Biomedical subjects

R A Meisch

Publications and source records attributed to R A Meisch.

At least 37 records · Page 2Linked to original sources

PubMed1995

Reinforcing effects of triazolam in sedative abusers: correlation of drug liking and self-administration measures.

Six male subjects with histories of sedative abuse were allowed to orally self-administer a maximum of 18 color-coded triazolam and placebo capsules during daily 3-h sessions. The schedule of reinforcement was a signaled fixed-interval 10-min schedule in which triazolam and placebo were concurrently available as mutually exclusive choices. Triazolam was shown to be a reinforcer in four of the six subjects. The two subjects who did not self-administer triazolam in preference to placebo also had lesser histories of drug dependence. Self-administration of triazolam (0.125 or 0.25 mg per capsule) was generally stable over 7-10 days. Manipulations of triazolam dose (0.0312-0.25 mg) per capsule in two subjects showed that the number of capsules self-administered was inversely related to capsule dose. Subject ratings of drug liking obtained from experimenter-administered doses of triazolam were correlated with self-administration behavior occurring 1-7 days later. Of the subject ratings, next day ratings obtained on the day after dosing resulted in significant correlations whereas same day ratings obtained while subjects were under the influence of triazolam did not. These results have important implications for abuse liability prediction and suggest that next day ratings have greater predictive validity than measures collected while subjects are under the influence of benzodiazepines.

Adult↗

PubMed1995

Oral self-administration of etonitazene in rhesus monkeys: use of a fading procedure to establish etonitazene as a reinforcer.

The establishment of orally delivered etonitazene (a potent opioid) as a reinforcer, was studied in eight rhesus monkeys. Initially, when given concurrent access to 2.5 micrograms/ml etonitazene and the water vehicle, five of the monkeys rejected the drug, whereas the other three monkeys consumed more drug solution than water. The five monkeys that rejected the drug solution underwent an acquisition phase to establish the drug as a reinforcer. A fading procedure was used to transfer control of responding from a 2% (wt/vol) ethanol solution to a 2.5 micrograms/ml etonitazene solution. Initially, responding was maintained by contingent deliveries of 2% ethanol. Next, across blocks of six or more sessions, increasing amounts of etonitazene were added in steps to the 2% ethanol solution. Subsequently, the 2% ethanol solution was decreased in steps to zero, leaving only the 2.5 micrograms/ml etonitazene present. When the fading procedure was completed, dose of etonitazene was varied by increasing the volume delivered, first under fixed ratio (FR 4) and then under an FR 8 reinforcement schedule. The same dose manipulations were made with the three monkeys who did not undergo the fading procedure because they preferred etonitazene over water when first tested. Etonitazene was established as a reinforcer for six of the eight monkeys because drug deliveries exceeded vehicle deliveries across a range of drug doses.

Administration, Oral↗

PubMed1995

Relative reinforcing effects of different doses of orally delivered cocaine.

The relative reinforcing effects of different doses of oral cocaine were investigated in two adult male rhesus monkeys. In the first experiment, a range of cocaine doses (0.1-0.8 mg/ml) was studied with drug and water concurrently available for 3 h each day under identical and independent fixed-ratio schedules. The side positions of the drug and vehicle were alternated from session to session. Drug deliveries always exceeded vehicle deliveries, i.e., orally delivered cocaine functioned as a reinforcer. The highest rates of responding occurred at either the lowest or next to lowest dose (0.1 or 0.2 mg/ml). In the second experiment, pairs of different cocaine doses were systematically presented under identical and independent fixed-ratio schedules. The higher of two concurrently available doses usually maintained the higher response rate. These findings suggest that the relative reinforcing effects of orally delivered cocaine increase with dose. Absolute response rates obtained with single cocaine doses and water concurrently available do not always reflect the magnitude of the reinforcing effects indicated when pairs of cocaine doses are studied together. The results of this study are in agreement with earlier investigations in which the relative reinforcing effects of pairs of intravenous cocaine doses or oral pentobarbital doses were studied. Taken together these findings indicate that, over a range of doses and across pharmacological classes and routes of administration, relative reinforcing effects of a drug increase directly as a function of increases in dose.

Administration, Oral↗

PubMed1994

Establishing benzodiazepines as oral reinforcers: midazolam and diazepam self-administration in rhesus monkeys.

Oral benzodiazepine self-administration was examined in four adult male rhesus monkeys with histories of ethanol- and pentobarbital-reinforced behavior. Drug solutions and vehicle were concurrently available for 3-hr each day under fixed-ratio (FR) reinforcement schedules. Initially, the monkeys rejected a midazolam solution (0.1 mg/ml) after direct substitution of the drug for an 8% ethanol solution. However, midazolam self-administration was subsequently established by using a fading procedure in which increasing amounts of drug (0.0125-0.2 mg/ml) were gradually added to an 8% ethanol solution, followed by gradual reduction of the ethanol concentration to zero. Midazolam was an effective reinforcer for three of four monkeys tested, i.e., responding that was maintained by the drug solution exceeded that maintained by the drug vehicle. The fourth monkey also self-administered midazolam but drug-maintained responding was not consistently greater than vehicle-maintained responding. The responding maintained by the drug was an inverted-U-shaped or bitonic function of midazolam concentration. The midazolam intake (in milligrams per kilogram) increased as a function of increases in the drug concentration. At the higher concentrations, marked sedative intoxication was observed. There was an inverse relationship between FR size (varied from FR 8 to FR 32) and the amount of drug self-administered. The three monkeys in which midazolam functioned as a reinforcer were then tested with diazepam (0.2 mg/ml), which maintained drug self-administration behavior on direct substitution for 0.2-mg/ml midazolam. Diazepam-maintained responding usually exceeded water responding as the diazepam concentration was increased to 0.8 mg/ml. These data demonstrate robust reinforcing effects of both "short-" and "long-acting" benzodiazepines delivered by the oral route.

Administration, Oral↗

PubMed1993

Concurrent pentobarbital- and saccharin-maintained responding: effects of saccharin concentration and schedule conditions.

Responses of rhesus monkeys were reinforced by delivery of either a pentobarbital (4.0 mg/ml) solution or a vehicle (water) or saccharin solution under a concurrent signaled differential reinforcement of low rates 30-s schedule. After 30 s of no responding, the first response on the pentobarbital or saccharin spout resulted in the delivery of the appropriate solution and reset the timing on both spouts (i.e. a mutually exclusive choice). In the first experiment, the concentration of saccharin was gradually increased across sessions. As saccharin concentration increased, pentobarbital deliveries decreased and saccharin as well as total session deliveries increased. In a second experiment, pentobarbital and 0.24 (mg/ml) saccharin were made available under concurrent signaled differential reinforcement of low rates 30-s schedules which operated independently. Under these conditions responding on one spout had no consequences with respect to the other spout. The reduction of pentobarbital deliveries was substantially attenuated when the choice was not mutually exclusive.

Animals↗

PubMed1993

Water deprivation-induced oral self-administration of cocaine in the Lewis rat: evidence for locomotor effects but not reinforcement.

Oral cocaine self-administration was studied in water-deprived Lewis rats. Liquid was available to rats only during daily 90-min sessions, in chambers equipped with spouts that delivered precise volumes of liquid following completion of lever-press responses. Blocks of training and testing sessions were alternately carried out during which increasing cocaine concentrations were presented: 0.0, 0.0125, 0.025, 0.05, 0.1, 0.2, 0.282, and 0.4 mg/ml. Although high cocaine intakes (23.3-33.0 mg/kg) were obtained, neither avoidance nor preference for cocaine developed. Subsequently, fixed-ratio size was increased, and then distinctive stimulus lights were correlated with each liquid. One rat showed a preference for water following these changes, but two rats continued to show no preference. To determine if the amounts of cocaine self-administered had behavioral effects, locomotor activity tests were run immediately following self-administration sessions. Locomotor activity was substantially higher following cocaine self-administration than following water self-administration. These results demonstrate that the cocaine intakes reached under the present conditions did produce locomotor, but not reinforcing, effects.

Animals↗

PubMed1993

Orally self-administered cocaine in rhesus monkeys: transition from negative or neutral behavioral effects to positive reinforcing effects.

The establishment of orally delivered cocaine as a reinforcer was examined with nine rhesus monkeys. A 2% ethanol solution served as a reinforcer for all nine monkeys, for it maintained substantially higher response rates than did the concurrently available water vehicle. A test was initially conducted to determine whether cocaine would function as a reinforcer when substituted for 2% ethanol. When an intermediate cocaine concentration (0.2 mg/ml) was substituted for the ethanol solution, the drug maintained behavior at rates less than (seven monkeys), equal to (one monkey), or greater than (one monkey) those maintained by water. Thus, for eight of nine monkeys simple substitution of cocaine for ethanol was not sufficient to establish orally delivered cocaine as a reinforcer. In the next phase a stimulus-fading procedure was used. Blocks of training and testing sessions alternated. Across blocks of training sessions, increasing amounts of cocaine (0.0125, 0.025, 0.05, 0.1 mg/ml) were added to the 2% ethanol solution and subsequently the ethanol concentration was gradually decreased until only the 0.1 mg/ml cocaine solution remained; water was always concurrently available. Between each block of training sessions, a block of test sessions was inserted. Test sessions compared relative rates of responding maintained by two concurrently available drug solutions: (1) a solution containing the combination of ethanol and cocaine used in the prior training block and (2) a solution containing the same concentration of ethanol but with no cocaine. Thus, differences in rates of behavior maintained by the two solutions could be attributed to the presence of cocaine and the existence and degree of any such differences could be monitored at each step in the acquisition procedure. The outcome of the training procedure was that cocaine came to function as a reinforcer for six of the eight monkeys tested (the ninth monkey was not put through the fading procedure, having shown higher cocaine than vehicle rates during the initial substitution procedure). During the phase when ethanol was faded from the drug solution, differences between the combination cocaine-ethanol solution and the ethanol-only solution emerged: for the six monkeys that developed cocaine reinforced behavior, the combination solution maintained higher rates of responding than the ethanol solution alone. The opposite results were obtained with the remaining two monkeys. That cocaine had been established as a reinforcer was confirmed by persistent and orderly responding when dose and fixed-ratio size were subsequently varied.

Administration, Oral↗

PubMed1993

Persistence of ethanol self-administration as a function of interreinforcer interval and concentration.

Dipper cups filled with an ethanol solution were presented to Long-Evans hooded rats according to multiple extinction x s fixed-ratio 1 (mult EXT x s FR1) schedules of reinforcement. The scheduled duration of the EXT component was varied to manipulate minimum interreinforcer interval. Increasing the minimum interreinforcer interval by increasing the EXT component was used to challenge responding maintained by ethanol for purposes of evaluating the persistence of ethanol-maintained responding. EXT durations of 0 s (baseline conditions of continuous reinforcement) to 480 s were examined across ethanol concentrations of 0 (water, vehicle), 2, 4, 8, 16, and 32% (w/v). Increasing the EXT component duration resulted in reductions in the number of dipper presentations obtained at each concentration. Reductions in dipper presentations were less, relative to 0-s baseline conditions, the higher the concentration of the ethanol solution available. It was concluded that increasing the ethanol concentration that is self-administered increases the strength of responding that is subsequently maintained in that drug-maintained behavior becomes more resistant to modulation by a procedure (scheduling minimum interreinforcer intervals) which generally reduces numbers of drug deliveries.

Alcohol Drinking↗

PubMed1992

Etonitazene delivered orally serves as a reinforcer for Lewis but not Fischer 344 rats.

Oral etonitazene self-administration was systematically investigated in two inbred strains of rats, Lewis (LEW) and Fischer 344 (F344). For LEW rats, etonitazene maintained higher rates of lever pressing and was consumed in larger volumes than the water vehicle when the reinforcement schedule was fixed ratio (FR) 8. In contrast, with F344 rats responding did not systematically exceed water values at any etonitazene concentration. LEW rats also drank substantially more etonitazene than F344 rats, and at FR 8 only LEW rats showed the typical inverted U-shaped function between etonitazene concentration and number of responses. For the LEW strain, response rate increased as FR size increased from FR 1 to FR 2 and FR 4, but decreased at FR 8. For the F344 strain, as FR size increased response rate showed small increases, but the response rates were far lower than those of the LEW strain. The results support the conclusion that etonitazene was an effective reinforcer for LEW but not F344 rats. These findings demonstrate genetic differences in opioid reinforcement of operant behavior and indicate that genotype can be an important determinant of whether etonitazene serves as a reinforcer.

Administration, Oral↗

PubMed1992

Sex differences in physical dependence on pentobarbital in four inbred strains of rats.

1. In Lewis (LEW), Fischer 344 (F344), Spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats, pentobarbital (PB)-induced sleep time was much longer in female than in male rats. 2. At the time of awakening, brain levels of PB were significantly higher in the female F344 than in the male rats, but there was no sex differences in other strains. 3. Each strain of rats was treated with PB-admixed food for 47 days. There were significant sex differences in mean drug intake of the SHR and LEW strains, but not the WKY and F344 strains during the final concentration. 4. Only female rats exhibited moderate to severe motor impairment by PB. 5. After PB treatment ended, various signs of PB withdrawal occurred in female, but not male, rats. These marked sex differences were observed in all four inbred strains. 6. The sex differences in physical dependence on PB may be due mainly to differences in rates of drug metabolism for the LEW, SHR and WKY rats, and to differences in CNS sensitivity for the F344 rats.

Animals↗

PubMed1992

Oral self-administration of pentobarbital by rhesus monkeys: relative reinforcing effects under concurrent signalled differential-reinforcement-of-low-rates schedules.

During daily 3-h sessions two separate pentobarbital solutions were concurrently available to rhesus monkeys under signalled differential-reinforcement-of-low-rates (signalled DRL) schedules of mouth contacts with spouts. The schedules were synchronized so that each time the 30-s DRL interval expired, lights above both spouts were illuminated and a liquid delivery could be obtained either from the left or right spout, but not both. First water and then each of four 'comparison-concentration' pentobarbital solutions (0.0625, 0.25, 1 and 4 mg/ml) were successively available under one schedule for a block of sessions. Concurrently, deliveries of a 'standard concentration' solution were available from the second spout under an identical DRL schedule; the concentration of this standard solution remained constant throughout the testing of the series of comparison solutions. Three pentobarbital concentrations (4, 1 and 0.25 mg/ml) in turn served as the standard concentration. Relative reinforcing effects were directly related to pentobarbital concentration: in general, within pairs of concurrently available pentobarbital solutions more behavior was maintained by the higher of the two drug concentrations. These findings are discussed in the context of previous studies using ratio and interval schedules which have found relative reinforcing effects to be directly related to reinforcer magnitude.

Administration, Oral↗

PubMed1991

Orally delivered cocaine functions as a positive reinforcer in C57BL/6J mice.

Cocaine serves as a reinforcer across several routes of administration and species. However, whether orally delivered cocaine serves as a positive reinforcer has not been systematically established. We determined the extent to which contingent access to orally delivered cocaine would maintain lever pressing behavior in C57BL/6J mice who had a prior history of operant ethanol-reinforced behavior. The findings presented in this report demonstrate that orally delivered cocaine can serve as a reinforcer of operant behavior. A drug substitution procedure where cocaine was substituted for gradually decreasing ethanol concentrations was successful in inducing pharmacologically significant intakes of cocaine under a fixed ratio (FR) schedule of drug access. When ethanol was removed, responding for cocaine continued. As FR size was increased, proportionate increases in responding occurred except at the highest FR value. Responding maintained by cocaine significantly exceeded responding maintained by vehicle, with the mice typically consuming 6-10 mg/kg cocaine per 30-min session. The utilization of inbred strains and the procedures followed in the present studies should prove useful in determining the extent of both genetic and environmental influences on various behavioral effects of cocaine and their mechanisms of action.

Administration, Oral↗

PubMed1991

Establishment of drug discrimination and drug reinforcement in different animal strains: some methodological issues.

The study of drug reinforcement and drug discrimination in different animal strains raises some methodological issues. Potential problems are discussed, and some possible solutions are mentioned. A distinction is made between establishment of drug reinforced behavior and the maintenance of drug reinforced behavior. A similar distinction holds for the establishment and maintenance of drug discriminations. Strain differences may arise during either the establishment or maintenance phases. Interpretation of findings of strain differences is also discussed. Lastly, a distinction is made between drug self-administration and drug reinforcement.

Alcohol Drinking↗

PubMed1991

The reinforcing and subjective effects of morphine in post-addicts: a dose-response study.

The reinforcing and subjective effects of morphine were determined in five human volunteers with histories of i.v. heroin abuse. Subjects responded under a second-order schedule of i.m. injection. Under this schedule, every 100 lever presses produced a brief stimulus light [fixed ratio (FR) 100:s]; the 30th completion of the FR 100 requirement turned on the light for 15 min and the subject received an i.m. injection of morphine [FR 30 (FR 100:s)]. Once each weekday morphine or placebo was available under this schedule. Each drug dose was available for 1 week. Under these conditions placebo did not maintain responding; 3.75 mg of morphine maintained responding in four of five subjects, and higher morphine doses (7.5, 15 and 30 mg) maintained responding in all five subjects. Subjective effects were measured concurrently: these included measures of drug liking, the Morphine Benzedrine Group scale of the Addiction Research Center Inventory, drug detection and identification. Subjects did not report subjective effects different from placebo for the lowest dose of morphine; the intermediate doses of morphine produced inconsistent effects, and the highest dose of morphine occasioned reports of drug liking and "dope" identifications. These results indicate that there can be a significant dissociation of the reinforcing and the subjective effects of opioids, which has implications for theories of opioid abuse, particularly those assuming that the reinforcing effects are causally related to the euphoric effects of opioids. Furthermore, these results confirm that measures of reinforcing effects and measures of subjective effects do not necessarily lead to identical predictions when used to assess the liability for abuse of a substance.

Analgesia, Patient-Controlled↗

PubMed1990

Reinforcing effects of a pentobarbital-ethanol combination relative to each drug alone.

The reinforcing effects of an orally delivered combination of 1 mg/ml pentobarbital plus 1% ethanol were evaluated in four rhesus monkeys. The drug combination and another liquid (either water, 1 mg/ml pentobarbital, or 1% ethanol) were concurrently available under identical fixed-ratio (FR) schedules. Substantially higher response rates were maintained by the drug combination than by any of the three other liquids. Thus, the reinforcing effects of the pentobarbital-ethanol combination were greater than those of either component drug. In a second experiment, water (the vehicle) was concurrently available with one other liquid (1 mg/ml pentobarbital, 1% ethanol, or the pentobarbital-ethanol combination). All three drug solutions functioned as reinforcers since they maintained much higher response rates than water. These results demonstrate that the greater relative reinforcing effects of the drug combination in the first experiment were not due to a lack of reinforcing effects of the 1 mg/ml pentobarbital or 1% ethanol solutions. In a final experiment, the drug combination was scheduled concurrently with 1 mg/ml pentobarbital, and FR size was systematically varied. The drug combination was then scheduled concurrently with 1% ethanol, and FR size was again varied. As FR size increased, the relative amount of responding maintained by the drug combination increased. Thus, differences in relative reinforcing effects that were evident in the first experiment were again evident in the final experiment when appropriate schedule-parameter values were used.

Administration, Oral↗

PubMed1990

Orally delivered cocaine as a reinforcer for rhesus monkeys.

Orally delivered cocaine was established as a reinforcer for six rhesus monkeys. Cocaine and its vehicle, water, were available from separate spouts under independent concurrent fixed-ratio schedules. The positions of cocaine and water were reversed between spouts from session to session. Cocaine consistently maintained higher response rates than water. Cocaine concentration was systematically varied for three of the six monkeys tested, and cocaine intake (mg of drug/kg of body wt.) increased with increases in drug concentration.

Administration, Oral↗

PubMed1990

Rate-depressant effects of ethanol on fixed-ratio responding in ALKO AA and ANA rats.

The ALKO AA and ANA rats have been selectively bred for high versus low ethanol preference, respectively. AA rats have been shown to self-administer ethanol, whereas ANA rats do not. These animals also show a range of differences on tasks which measure sensitivity to ethanol, but the relationship between ethanol intake and sensitivity to this drug in these rats is not clear. This study examined sensitivity to ethanol in AA and ANA rats as determined by ethanol's rate depressant effects on schedule controlled (Fixed-Ratio (FR) 32) responding reinforced by water deliveries. Non-drug rates of responding were similar for both lines across baseline, sham injection and vehicle conditions. Ethanol produced dose-dependent decreases in responding in both the AA and ANA rats. Dose-response curves indicated that AA rats were slightly more sensitive to the acute effects of ethanol than were ANA rats, with ED50 values of 0.52 and 0.69 g/kg for AA and ANA rats, respectively. Overall, however, the effects of ethanol on rats of responding were similar across the two lines of rats. While it is possible that constraints on behavior imposed by FR schedules could be masking underlying differences in tissue sensitivity between these animals, the results indicate that ethanol intake under preference or reinforcement conditions does not appear to be highly controlled by initial sensitivity to ethanol as measured by effects on operant performance.

Alcohol Drinking↗

PubMed1990

The behavioral pharmacology of alcohol and other drugs. Emerging issues.

Alcohol and other drugs are compared with respect to their abuse liability and dependence potential. Drug-reinforced behavior is defined, and factors related to the establishment of this behavior that have received increasing experimental attention in recent years are reviewed. Acquisition techniques, schedule of access, route of self-administration, and organism factors, such as species, gender, and genetic background, are discussed. Other areas of emerging interest are the effect of feeding regimens, alternative reinforcers, and social conditions on drug-reinforced behavior. Also, biochemical factors such as neurochemical alterations, hormonal changes, and alcohol and other drug combinations, are considered. Finally, dependence potential is considered in terms of observational changes and performance alterations that seem to be sensitive indicators of the protracted aspects of drug withdrawal. The relationship between drug-seeking behavior and withdrawal is examined.

Alcohol Drinking↗