Biomedical subjects

R A Meisch

Publications and source records attributed to R A Meisch.

At least 19 recordsLinked to original sources

PubMed2002

Orally delivered alprazolam, diazepam, and triazolam as reinforcers in rhesus monkeys.

RATIONALE: Benzodiazepines are among the most frequently prescribed drugs and are usually taken by mouth. However, there have been few studies of oral self-administration of these drugs, and the results of IV self-administration studies indicate that benzodiazepines are modest reinforcers. OBJECTIVES: To determine if orally delivered alprazolam, diazepam, and triazolam could serve as reinforcers for rhesus monkeys, and to determine some of the conditions under which benzodiazepine reinforced behavior occurs. METHODS: Diazepam or midazolam was initially established as a reinforcer by a fading procedure whereby increasing concentrations were added to a 1 or 2% ethanol solution, and subsequently the ethanol concentration was decreased in steps to zero. Diazepam- and midazolam-reinforced responding persisted in the absence of ethanol. Triazolam and alprazolam served as reinforcers when substituted for diazepam or midazolam. RESULTS: Alprazolam, diazepam, and triazolam served as effective reinforcers across a wide range of concentrations and under fixed-ratio sizes of 16 and 32. Rates of responding were usually far higher than that for the concurrently available vehicle, water. Drug intake (mg drug/kg body weight) generally increased with increases in drug concentration. When large drug amounts were consumed, signs of intoxication were observed. CONCLUSIONS: In contrast to reports of low response rates and weakly maintained behavior, the present results show that the three benzodiazepines can serve as effective reinforcers.

Administration, Oral↗

PubMed2001

Reinforcement by orally delivered methadone, cocaine, and methadone-cocaine combinations in rhesus monkeys: are the combinations better reinforcers?

RATIONALE: Polydrug abuse is a problem that has been infrequently examined. In the present study, drug self-administration procedures were used to investigate the reinforcing effects of drug combinations. OBJECTIVES: To determine the absolute and relative response rates maintained by orally delivered methadone, cocaine, and their combinations under sequential and concurrent access. Choice between drug combinations containing different concentrations of cocaine was also determined. METHODS: Oral intake of methadone, cocaine, and their combinations was studied with rhesus monkeys during daily 3-h sessions. Lip contact (the operant response) was reinforced by delivery of liquid contingent upon completion of a fixed-ratio schedule. In one series, the drugs and drug combinations were studied sequentially with the water vehicle concurrently available. In the next series, the drugs and drug combinations were concurrently available. In the third series, pairs of drug combinations containing different concentrations of cocaine were also concurrently available. RESULTS: Methadone, cocaine and their combinations functioned as reinforcers. Under sequential access, response rates for the drug combinations and the component drugs were often similar. However, under concurrent access, response rates for the drug combinations were greater than response rates for the component drugs at the highest FR size for each condition. Also, drug combinations containing higher cocaine concentrations were preferred to combinations containing lower cocaine concentrations. CONCLUSIONS: Combinations of methadone and cocaine have relatively greater reinforcing effects than the component drugs, and these greater reinforcing effects are better detected with concurrent measures than with sequential measures.

Administration, Oral↗

PubMed2001

Oral drug self-administration: an overview of laboratory animal studies.

Many abused drugs can be established as orally delivered reinforcers for rhesus monkeys and other animals. Benzodiazepines, barbiturates, opioids, psychomotor stimulants, dissociative anesthetics, and ethanol can come to serve as reinforcers when taken by mouth. The principal problems in establishing drugs as reinforcers by the oral route of administration are (1) aversive taste, (2) delay in onset of central nervous system effects, and (3) consumption of low volumes of drug solution. Strategies have been devised to successfully overcome these problems, and orally delivered drugs can be established as effective reinforcers. Reinforcing actions are demonstrated by consumption of greater volumes of drug solution than volumes of the water vehicle, and supporting evidence for reinforcing effects consists of the maintenance of behavior under intermittent schedules of reinforcement and the generation of orderly dose-response functions. This article presents an overview of studies of behavior reinforced by oral drug reinforcement. Factors that control oral drug intake include dose, schedule of reinforcement, food restriction, and alternative reinforcers. Many drugs, administered by the experimenter, can alter oral drug reinforcement. Relative reinforcing effects can be assessed by choice procedures and by persistence of behavior across increases in schedule size. In general, reinforcing effects increase directly with dose. Rhesus monkeys prefer combinations of reinforcing drugs to the component drugs. The taste of drug solutions may act as a conditioned reinforcer and a discriminative stimulus. Consequences of drug intake include tolerance and physiological dependence. Findings with orally self-administered drugs are similar to many findings with other positive reinforcers, including intravenously self-administered drugs.

Administration, Oral↗

PubMed2001

Human methadone self-administration: effects of diazepam pretreatment.

The effect of diazepam on methadone self-administration was examined. Five methadone-maintained patients with a history of benzodiazepine abuse were recruited. Patients were stabilized on 80 mg of methadone per day. After stabilization patients participated in methadone self-administration sessions. During each session, 128 presses (fixed ratio 128) of 1 button delivered 10 ml of 0.054 mg/ml methadone solution. The same number of button presses on a 2nd button delivered 10 ml of vehicle. Forty-five min prior to the self-administration session, 0 (placebo), 5, 10, or 20 mg per 70 kg body weight diazepam was administered. Ratings of drug liking, goodness, strength, and high were collected 5, 30, 60, 90, and 150 min after the end of the self-administration session. Diazepam pretreatment significantly decreased the amount of methadone consumed. The 10- and 20-mg diazepam doses significantly increased reports of good, like, strong, and high.

Adult↗

PubMed2000

Reinforcing effects of contingently administered subcutaneous injections of etonitazene in rats.

RATIONALE: Response-contingent injections of opioids have been shown to control behavior in various species. OBJECTIVE: To determine whether s.c. injections of etonitazene (ETZ) could maintain behavior in rats when administered under a single fixed-interval schedule. METHODS: Rats were trained to lever press for eight 45-mg food pellets under a single fixed-interval (FI) 10-min schedule of reinforcement: following passage of the 10-min interval, each lever press resulted in a pellet delivery until eight pellets were obtained. Delivery of the reinforcer was signaled by a change in visual stimulus conditions. Once stable responding for the food pellets under the FI 10-min schedule was established, a s.c. injection of 3.2 micrograms/kg ETZ was administered to the rat by the investigator following schedule completion and delivery of the food pellets. After receiving the drug injection, rats were returned to the experimental chamber for 30 min and exposed to the same stimulus conditions that accompanied food reinforcement. Across sessions, the number of food pellets was decreased until rats were responding solely for the drug. RESULTS: Responding for the s.c. administered drug stabilized and persisted across sessions. When saline vehicle injections were substituted for the drug injections, responses diminished across sessions to levels below that of the drug baseline. Subsequent alternating blocks of ETZ and vehicle injections produced respective increases and decreases in responding. CONCLUSION: This study demonstrates that response-contingent s.c. injections of a drug can control behavior in rats, systematically replicating a previous experiment that used the i.p. route. Since all pertinent operant behavior is emitted prior to the administration of drug, this procedure can be used for testing the reinforcing effects of a drug without interference from any direct (rate-altering) drug effects. The present findings also extend the conditions under which drugs of abuse may reinforce behavior.

Animals↗

PubMed2000

Relative persistence of behavior: a fundamental measure of relative reinforcing effects.

Relative persistence of behavior is measured in terms of rates of behavior at a higher schedule value divided by rates of behavior at a lower schedule value and then multiplied by 100 to express the result as a percentage. Relative persistence of behavior is a direct function of reinforcer size over a broad range of values. In 1 study, food was the reinforcer; however, in most studies of persistence, drug reinforcers were used, and the drugs were taken orally or intravenously. A variety of reinforcing drugs were studied: barbiturates, opioids, psychomotor stimulants, a dissociative anesthetic, and alcohol. Both ratio and interval schedules were used to study relative persistence of behavior in human participants, male and female rhesus monkeys (Macaca mulatta), and rats. Thus, studies of persistence are based on results of an extensive set of conditions. The results support the proposition that relative persistence of behavior is a fundamental measure of relative reinforcing effects.

Animals↗

PubMed1999

Orally delivered methadone as a reinforcer: Effects of the opioid antagonist naloxone.

The effects of the opioid antagonist naloxone were studied with three monkeys under a mutually exclusive fixed-interval 15 s (FI 15 s) schedule of reinforcement. Under this schedule, at the end of each interval, the monkey could obtain one liquid delivery from either the spout that delivered methadone (0.8 mg/ml) or the spout that delivered vehicle (deionized water). Naloxone doses from 0.0125 to 0.2 mg/kg (IM daily 10 min prior to the session) were studied in an ascending then descending order. In the ascending series, low naloxone doses produced increases of methadone deliveries in the first hour of the session for three monkeys and increases over the entire 3-h session for two of the three monkeys. At higher doses naloxone decreased methadone deliveries in all three monkeys. Naloxone's effects were usually greater during the descending dose series than during the ascending series. These findings suggest that a history of naloxone injections is one determinant of response to the drug. Vehicle maintained responding was generally low and not changed by naloxone in a systematic way. The time course of methadone deliveries showed that naloxone's effects were greatest in the first hour of the session and were a direct function of dose. These experiments demonstrate that oral methadone reinforced behavior is sensitive to naloxone pretreatment and that the effects of naloxone are a direct function of dose.

Administration, Oral↗

PubMed1999

Cocaine self-administration under conditions of restricted and unrestricted food access.

Four rhesus monkeys (Macaca mulatta), maintained at reduced body weight and restricted food availability, had access to a 0.8-mg/ml cocaine solution and vehicle under a concurrent fixed-ratio (FR) 8 schedule. Over days, the cocaine concentration was reduced (0.57, 0.4, 0.2, 0.1, 0.05, 0.025) and then returned, gradually over days, to 0.8 mg/ml. The ratio value was then varied (to 16, 32, 64, 128, and 8). Food access was unrestricted, and the ratio and the concentration manipulations were then repeated. During food restriction cocaine served as a reinforcer for all monkeys, whereas during free feeding cocaine functioned as a reinforcer for 3 of 4 monkeys; with these monkeys, the dose-response curve obtained under free feeding was shifted to the right of that obtained under food restriction. There were no differences in FR response curves obtained during food restriction and unrestricted feeding. These data suggest that food restriction increases cocaine's reinforcing effects and that the higher the cocaine dose, the greater are the reinforcing effects. A demand curve analysis was completed, and data are discussed in terms of microeconomic principles.

Algorithms↗

PubMed1998

Lever-press responding maintained by contingent intraperitoneal administration of etonitazene in Long Evans hooded rats.

Lever pressing maintained by intraperitoneal (i.p.) injections of etonitazene was established in five Long Evans hooded rats. Each training session consisted of an 8-min fixed interval (FI) during which lever pressing was maintained by food pellets delivered at the end of the interval. Food delivery was accompanied by illumination of stimulus lights in the chamber. Every 20th response during the 8 min interval also produced a brief illumination of the stimulus lights (FI 8 min (FR 20:S)). Administration of etonitazene was then introduced. Immediately following food delivery, the rat received an i.p. drug injection and was returned to the operant chamber for 30 min. During this confinement, the stimulus lights remained illuminated. This procedure resembles conditioned place preference in that an environment is paired with the effects of an investigator-delivered drug. When food pellet delivery subsequently was discontinued, responding persisted when followed by drug, but not saline, administration. Alternating blocks of sessions with administration of etonitazene (6.0-9.0 microg/kg) or saline produced corresponding increases or decreases in responding. These results indicate that etonitazene can function as a reinforcer when administered to rats by the i.p. route, and thus extend the range of conditions under which drug reinforcement can be investigated.

Animals↗

PubMed1998

Reinforcing effects of a combination of ethanol and methadone relative to each drug alone.

Studies report a high incidence of alcohol abuse in methadone maintenance patients. There is, however, little data on the reinforcing effects of combinations of ethanol and methadone. In the present study, oral self-administration of a combination of 1% (w/v) ethanol and 0.2 mg/ml methadone was compared to each drug alone in three rhesus monkeys in which methadone alone was not a reinforcer. In Experiment 1, ethanol and the combination, but not methadone alone, served as reinforcers. In Experiment 2, there was no preference for ethanol or the combination at fixed ratio (FR) 8 or 16. When the FR size was doubled (FR 16 or 32), all three animals preferred the combination to 1% ethanol. Experiment 3 further examined the effect of work requirement on preference for ethanol or the combination by varying FR values [1, 2, 4, 8, 16, or 32]. At lower FRs, ethanol was significantly preferred to the combination. As FR was increased, there was a significant reduction in preference for ethanol over the combination. The results show that an ethanol + methadone combination will be orally self-administered by monkeys and suggest that work requirement differentially modifies preference for the combination and ethanol alone.

Animals↗

PubMed1998

Ratio size and cocaine concentration effects on oral cocaine-reinforced behavior.

Monkeys were given a choice between cocaine solutions and water under concurrent fixed-ratio reinforcement schedules. The operant response was spout contact. Six rhesus monkeys served as subjects. The cocaine concentration was varied from 0.0125 to 0.8 mg/ml, and the fixed-ratio value was varied from 8 to 128. Cocaine maintained higher response rates than did water over a wide range of conditions. Response rate and number of cocaine deliveries per session were inverted U-shaped functions of concentration. These functions were shifted to the right as the fixed ratio was increased. The number of cocaine deliveries was more persistent as fixed-ratio value was increased when the unit dose was larger rather than smaller. Cocaine consumption was analyzed as a function of unit price (fixed-ratio value divided by cocaine concentration), and unit price accounted for between 77% and 92% of the variance in cocaine consumption for individual monkeys. The current data support the claim that a drug's reinforcing effects increase directly with dose and underscore the need to gather parametric data when examining the effects of experimental manipulations on a drug-reinforced baseline.

Animals↗

PubMed1998

Matching under nonindependent variable-ratio schedules of drug reinforcement.

Response-contingent deliveries of oral pentobarbital maintained responding of 3 rhesus monkeys during daily 3-hr sessions. Deliveries of pentobarbital were arranged under nonindependent concurrent variable-ratio variable-ratio schedules. Responses to either schedule counted toward completion of both variable-ratio schedule requirements. This schedule is similar in some respects to conventional concurrent variable-interval variable-interval schedules, in which passage of time counts toward completion of the interval value on both schedules. Restricted nonindependent concurrent variable-ratio variable-ratio schedules were also studied. On that schedule, when a drug delivery was assigned to one spout, it had to be collected before responses on the opposite spout again counted toward completion of the schedule requirements. Relative reinforcer magnitude was varied by changing the drug concentration on one schedule while keeping the drug concentration constant on the other variable-ratio schedule. Under both types of concurrent variable-ratio schedules, the relative rate of responding corresponded to the relative drug intake. Unlike earlier studies of concurrent variable-interval variable-interval intravenous cocaine reinforcement, preference was proportionate to concentration, and exclusive preferences did not develop. The relationship between relative rate of responding and relative drug intake was well described by the generalized matching law.

Animals↗

PubMed1998

Effects of acute and chronic doses of naltrexone on ethanol self-administration in rhesus monkeys.

The effects of acute and chronic administration of intramuscular naltrexone (0.1, 0.3, 1.0, and 3.0 mg/kg) on oral ethanol (8%) self-administration were examined. Naltrexone (1.0 mg/kg) effects on the self-administration of ethanol concentrations ranging from 0.5 to 8% (w/v) were also investigated. Rhesus monkeys with substantial histories of drug and ethanol drinking served as subjects. During daily 3-hr sessions, monkeys were presented with ethanol solutions, concurrently available with water, under fixed-ratio reinforcement schedules. Naltrexone decreased the consumption of ethanol (g/kg). Biphasic temporal effects were observed within sessions. Naltrexone dose-dependently decreased the number of ethanol deliveries by a maximum of 56% (n = 18; 3 monkeys x 6 sessions) during the first hour of the session. During the second and third hours, however, ethanol intake recovered such that maximum decreases over the 3-hr session were approximately 27% (n = 18), and the mean decrease was 16% (n = 18). Often marked tolerance was observed, such that the effects of acute naltrexone administration were greater than effects after chronic administration. The self-administration of low ethanol concentrations (< or =2% w/v) was increased in several monkeys, by up to 340%, after naltrexone pretreatment. In summary, the effects of naltrexone on ethanol self-administration, in drug- and alcohol-experienced rhesus monkeys, are not characterized by unitary decreases in measures of ethanol self-administration. Rather, differential naltrexone effects were a function of experimental parameters, including the dose and number of naltrexone injections, the ethanol concentration, and the time point of measurement.

Alcohol Drinking↗

PubMed1997

Alprazolam-reinforced medication use in outpatients with anxiety.

The reinforcing effects of alprazolam were investigated in 14 patients who had generalized anxiety or panic disorder, but were not current users/abusers of other psychoactive substances. Using a double-blind outpatient choice procedure, color-coded alprazolam (0.5 mg) and placebo capsules were provided to patients for use 'as needed' in the treatment of anxiety symptoms. Comparisons of alprazolam and placebo during a 2 week sampling period in which placebo and alprazolam were available sequentially revealed no significant differences on measures of medication usage or anxiety levels, although alprazolam did increase subjective ratings of drug effects side effects. During a 4 week choice period, alprazolam was strongly preferred over placebo in 11 out of 14 patients indicating that alprazolam functioned as a reinforcer. Medication usage ranged from zero to 4.0 mg alprazolam in a day. Variations in daily medication-use were positively correlated with anxiety level fluctuations for a majority of patients. For a majority of patients, the results indicate that alprazolam functioned as a reinforcer without accompanying signs of abuse or addiction.

Adult↗

PubMed1997

Food-deprivation increases cocaine-induced conditioned place preference and locomotor activity in rats.

Food-deprivation increases the reinforcing efficacy of cocaine and other drugs within self-administration experiments. In this study, the effects of food-deprivation on cocaine-induced conditioned place preference were investigated. Male Sprague-Dawley rats were assigned to one of two feeding conditions: satiated (with ad libitum food) or deprived (maintained at 80% of free-feeding body weights). During conditioning trials, on alternate days, rats received IP injections of cocaine (0.0, 2.5, 5.0, or 10.0 mg/kg; n = 12 per dose group) and were confined for 30 min in one of two distinct environments. On intervening days, the same rats were injected with saline and confined for 30 min in the opposite environment. After four cocaine and four saline trails, a 15-min choice test (with no injections) was given. During this time, the rats were able to move freely through a passageway between both environments. Relative to the food-satiated rats, the food-deprived rats showed a greater conditioned preference for the cocaine-paired environment during the choice test, greater cocaine-induced locomotor activity during conditioning trials, and a greater degree of sensitization to the activating effects of cocaine across conditioning trials. This study extends the general findings of food deprivation-induced increases in the reinforcing efficacy of cocaine to include the conditioned place preference paradigm.

Animals↗

PubMed1997

Human ethanol self-administration. I: The interaction between response requirement and ethanol dose.

The effects of work requirement on human ethanol self-administration were systematically examined. Healthy volunteers with a history of moderate alcohol consumption (12 to 16 drinks per week) were recruited as subjects. Four subjects self-administered 4, 8 or 16% w/v ethanol solution contingent upon completion of a fixed-ratio (FR) response requirement. The ratio requirements were FR 32, FR 64 and FR 128 responses. Ethanol consumption at lower doses decreased with increases in FR. Ethanol consumption at the high dose was greatest across all ratio requirements and was unchanged by increases in the ratio requirement, indicating greater relative reinforcing effects of the high dose of ethanol. Ethanol consumption was sensitive to unit price with 53-82% of the variance explained by the unit price analysis.

Adult↗

PubMed1996

Orally delivered methadone as a reinforcer in rhesus monkeys.

Methadone usually is taken orally for drug abuse treatment in humans but oral methadone self-administration by laboratory animals has not been investigated extensively. The present study examines acquisition and maintenance of oral methadone maintained responding in four adult male rhesus monkeys. Drug solution was available from one liquid delivery system and water from a second system during daily 3-h sessions. Locations of liquids were reversed each session, and liquid (0.65 ml per delivery) was delivered according to a fixed-ratio reinforcement schedule. Initially a test for the reinforcing effects of 0.00625-0.4 mg/ml methadone solutions was carried out but a consistent preference for drug over water was not seen. To establish methadone as a reinforcer, a fading procedure was used in which responding was first maintained by solutions of methadone (0.00625-0.4 mg/ml) combined with ethanol (0.0325-2.0% w/v). Subsequently, the concentration of the ethanol in the combination was gradually reduced to zero. Methadone-maintained responding (0.4 mg/ml) persisted when ethanol was no longer present. To confirm that the drug was serving as a reinforcer, the dose was varied: (a) by changing the volume delivered while the concentration was held constant and (b) by changing the concentration of the methadone while the volume per delivery was held constant. Over a wide range of doses, deliveries of methadone solution usually exceeded deliveries of concurrently available water. Orderly relationships were observed among methadone dose, response rate, and drug intake. The study of oral self-administration of opioid drugs by nonhuman primates may be a useful strategy for the development and evaluation of new drug substitution or replacement therapies.

Administration, Oral↗

PubMed1996

Orally delivered methadone as a reinforcer for rhesus monkeys: the relationship between drug concentration and choice.

The relative reinforcing effects of orally delivered methadone were studied in five male rhesus monkeys. Drug deliveries were available under either a fixed-ratio (FR) or a fixed-interval (FI) schedule. Three concentrations of methadone, low (0.05 mg/ml), intermediate (0.2 mg/ml), and high (0.8 mg/ml) were delivered in 0.65 ml volumes. In the first experiment, monkeys were presented with a choice paradigm. Under independent FR schedules responding led to a delivery of either a methadone solution or the water vehicle. For each concentration, deliveries of a methadone solution maintained higher response rates than did deliveries of water. In the second experiment, methadone concentrations were tested in pairs in the following sequence: high vs. low, high vs. intermediate, intermediate vs. low, high vs. intermediate (retest), and high vs. low (retest). The retest of the last two pairs was designed to counterbalance the test sequence, so that order effects, if they existed, could be detected. Regardless of the schedule, the higher concentration of the methadone pair maintained a greater response rate than did the lower concentration. The present results are consistent with the generalization based on other studies that over a broad range of concentrations and across pharmacological classes, reinforcement schedules, and routes of administration, reinforcing effects increase with increases in drug concentration.

Animals↗