Schedule control of quantal and graded dose-effect curves in a drug-drug-saline discrimination

Pigeons were trained to discriminate among 5 mg/kg pentobarbital, 5 mg/kg morphine, and saline when responding was maintained under fixed-interval (FI) or fixed-ratio (FR) reinforcement schedules. After the discrimination was established, other drugs were substituted for the training drugs. After low doses of pentobarbital and chlordiazepoxide, responding shifted from the saline key to the pentobarbital key under both FR and FI schedules. After low doses of morphine and methadone, responding shifted from the saline key to the morphine key under both reinforcement schedules. After all doses of d-amphetamine, responding occurred largely on the saline key under both schedules. Responding also was confined largely to the saline key after phencyclidine administration under the FR schedule, but under the FI schedule, responding shifted from the saline key to the pentobarbital key at high doses of phencyclidine. When responding was maintained under the FR schedule, the dose-response curves for drugs that generalized to the training drugs were quantal in shape, while under the FI schedule, the dose-response curves for drugs that generalized to the training drugs were graded. These data extend observations that FR schedules generate quantal dose-response curves, and FI schedules generate graded dose-response curves to complex three-key drug discriminations.     

Behavioral effects of caffeine, (-)N-((R)-1-methyl-2-phenylethyl)-adenosine (PIA), and their combination in the mouse

The effects of caffeine (1–100 mg/kg, IP), (-)N-((R)-1-methyl-2-phenylethyl)-adenosine (PIA) (0.01–1 mg/kg, IP), and of the two drugs in combination were studied in mice responding under a mult FR30 FI600 s schedule of food presentation. The lowest dose of caffeine, 1 mg/kg, had no effect on responding under either component of the mult schedule. Intermediate doses of caffeine (3 and 10 mg/kg) slightly increased responding under the FI component, while higher doses decreased responding. Caffeine only decreased responding, at doses above 30 mg/kg, under the FR component. PIA decreased responding under both components of the mult schedule in a dose-dependent, and similar, manner. In most cases, the rate-increasing effect of caffeine on FI responding was diminished when combined with a rate-decreasing dose of PIA. However, when 0.01 mg/kg PIA, a dose that had no effect alone, was combined with 3 mg/kg caffeine, the increase in rate exceeded that of caffeine alone. Rate-deceasing effects of PIA were antagonized by caffeine; with larger doses of PIA, larger doses of caffeine were required for antagonism. Thus, while the rate-increasing effects of caffeine can be either enhanced or diminished, when combined with different doses of PIA, the rate-decreasing effects of PIA are clearly antagonized by caffeine in a dose-dependent manner.     

Discriminative-stimulus control by morphine in the pigeon under a fixed-interval schedule of reinforcement

The stimulus control by morphine under a fixed-interval (FI) 180-s schedule of reinforcement was examined in five pigeons trained to discriminate 5.0mg/kg of i.m. morphine from saline. After training, dose-response relationships were determined for morphine, d-amphetamine, pentobarbital, fentanyl, and MK-801. At low doses of morphine, responding of individual subjects was predominantly on the saline-appropriate key. At intermediate doses responding occurred on both keys throughout the interval. Following doses of 5.6mg/kg and higher, responding on both keys was observed in the early portions of the interval with responding shifting to the morphine-appropriate key as the interval progressed. Thus, a graded dose-effect curve for morphine was obtained under the FI schedule. The fentanyl dose-effect curve was similar to that obtained with morphine, but the other test drugs were not generalized. Five other pigeons were trained to discriminate 5.0mg/kg of morphine from saline under a fixed-ratio (FR) 100 schedule of reinforcement. During testing with morphine, responses were confined to the saline-appropriate key at 0.3 and 1.0mg/kg of morphine, but at higher doses responses were confined to the drug key. In contrast to the results obtained using the FI schedule, a quantal relationship for responding on the two keys was observed when a FR schedule was employed.     

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.     

Discrimination of pentobarbital doses and drug mixtures under fixed-ratio and fixed-interval reinforcement schedules

Pigeons were trained to discriminate among 5 mg/kg pentobarbital, 10mg/kg pentobarbital, and saline, under either fixed-interval (FI) or fixed-ratio (FR) reinforcement schedules. When baseline responding stabilized, a higher percentage of responses occurred on the key that produced the reinforcer under the FR schedule than under the FI schedule. After low doses of pentobarbital, responding shifted from the saline key to the 5 mg/kg pentobarbital key; at higher doses of pentobarbital responding shifted to the 10mg/kg pentobarbital key under both schedules. After low doses of ethanol and chlordiazepoxide, responding shifted from the saline key to the 5 mg/kg pentobarbital key, but after high doses of these drugs, responding continued to occur on the 5 mg/kg pentobarbital key under both reinforcement schedules. A 5 mg/kg dose of pentobarbital increased responding on the 10 mg/kg pentobarbital key when it was combined with pentobarbital, ethanol or chlordiazepoxide. Phencyclidine and D-amphetamine produced responding largely on the saline key under both reinforcement schedules. Under the FR schedule, pentobarbital dose-response curves were usually quantal, whereas under the FI schedule the pentobarbital dose-response curves usually were graded.     

Behavioral effects of cocaine and its interaction with d-amphetamine and morphine in rats

Drugs of abuse are commonly co-abused, and frequently these combinations produce effects which cannot be predicted by studying the effects of the individual drugs. To investigate the behavioral interactions which occur following combinations of cocaine plus amphetamine or cocaine plus morphine, rats were trained to respond under a differential reinforcement of low rates (DRL) schedule (10-14 sec). Cocaine (0.1-10 mg/kg) and d-amphetamine (0.1-3 mg/kg) decreased the percentage of reinforced responses (efficiency) at doses which had no effect on overall rate of responding. Following moderate doses of either drug, the interresponse time (IRT) distribution showed an increase in the percentage of shorter (less than 10 sec) IRT's. Morphine (0.1-10 mg/kg) also decreased efficiency, but the decrease which occurred was only observed at doses which also decreased overall response rates. As might be expected, the IRT distribution for morphine showed a dose-related increase in the percentage of long IRT's (greater than 14 sec). When doses of morphine which had no significant effect when administered alone (1 or 3 mg/kg) were combined with cocaine, the cocaine dose-response curve for efficiency was shifted down and to the left and response rates were increased. Analysis of the IRT distribution showed that the combination of an ineffective dose of cocaine, 1 mg/kg, plus 3 mg/kg morphine produced a shift in the IRT distribution to the left (an increase in the percentage of short IRT's). When cocaine was combined with 0.3 mg/kg d-amphetamine, a dose which had no effect when given alone, no significant interactions were observed on efficiency or overall rate of responding.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effects of behavioral history on cocaine self-administration by rhesus monkeys

The purpose of the present study was to examine whether a history of responding under schedules that generate either high or low response rates could modify previously established cocaine self-administration. Eight experimentally naive rhesus monkeys were trained to respond on one of two levers under a fixed-interval (FI) 5-min schedule of intravenous cocaine (0.03 mg/kg per injection) presentation. When responding was stable a cocaine dose-response curve (saline, 0.01–0.3 mg/kg per injection) was determined. Following completion of the dose-response curves, the monkeys were randomly assigned to one of two groups (n=4/group) and trained to respond on the other lever under either a fixed-ratio (FR) 50 or inter-response times (IRT) > 30-s schedule of cocaine (0.03 mg/kg per injection) presentation. After 65 sessions responding was again maintained under the FI5-min schedule of 0.03 mg/kg per injection cocaine for 60 sessions, followed by redetermination of the cocaine dose-response curve. During the initial exposure to the FI schedule, the mean rate of responding was 4.02 (± 0.33) responses/min and the cocaine dose-response curve was characterized as an inverted-U shape function of dose, with peak responding at 0.03 mg/kg per injection. The FR50 schedule generated high rates (66.80 ± 5.6 responses/min), while response rates under the IRT > 30-s schedule were low (2.62 ± 0.2 responses/min). Following different behavioral histories, response rates under the FI5-min schedule were significantly higher for 60 sessions in FR-history monkeys compared to IRT-history subjects. Compared to the initial FI baselines, cocaine intake (mg/kg per session) was significantly higher following an FR-history and significantly lower following training under an IRT schedule, for 60 consecutive sessions. In addition, there was a significant effect of behavioral history on the cocaine dose-response curve, such that descending limb was shifted farther to the right in FR-history subjects compared to IRT-history monkeys. Results from the present study indicate that previously established drug-seeking behavior can be modified by training under different reinforcement schedules. Knowledge of such historical variables may be important in understanding the determinants of drug self-administration.     

Attenuation of the behavioral effects of meperidine and normeperidine by daily administration of diazepam

The effects of meperidine, normeperidine, morphine, pentobarbital and d-methadone were determined on the key-pecking behavior of pigeons responding under a multiple fixed-ratio (FR), fixed-interval (FI) schedule of grain presentation. Dose-effect curves were obtained for each drug alone and during daily administration of 10 mg/kg of diazepam. The daily administration of diazepam had little effect on the behavior itself. Meperidine and normeperidine caused dose-related decreases in both FI and FR responding. The dose-effect curves for these drugs during daily administration of diazepam were shifted to the right compared to the dose-effect curves determined in the absence of daily diazepam. In contrast, the effects of morphine, d-methadone and pentobarbital either were not affected by daily administration of diazepam or were shifted to the left by daily administration of diazepam. These data further support the hypothesis that the behavioral effects of meperidine and normeperidine are due to a proconvulsive action produced by these drugs. In contrast, the effects of morphine, d-methadone and pentobarbital are not due to such a proconvulsive action.     

Effects of 5-HT3 antagonists on fixed-interval behavior in rats.

The effects of 5-hydroxytryptamine3 (5-HT3) antagonists were studied in rats responding under a fixed-interval (FI) schedule of food presentation. BRL 43694, GR 38032F, ICS-205,930 and zacopride had no effect on FI responding up to 10.0 mg/kg IP. Response rate decreases were observed only at high doses (30.0 or 56.0 mg/kg); rate increases were not observed. In comparison, caffeine (1.0-10.0 mg/kg) and cocaine (3.0-18.0 mg/kg) increased and lorazepam (0.3 mg/kg) decreased FI responding. The effects of caffeine, cocaine, and lorazepam were unchanged when coadministered with the 5-HT3 antagonists. The results show that 5-HT3 antagonists, when given alone or with other CNS-active drugs, have little effect on FI responding of rats.     

Effects of LY150720 (picenadol), a novel mixed-action opioid, on schedule-controlled responding in the squirrel monkey

The opioid LY150720 is a racemic mixture whose resolution results in a highly stereospecific separation of agonist and antagonist activity. The effects of LY150720 (0.3-3.0 mg/kg), its agonist (dextro) isomer LY136596 (0.3-1.7 mg/kg) and morphine (0.03-1.0 mg/kg) were studied alone and in combination with naloxone (0.001-1.0 mg/kg) in squirrel monkeys whose responding was maintained under a multiple fixed-ratio 30-response fixed-interval 5-minute (mult FR-30 FI 5-min) schedule of food presentation. LY150720, LY136596 and morphine generally decreased responding under both schedule components, although in several instances increases in responding under the FI component were noted, particularly following LY150720 and LY136596. Naloxone (0.1-3.0 mg/kg) generally had little effect on responding, whereas the antagonist (levo) isomer LY136595 (0.3-10.0 mg/kg) decreased responding under both schedule components. The rate-decreasing effects of morphine, LY150720 and LY136596 were reversed by naloxone; doses of naloxone required to reverse the effects of all three drugs were comparable. When combined with morphine, naloxone restored rates and patterns of responding to control values, whereas combinations of LY150720 or LY136596 and naloxone increased responding under the FI component in excess of control values. These increases appear to be due to anticholinergic actions of LY150720 and LY136596, as they are reversed by physostigmine (0.01 mg/kg) and similar increases are produced by scopolamine (0.01-0.1 mg/kg).     

Effects of Delta 9-tetrahydrocannabinol, (R)-methanandamide, SR 141716,and d-amphetamine before and during daily Delta 9-tetrahydrocannabinol dosing

We examined the effects of Delta 9-tetrahydrocannabinol (Delta 9-THC), (R)-(+)-arachidonyl-1'-hydroxy-2'-propylamide ((R)-methanandamide, AM 356), SR 141716, and d-amphetamine on fixed-ratio (FR) responding maintained by food in rats before and during daily dosing with Delta 9-THC. Rats responded under a FR 10 schedule of food reinforcement. Cumulative dose-response curves for the various drugs were determined before and during daily Delta 9-THC administration. All four drugs dose-dependently decreased responding both before and during daily dosing with Delta 9-THC (18 mg/kg/day). The dose-response curves for both Delta 9-THC and (R)-methanandamide were shifted to the right with daily dosing with Delta 9-THC, indicating tolerance to the effects of Delta 9-THC and cross-tolerance to the effects of (R)-methanandamide. The doses of d-amphetamine examined produced similar effects both before and during daily dosing with Delta 9-THC. The effects of SR 141716 were not consistently altered by daily Delta 9-THC administration. These results indicate that tolerance develops to the effects of Delta 9-THC, when Delta 9-THC is administered repeatedly. These results also indicate that cross-tolerance to (R)-methanandamide develops with repeated Delta 9-THC administration.     

Effects of chronic caffeine exposure on adenosinergic modulation of the discriminative-stimulus effects of nicotine, methamphetamine, and cocaine in rats

RATIONALE: Adenosine receptors are involved in cocaine and methamphetamine discrimination and exposure to caffeine can affect behavioral effects of nicotine in rats. OBJECTIVES: Here we investigated the relative involvement of adenosine A(1) and A(2A) receptors in nicotine, cocaine, and methamphetamine discrimination, before and/or during chronic caffeine exposure. MATERIALS AND METHODS: The nonselective adenosine receptor antagonist caffeine, the A(1)-receptor antagonist cyclopentyltheophylline (CPT), and the A(2A)-receptor antagonist MSX-3 were evaluated in rats trained to discriminate 0.4 mg/kg nicotine from saline under a fixed-ratio schedule of food delivery. Effects of adenosine receptor antagonists were then compared in rats discriminating nicotine, methamphetamine, or cocaine from saline during chronic caffeine exposure in their drinking water. RESULTS: Caffeine, CPT, and MSX-3 partially generalized to nicotine and shifted nicotine dose-response curves leftwards. During chronic caffeine exposure, however, all three ligands failed to generalize to nicotine and failed to shift nicotine dose-response curves. In previous experiments, CPT and MSX-3 partially generalized to methamphetamine and cocaine and shifted dose-response curves leftwards. In the present experiments, CPT neither generalized nor shifted dose-response curves for methamphetamine or cocaine during chronic caffeine exposure. However, MSX-3 partially generalized to both psychostimulants and shifted their dose-response curves leftwards. Caffeine partially generalized to cocaine, but not methamphetamine, and shifted both dose-response curves leftwards. CONCLUSIONS: Both adenosine A(1) and A(2A) receptors are capable of modulating the discriminative-stimulus effects of nicotine. Chronic caffeine exposure produces complete tolerance to both A(1)- and A(2A)-mediated effects in nicotine-trained rats. In contrast, chronic caffeine exposure produces tolerance to adenosine A(1)-mediated, but not A(2A)-mediated, effects in methamphetamine- and cocaine-trained rats.     

Drug discrimination in pigeons trained to discriminate among morphine, U50488, a combination of these drugs, and saline

This study compared fixed-ratio (FR) and fixed-interval (FI) schedules to investigate the discriminative stimulus properties of μ-opioid and/or κ-opioid receptor agonists. Pigeons were trained to discriminate among morphine (μ agonist), U50488 (κ agonist), the combination, and saline under FR 20-s or FI-300-s schedule. After training, correct-key responding averaged 94.4 (FR) and 66.5% (FI) after administration of training drugs. Dose-response curves were generally quantal under the FR and graded under the FI schedules, but highly variable among subjects under the FI. Under the FR schedule, the dose of naltrexone that blocked morphine's discriminative stimuli also blocked U50488. Combining high doses of morphine with low doses of U50488 produced responding on the morphine key and combining high doses of U50488 with low doses of morphine produced responding on the U50488 key. Combining high doses of both drugs produced responding on the drug-combination key. Increasing d,l-pentazocine doses shifted responding from the saline key to the U50488 key, then to the morphine key, and finally to the drug-combination key. Butorphanol and ethylketocyclazocine produced similar effects, except responding on the morphine key increased before responding on the U50488 key. The four-choice procedure under the FR schedule has the potential for determining the discriminative stimulus effects of mixed agonists.     

Antagonism of cocaine self-administration by selective dopamine D(1) and D(2) antagonists

Effects of the dopamine D(1) antagonist SCH 39166 were compared with those of the D(2) antagonist eticlopride in squirrel monkeys responding under a second-order fixed-interval schedule of i.v. self-administration of cocaine. Dose-response curves were determined for a range of doses of self-administered cocaine (0.01-1.7 mg/kg/injection) alone and after pretreatment with SCH 39166 (0.01-0.1 mg/kg) or eticlopride (0.001-0.006 mg/kg). Cocaine maintained self-administration behavior in a dose-related manner; as the dose of cocaine was increased, rates of responding first increased and then either decreased or leveled off. Optimum doses (0.03-0.3 mg/kg) maintained high rates of responding (0.7-1.7 responses per second) among the different monkeys, and patterns of responding that were characteristic for second-order schedules. Pretreatment with either SCH 39166 or eticlopride altered self-administration behavior in all monkeys. In most cases, dose-response curves for cocaine were shifted to the right, indicative of surmountable antagonism, and a 3 to 6-fold increase in dose of cocaine was necessary to restore optimal performances. In some instances, dose-response curves were shifted either downward or downward and to the right, indicating that the antagonistic effects of SCH 39166 and eticlopride were not always fully surmountable. These results show that self-administration of cocaine can be comparably modified by drugs that selectively block dopamine D(1) or D(2) receptors.     

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 carbon monoxide in combination with behaviorally active drugs on fixed-ratio performance in the mouse

The effects of carbon monoxide (3.75, 7.5, 15 and 30 ml/kg, IP) alone and in combination with ethanol (1.1 g/kg), nicotine (1.1 mg/kg), caffeine (36.1 mg/kg), chlorpromazine (2.2 mg/kg), diazepam (10 mg/kg), pentobarbital (23.1 mg/kg), d-amphetamine (1.4 mg/kg) or morphine (13.3 mg/kg) were evaluated in mice. Animals were trained to lever press under a fixed-ratio 32 schedule of water reinforcement. Response rates following CO-drug combinations were compared with the expected additive effects determined by the sum of the effects of each agent administered alone. CO (15 and 30 ml/kg) in combination with ethanol produced supra-additive effects. CO-chlorpromazine and CO-d-amphetamine combinations often produced greater than additive response-rate suppression, although differences from additivity did not reach statistical significance. The effects on response rates following CO in combination with nicotine, caffeine, diazepam, pentobarbital, or morphine were additive. These results suggest that concurrent use of therapeutic or abused drugs and CO exposure may place an individual at higher risk for behavioral toxicity.     

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.     

Opioid modulation of the discriminative stimulus effects of cocaine: comparison of µ, kappa and delta agonists in squirrel monkeys discriminating low doses of cocaine

Modulation of the discriminative stimulus effects of cocaine by the μ agonist morphine, the kappa agonist U 50, 488, and the delta agonist BW 373U86 was investigated in squirrel monkeys using a two-lever drug discrimination procedure. Monkeys initially were trained to discriminate intramuscular injections of 0.3 or 0.56mg/kg cocaine from vehicle and subsequently retrained to discriminate a 3- to 5.6-fold lower dose of cocaine (0.1 or 0.18mg/kg). After retraining, dose-response functions for the discriminative stimulus effects of cocaine were shifted to the left and ED(50) values were reduced 2- to 6-fold compared to values obtained with the higher training doses. In drug substitution experiments, morphine (0.03-1.0mg/kg), U 50,488 (0.1-3.0mg/kg) and BW 373U86 (0.001-0.1mg/kg) did not reproduce the discriminative stimulus effects of the low training doses of cocaine, although U 50,488 engendered a majority of responses on the cocaine-associated lever in two of three monkeys. In drug interaction experiments, pretreatment with morphine (0.3mg/kg) potentiated the discriminative stimulus effects of the low training doses of cocaine such that the cocaine dose-response functions were shifted to the left and ED(50) values were reduced 3- to 7-fold. Pretreatment with U 50,488 (0.3mg/kg), on the other hand, attenuated the discriminative stimulus effects of the low training doses of cocaine such that the cocaine dose-response functions were shifted to the right and ED(50) values were increased approximately 4-fold. The cocaine-modulating effects of morphine and U 50,488 in these experiments were qualitatively similar to those observed previously when the monkeys were trained to discriminate higher doses of cocaine. In contrast to the effects of the μ and kappa agonists, pretreatment with BW 373U86 (0.01 or 0.03mg/kg) did not systematically alter the discriminative stimulus effects of cocaine regardless of training dose.     

Effects of morphine alone and in combination with naloxone or d-amphetamine on shock-maintained behavior in the squirrel monkey

Key-pressing behavior in the squirrel monkey was maintained under an 8-min fixed-interval (FI) schedule of electric-shock delivery. The acute i.m. administration of morphine prior to a daily session decreased response rates at doses of 1.0–3.0 mg/kg but had little systematic effect on rate at doses of 0.03–0.3 mg/kg. When naloxone was administered concomitantly with morphine prior to a session, 0.01 mg/kg naloxone required a three-fold increase in the dose of morphine necessary to obtain decreased response rates, 0.1 mg/kg naloxone required a 30-fold increase in morphine, and 1.0 mg/kg required more than a 30-fold increase in morphine. Moreover, the administration of naloxone with morphine resulted in increased rates of responding at certain combinations of doses of the two drugs. The administration of d-amphetamine (0.03 or 0.1 mg/kg) alone increased mean response rates under the FI schedule; when combined with 0.03–0.3 mg/kg morphine the increases in responding were greater than obtained with d-amphetamine alone. The negative slope of the linear regression lines relating the effects of morphine to control rates of responding engendered under the FI schedule was decreased when morphine was combined with naloxone, but not with d-amphetamine. These results show that naloxone, but not d-amphetamine, can antagonize the response-rate decreasing effect of morphine when responding in the squirrel monkey is maintained by response-produced electric shock.     

Cumulative dose-response curves in behavioral pharmacology

Cumulative dose-response curves have been widely used in many areas of pharmacology. To date, the applicability of cumulative dose-response curves has not been assessed in behavioral pharmacology. To determine the feasibility of this procedure, mice were trained to respond under a multiple time-out 5 min, fixed-ratio 30(mult TO 5, FR 30) schedule of reinforcement. The FR 30 component consisted of 15 presentations of an FR 30hedule of reinforcement. At the start of each TO 5 component, an intraperitoneal (IP) injection was given, and the effect on the response rate during the following 15 presentations of the FR 30 schedule was assessed. d-Amphetamine (0.3–30 μ moles/kg), pentobarbital (3–300 μ moles/kg), morphine (1–100 μ moles/kg), ketamine (3–300 μ moles/kg), and phencyclidine (1–100 μ moles/kg) all produced dose-related decreases in FR responding. In each case the lowest dose tested was without effect, and the highest dose tested essentially eliminated responding. As a control, the normal 4th dose in the ascending series of each drug was given preceded by 3 saline injections. Whether this dose of each drug was preceded by 3 separate saline injections or by 3 lower ascending doses of the same drug, the observed effect was identical. Five consecutive saline injections during the experimental session were without effect. The application of this procedure should greatly decrease the time required to examine the behavioral effects of a wide range of doses.