects of apomorphine on punished and unpunished responding in the rat

Apomorphine has been reported to increase shock-suppressed drinking, which suggests that it might have antianxiety activity. Because some drugs that increase shock-suppressed drinking are not active in other punishment procedures, the effects of apomorphine on punished and unpunished responding maintained by a multiple fixed-interval, fixed-interval schedule of food presentation were studied in rats. At doses from 3.125 to 100 μg/kg, apomorphine failed to increase punished or unpunished responding. In contrast, pentobarbital produced large increases in punished responding maintained by a fixed-interval schedule of food presentation.

GABA-related drugs modulate the behavioral effects of lorazepam.

The behavioral effects of the GABA-related drugs SL 75102 (4-[[(4-chlorophenyl)-(5-fluoro-2-hydroxyphenyl)-methylene]amino]butyric acid) and THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyrindin-3-ol) were studied alone and in combination with lorazepam. Two groups of squirrel monkeys responded under a fixed-interval schedule of food presentation. In one group, responding was suppressed by superimposing a fixed-ratio schedule of response-produced electric shock; responding was not suppressed in the second group. Dose-response curves were determined by administering cumulative doses IV during timeout periods that preceded sequential components of the fixed-interval schedule. Neither SL 75102 (1.0-30.0 mg/kg) nor THIP (0.1-3.0 mg/kg) significantly altered rates of either suppressed or nonsuppressed responding, whereas lorazepam (0.01-0.3 mg/kg) produced dose-related increases in response rate under both schedules. Pretreatment with 1.0 mg/kg SL 75102 significantly enhanced the rate-increasing effects of lorazepam on suppressed responding. Pretreatment with 10.0 mg/kg SL 75102 also enhanced the rate-increasing effects of lorazepam on nonsuppressed responding. In contrast, the rate-increasing effects of lorazepam were not enhanced by pretreatment with 0.3 or 1.0 mg/kg THIP under either schedule. Moreover, pretreatment with 1.0 mg/kg THIP attenuated the rate-increasing effects of lorazepam on nonsuppressed responding. Enhancement of the behavioral effects of lorazepam by SL 75102 may reflect positive allosteric interactions between the two drugs at the benzodiazepine-GABA receptor complex.

Variability in the effects of 4-bromo-2,5-dimethoxyamphetamine (DOB) on operant behavior of squirrel monkeys

Effects of the hallucinogenic drug (+/−)-4-bromo-2,5-dimethoxyamphetamine HCl (DOB, 0.003–0.3 mg/kg) were studied in squirrel monkeys. Only decreases in responding were seen in monkeys studied under 5-min fixed-interval schedules of food presentation. These decreases were blocked by pretreatment with the 5-HT 2 antagonist ketanserin (0.1–1.0 mg/kg) and by the non-selective 5-HT antagonists methysergide (0.3 mg/kg) or mianserin (0.1–1.0 mg/kg). Similar decreases in responding and antagonism by 5-HT antagonists were seen at slightly higher doses of DOM HCl (methyl rather than bromo at the 4 position). In contrast to effects under the food schedule. DOB initially produced marked increases in responding of three monkeys studied under schedules of shock avoidance. However, a complex pattern of changes in the effects of DOB emerged when the same doses were given on subsequent occasions. In one monkey, there were graded increases in responding to a peak of just over 200% of control at 0.17 mg/kg when DOB was given in a roughly ascending dose series. However, no increases in responding were observed at any dose when DOB was given on many subsequent occasions (some very widely spaced). A second monkey showed similar increases initially, but responding was suppressed by a formerly rate-increasing dose of DOB (0.1 mg/kg) on two subsequent test days. Later, this dose again produced increases in responding of about the same magnitude as seen initially, but these increases eventually diminished and were no longer observed. In the third monkey, increases in responding after the initial ascending dose series diminished in an irregular manner over the course of successive redeterminations.

Modification of drug effects by l-α-acetylmethadol

The effects of drugs on rate of responding by rats under a multiple fixed-ratio fixed-interval schedule of food presentation were studied before and during chronic administration of l-α-acetylmethadol (LAAM). Small doses of methadone, phencyclidine, chlordiazepoxide and pentobarbital increased rates of responding under the fixed-interval component of the schedule. At higher doses, these drugs, as well as LAAM, morphine and haloperidol, decreased rates of responding under both schedule components. Chronic LAAM administration shifted the dose-effect curves for LAAM, morphine, methadone, and to some extent, perhaps pentobarbital, to the right, but did not shift the dose-effect curves to the right for chlordiazepoxide, phencyclidine and haloperidol. The rate-increasing effects of small doses of methadone, phenccylidine, pentobarbital and chlordiazepoxide were attenuated during chronic LAAM administration.

Rate-dependent effects of d- and l-amphetamine on schedule-controlled responding in pigeons and squirrel monkeys

The effects of d- and l-amphetamine were studied on key-pressing responses of squirrel monkeys maintained under fixed-interval schedules of electric shock presentation, and on key-pecking responses of pigeons maintained under multiple fixed-ratio, fixed-interval schedules of food presentation. Under the fixed-interval schedules, responding followed a pause and occurred at increasing rates as the interval elapsed. Both isomers produced comparable increases in rates of responding under relatively long fixed-interval schedules with small to intermediate doses; maximal effects of the d-isomer were obtained at doses one-half log unit smaller than the doses of the l-isomer. Responding of pigeons maintained under relatively short fixed-interval schedules was only decreased by either amphetamine isomer. Responding of pigeons maintained under fixed-ratio schedules occurred at the highest rates and was also only decreased by either amphetamine isomer. Decreases in response rate produced by the d-isomer were generally obtained at doses one-half log unit smaller than doses of the l-isomer that produced comparable effects. Both isomers increased responding that occurred at low rates early in the fixed-interval to a proportionally greater extent than higher rates from later in the interval. The highest rates in the fixed-interval were generally decreased. Differences in potency between the two isomers in producing rate-dependent effects were small, most noticable with larger doses, and less than the potency differences between the two isomers in producing changes in response rate.

Magnitude and duration of the effects of cocaine on conditioned and adjunctive behaviors in the chimpanzee.

Characteristic patterns of conditioned key-pressing were maintained in the chimpanzee under a multiple 30-response fixed-ratio, 10-minute fixed-interval schedule of food presentation. Adjunctive drinking occurred with regularity during the fixed-interval schedule and, with less frequency, during 1-minute timeout periods that followed each food presentation; drinking seldom occurred during the fixed-ratio schedule. Cocaine increased key pressing under the fixed-interval schedule at doses between .1 and 3.0 mg/kg, but adjunctive drinking and key pressing under the fixed-ratio schedule did not increase at any dose. Conditioned and adjunctive behaviors were disrupted and suppressed for different durations at 10,0 mg/kg, a dose which induced convulsive seizures within 10 minutes after intramuscular injection. A time-course analysis showed the magnitude and duration of the effects of cocaine on key pressing under the fixed-interval schedule and on adjunctive drinking to be dose-related. Moreover, a given dose of cocaine had diverse effects, depending on the behavior and the time since drug administration.

The acute behavioral effects of diisopropyl fluorophosphate in the chicken, pigeon, and rhesus monkey

The effects following oral and intramuscular injection of diisopropyl fluorophosphate (DEP) were studied in chickens and pigeons responding under a multiple fixed-ratio, fixed-interval schedule of food presentation. The effects for both routes for DFP were also studied in chickens responding on a multiple fixed-ratio, time-out schedule of food presentation. In addition, the effects of intramuscular DFP were also studied in a rhesus monkey responding under a chain fixed-ratio, fixed-ratio schedule of sucrose presentation. The effects of DFP were to cause a general depression of fixed-ratio, fixed-interval, and time-out responding with no mean response rate increases. Doses producing behavioral effects also produced acute cholinergic effects in the chicken and the rhesus monkey but not in the pigeon. The potency and duration of DFP effects depended on the species and route of administration. The monkey was the most sensitive animal with the lowest active intramuscular dose (0.1 mg/kg) disrupting responding for 5 days. A higher dose (0.125 mg/kg) disrupted responding for 8 days. Intramuscular DFP disrupted responding in the chicken in a dose-related manner and with 0.25 mg/kg being the lowest active dose. Higher doses (0.5 and 0.75 mg/kg) disrupted responding for 2 days after administration. Oral DFP was much less potent than the intramuscular route in both chickens and pigeons, with a marginally active dose being 1 mg/kg. Effects following oral administration lasted less than 1 day. Potency was the same in the pigeon by both the oral and intramuscular routes.

A comparison of the keypeck and treadle-press operants in the pigeon: Fixed-interval schedule of reinforcement

Four pigeons were tested under 30-, 100-, 600-, and 1,000-sec values of the fixed-interval schedule of food presentation using both the treadle-press and the keypeck operants. Response rate was higher for the keypeck response at all schedule values, but the response pattern was similar for both operants. Quantitative measures of response rate and curvature showed considerable variability, with indication of a differential change in quarter-life as a function of schedule value, with the function being steeper for the treadle response than for the key response. Overall, responding on the key and treadle showed more similarities than differences.

PENTOBARBITAL AND d‐AMPHETAMINE EFFECTS ON CONCURRENT PERFORMANCES

The effects of pentobarbital and d-amphetamine were studied in pigeons responding under several concurrent fixed-ratio variable-interval and concurrent fixed-ratio fixed-interval schedules of food presentation. Drug effects were compared with different fixed ratios, fixed and variable intervals, changeover delays, and with the schedules operating singly. Doses of d-amphetamine that increased or did not affect responding under the interval schedules decreased responding under the fixed-ratio schedule, whereas doses of pentobarbital that increased responding under the fixed-ratio schedule decreased or eliminated responding under the interval schedules. These effects depended both on the schedule of food delivery and the parameters of schedules arranged concurrently. Pentobarbital increased responding under the fixed-ratio schedule with 4-minute and 10-minute interval schedules arranged concurrently, but not with 1.5-minute schedules. d-Amphetamine decreased concurrent ratio and interval responding with the 1.5-minute interval schedules, but either increased or did not affect responding with the longer intervals. Changes in the parameter of one schedule altered responding controlled by that schedule and also other concurrent performances. As a consequence, the effects of drugs on each behavior were altered.