PubMed Health⌕ Search

Biomedical subjects

W L Woolverton

Publications and source records attributed to W L Woolverton.

At least 37 records · Page 2Linked to original sources
PubMed1999

Discriminative stimulus effects of ethyl-beta-carboline-3-carboxylate at two training doses in rats.

RATIONALE AND OBJECTIVES: The role of benzodiazepine (BZ) receptor mechanisms in modulating the stimulus effects of the BZ partial inverse agonist ethyl-beta-carboline-3-carboxylate (beta-CCE) are not well understood. The purpose of the present experiments was to assess the role of BZ and non-BZ receptor stimulation in the discriminative stimulus effects of beta-CCE in rats. METHODS: Adult male rats were trained to discriminate either a relatively high dose (10 mg/kg, n = 8) or a relatively low dose (5.0 mg/kg, n = 7) of beta-CCE from saline under a fixed-ratio 10 schedule of food presentation. RESULTS: Under the high-dose training condition, beta-CCE engendered an increase in responding on the drug-paired lever up to 100% drug-lever responding, with no decrease in response rate. Diazepam, pentobarbital, flumazenil, (+)-amphetamine, and morphine did not share stimulus effects with 10 mg/kg beta-CCE up to doses that suppressed rate of responding. The BZ full inverse agonist dimethoxy-4-ethyl-beta-carboline-3-carboxylate also did not engender > or = 80% beta-CCE-lever responding up to doses that suppressed response rate and produced seizures in some animals. The BZ partial inverse agonists Ro 15-4513 and sarmazenil fully reproduced the stimulus effects of beta-CCE. Flumazenil antagonized the effects of beta-CCE with an in vivo apparent pA2 value of 6.1 (slope = -0.86). Under the low-dose condition, beta-CCE engendered an increase in drug-lever responding, with no changes in response rate. In contrast to the high-dose condition, diazepam, pentobarbital, and (+)-amphetamine engendered high levels of beta-CCE-lever responding (up to 77, 96, and 75%, respectively), whereas flumazenil and morphine did not engender full beta-CCE-lever responding. CONCLUSIONS: These results indicated that the stimulus effects of the high dose of beta-CCE appeared consistent with mediation by the drug's partial inverse agonist effects at BZ receptors. The discriminative stimulus effects of beta-CCE at the lower training dose, however, appeared to be relatively non-specific.

Animals↗
PubMed1998

Dopamine D1 and D2 receptor selectivities of phenyl-benzazepines in rhesus monkey striata.

Several phenyl-benzazepine compounds, putatively selective dopamine D1 receptor agonists, have been used to study the effects of dopamine D1 receptor stimulation in rodents and nonhuman primates. However, the dopamine receptor selectivities of these compounds have not been established in nonhuman primates. Accordingly, the relative selectivities of six phenyl-benzazepines for dopamine D1-like and D2-like receptors were assessed in rhesus monkey and, for comparison, rat striata. The compounds tested had higher affinity for D1 than D2 receptors in both species; however, their selectivity varied by up to three orders of magnitude. GTP (100 microM) reduced agonist binding at the high-affinity state of the dopamine D1 receptor, but the magnitude of the effect of GTP did not reliably predict a compound's efficacy. Furthermore, a history of cocaine self-administration did not appear to influence dopamine receptor binding characteristics in the rhesus monkeys in this study. The present results will aid the comparison of dopamine receptor binding characteristics and behavioral effects of D1 dopamine receptor agonists.

Animals↗
PubMed1998

Choice maintained by cocaine or food in monkeys: effects of varying probability of reinforcement.

Several theoretical models of choice, including matching, maximizing and probability matching, have evolved from the experimental analysis of behavior. However, these models are based largely on results of studies involving non-drug reinforcers. The extent to which the choice to self-administer a drug of abuse conforms to these models is largely unknown. The present study was designed to examine the effects of varying probability of reinforcement of two options on choice by rhesus monkeys maintained under a discrete-trials choice procedure. One group of monkeys (n=5) was prepared with chronic indwelling venous catheters and responding was maintained by i.v. injections of cocaine (0.05 or 0.2 mg/kg per injection). In a second group, behavioral conditions were identical, except that responding was maintained by the delivery of food pellets. Two choice options were available to each group. Each option was maintained by the identical dose of cocaine or amount of food, but with varying probabilities of delivery. The percentage of trials on which monkeys chose option 1 increased with its probability of reinforcement for cocaine (0.05 or 0.2 mg/kg per injection) and this effect did not change with dose of cocaine. When probabilities of reinforcement for option 1/option 2 were 0.75/0.25, choice was exclusive for the higher probability option. Results were identical when behavior was maintained by food. The present experiment supports the conclusion that exclusive choice of the alternative with the higher probability of reinforcement can be extended to cocaine as a reinforcer. The present results also extend the known conditions under which drug-maintained responding is similar to food-maintained responding to situations involving options with different probabilities of reinforcement, i.e., probability choice. Probability matching was not observed, arguing that this model does not predict drug or food choice.

Animals↗
PubMed1998

Discriminative stimulus effects of benzodiazepine agonists and partial agonists in pentobarbital-trained rhesus monkeys.

The present study examined the relationship between the intrinsic efficacy of benzodiazepines and their ability to reproduce the discriminative stimulus effects of pentobarbital. Rhesus monkeys (n=5) were trained to discriminate pentobarbital (10mg/kg) from saline using a discrete trials shock avoidance procedure (fixed-ratio 5). Drug-appropriate responding and response rate were assessed after intragastric administration of pentobarbital, the high efficacy benzodiazepines triazolam and clonazepam, and the low efficacy benzodiazepines imidazenil and bretazenil. Pentobarbital increased drug-appropriate responding to 100% and decreased the response rate. Triazolam and clonazepam occasioned 80% or greater drug-appropriate responding in four out of four monkeys, and decreased response rate in three out of four monkeys. The antagonist flumazenil decreased drug-appropriate responding and increased response rate after triazolam and clonazepam, consistent with antagonism of the discriminative stimulus and the rate-altering effects of these ligands. Imidazenil occasioned 80% or greater drug-appropriate responding in three out of four monkeys and suppressed the response rate in two out of four monkeys, whereas bretazenil occasioned 80% or greater drug-appropriate responding in two out of four monkeys and decreased the response rate slightly. Bretazenil, when co-administered with a dose of triazolam that produced 90-100% drug-appropriate responding, decreased responding to 0-60% but did not alter the rate-suppressing effects of this ligand. The rank order of potency (based on pmol/kg ED, values) was: triazolam > clonazepam > or = imidazenil > bretazenil. These results demonstrate differences in the pentobarbital-like discriminative stimulus and response rate-decreasing effects among benzodiazepine agonists. Specifically, full agonists engendered pentobarbital-like responding in all subjects with decreased response rates in most subjects, whereas partial agonists engendered pentobarbital-like responding and decreased response rates in subsets of subjects.

Animals↗
PubMed1998

Self-administration of cocaine-heroin combinations by rhesus monkeys: antagonism by naltrexone.

Low, nonreinforcing doses of heroin have been shown to shift the dose-response function of cocaine leftward in rhesus monkeys trained under a progressive-ratio schedule of i.v. drug injection. Our study sought to determine 1) whether a reciprocal enhancement of heroin self-administration would be observed when heroin was combined with low, nonreinforcing doses of cocaine, and 2) whether self-administration of cocaine-heroin combinations could be antagonized by the opioid antagonist naltrexone. Rhesus monkeys (n = 4) were prepared with i.v. catheters and trained to self-administer cocaine under a progressive-ratio schedule. The initial response requirement of this schedule was fixed-ratio 120, which doubled across the session to a maximum of 1920. Injections were separated by a 30-min time out. Cocaine dose-response functions (6.4-100 micrograms/kg/injection) for injections/session and breakpoints were monophasic, i.e., increased with dose until responding reached a maximum. Heroin dose-response functions (1.6-25 micrograms/kg/ injection) either increased to a peak and then decreased or reached an asymptote. When nonreinforcing doses of cocaine (3.2-25 micrograms/kg/injection) were combined with heroin, the heroin dose-response function was shifted to the left, without change in maximum injections/session. Pressession treatments with naltrexone (3.2-1600 micrograms/kg, i.m., 10-min presession) antagonized self-administration of heroin and heroin + cocaine combinations in a dose-dependent fashion. However, naltrexone treatment had no effect on cocaine self-administration. Antagonism by naltrexone of self-administration of heroin and heroin + cocaine was surmounted by increasing the dose of heroin either alone or in the heroin + cocaine combination. In vivo apparent pA2 and pKB analyses of these data revealed values of approximately 8.0, consistent with a role for mu opioid receptors in the self-administration of heroin and cocaine-heroin (i.e., "speedball") combinations.

Animals↗
PubMed1997

Effects of some phenylethylamines in rhesus monkeys trained to discriminate (+)-amphetamine from saline.

Although the structure-activity relationships (SAR) for the discriminative stimulus (DS) effects of phenylethylamines (PEAs) have been extensively evaluated in rats, only isolated components of the SAR have been studied in other species. Since DS effects in animals predict subjective effects in humans, it is important to establish cross-species generality of substitution results. In the present experiment, rhesus monkeys (n = 4) were trained to discriminate (+)-amphetamine (0.56 or 1.0 mg/kg, i.g.) from saline in a two-lever drug discrimination paradigm. Responding was maintained under a fixed-ratio discrete-trials schedule of shock avoidance. (+)-Amphetamine, and the N-substituted phenylethylamines (+)-methylamphetamine, and (+)-ethylamphetamine all engendered dose-dependent, full substitution for (+)-amphetamine and had no effect on rate of responding. In contrast, the ring-substituted compounds (+/-)-4-methoxyamphetamine (PMA), (+/-)-2,5-dimethoxy-4-methylamphetamine (DMA), (+/-)-2,5-dimethoxy-4-methylamphetamine (DOM), and (+/-)-3,4, 5-trimethoxyamphetamine (TMA) occasioned little or no (+)-amphetamine-appropriate response up to doses of 3.0 or 10 mg/kg. Therefore, it appears that monkeys respond to N-substituted amphetamines in the same way as rats, at least qualitatively. Considering that ring-substituted compounds have been found to partially substitute for (+)-amphetamine in rats, it is possible that the (+)-amphetamine DS may be pharmacologically more selective in monkeys. However, methodological differences may also explain differences between experiments.

Amphetamine↗
PubMed1997

Choice between cocaine and food in a discrete-trials procedure in monkeys: a unit price analysis.

In behavioral economics, the unit price (UP) model of drug consumption defines UP as the ratio of the response requirement to the dose of drug. This model makes two predictions: increasing UP will decrease consumption, and consumption at a given UP will be constant regardless of the response requirement and dose that make up the UP. The present experiment was designed to test the UP model in rhesus monkeys allowed to choose between an IV injection of cocaine and food in a discrete-trials choice procedure. Both response requirement/injection and dose of cocaine were varied in such a way as to yield UPs from 40 to 10,000 responses per mg/kg. The response requirement for food was always 30 and there was a 30-min time-out between trials to allow the direct effects of cocaine on responding to dissipate. Consistent with the UP model, cocaine consumption decreased as UP increased. However, at a given UP, cocaine consumption was usually higher at the higher dose. Thus, under the conditions of the present experiment an important component of the UP model of drug consumption was not supported. It may be that UP is not a reliable predictor of consumption under conditions in which the direct effects of a drug on responding are minimized.

Animals↗
PubMed1997

Self-administration of cocaine and heroin combinations by rhesus monkeys responding under a progressive-ratio schedule.

The present study examined the reinforcing effects of cocaine and heroin, alone and combined, in rhesus monkeys (n = 4) responding under a progressive-ratio (PR) schedule. The PR schedule consisted of five components, each made up of four trials (i.e., 20 trials total), with each trial in a component having the same response requirement. The initial response requirement was fixed-ratio (FR) 120, which doubled across components to a maximum of FR1920. A trial ended with an injection or the expiration of a 15-min limited hold and the inter-trial interval was 30 min. Cocaine dose-response functions (13-400 micrograms/kg per injection) for injections/ session were monophasic, i.e., increased with dose until responding reached an asymptote or a peak. Heroin dose-response functions (1.6-100 micrograms/kg per injection) for injections/session were biphasic functions. i.e., increased to a peak and then decreased, whereas heroin dose-response functions for response rate were monophasic and reached an asymptote. When cocaine (1.6-200 micrograms/kg per injection) was combined with heroin (0.4-6.4 micrograms/kg per injection), low doses of cocaine (3.2-25 micrograms/kg per injection) and heroin (0.4-1.6 micrograms/kg per injection) that did not maintain behavior when tested alone did so when tested in combination. Combination with heroin resulted in a leftward shift in the cocaine dose-response functions, indicating that heroin increased the potency of cocaine as a reinforcer. This heroin-induced increase in cocaine's reinforcing potency may be a contributing factor to abuse of cocaine and heroin combinations (i.e., "speedballs") in humans. However, maximum injections/session for cocaine combined with heroin were not different from cocaine alone, suggesting that the reinforcing efficacy of combinations of cocaine and heroin were not higher than that of cocaine alone.

Animals↗
PubMed1997

Further analysis of choice between cocaine and food using the unit price model of behavioral economics.

Behavioral economics defines unit price (UP) as the ratio of the response requirement to magnitude of reinforcer. When applied to drug self-administration, the UP model defines UP as the ratio of the response requirement to the unit dose of drug. This model makes two predictions about drug self-administration: increasing UP decreases consumption and consumption at a given UP will be constant regardless of the response requirement and dose that make up the UP. In previous experiments conducted in rhesus monkeys allowed to choose between an i.v. injection of cocaine and food, the UP model has failed to adequately predict drug consumption in that consumption varied (increased with dose) at a given UP. However, previous experiments have allowed a fixed number of choice trials/day, thereby imposing a procedural ceiling on consumption that may have influenced conformity to the UP model. In the present experiment, the number of choice trials available was varied in such a way that constant drug consumption was possible over the range of UPs tested. The response requirement for cocaine was varied between 15 and 1200 lever presses/injection and the dose of cocaine was varied between 0.05 and 0.2 mg/kg/inj, yielding UPs from 300 to 5600 responses/mg/kg. The response requirement for food was always 30. As predicted by the UP model, cocaine consumption decreased as UP increased. Moreover, in contrast to previous experiments, consumption did not vary significantly across the response requirement/dose combinations that made up a UP. A detailed analysis suggested that a decrease in magnitude of the alternative reinforcer (one rather than three food pellets), rather than the increase in trials, was responsible for the improved conformity to the UP model in the present experiment relative to previous experiments. Taken together with previous experiments, the present experiment suggests that conformity to the UP model of drug consumption in a choice situation is dependent upon the magnitude of alternative reinforcers that are available. Consumption was best predicted by the UP model when the magnitude of the alternative reinforcer was small.

Animals↗
PubMed1997

Discriminative stimulus effects of zolpidem in pentobarbital-trained subjects: I. Comparison with triazolam in rhesus monkeys and rats.

The present study compared the discriminative stimulus effects of the imidazopyridine, zolpidem, with a triazolobenzodiazepine, triazolam, in pentobarbital-trained rhesus monkeys and rats. Rhesus monkeys (n = 4), trained to discriminate pentobarbital (10 mg/kg intragastric [i.g.]) from saline under a FR 1 discrete-trials shock avoidance procedure, were given zolpidem (0.10-30 mg/kg i.g.) or triazolam (0.01-0.3 mg/kg i.g.). Both zolpidem and triazolam produced dose-dependent increases in pentobarbital-appropriate responding that reached 80% or greater at the highest doses tested. Zolpidem, but not triazolam, increased latency to respond in a dose-dependent manner. Sprague-Dawley rats (n = 12), trained to discriminate pentobarbital (8.0 mg/kg i.p.) from saline under a FR 10 schedule of food reinforcement, were given zolpidem (0.50-4.0 mg/kg i.p.; 5-, 15- and 45-min pretreatment) or triazolam (0.025-0.20 mg/kg i.p., 15-min pretreatment). Zolpidem occasioned intermediate drug-appropriate responding (maximum group mean = 48%) at the 5- and 15-min pretreatment times and no drug-appropriate responding at the 45-min pretreatment time. In contrast, triazolam occasioned > or = 80% pentobarbital-appropriate responding at 0.10 and 0.20 mg/kg. Both zolpidem and triazolam produced dose-dependent decreases in the rate of responding. The rate-decreasing effects of zolpidem were maximal at the 5-min pretreatment time and had dissipated after the 45-min pretreatment time. Further studies were conducted in rats to equate procedural variables between the monkey and rat studies. When the FR was reduced from 10 to 1, zolpidem occasioned 26 to 62% pentobarbital-appropriate responding over a dose range of 1.0 to 6.0 mg/kg i.p. After i.g. administration, zolpidem occasioned 100% drug-appropriate responding at the highest dose tested (6.0 mg/kg); however, only two of seven rats responded. Taken together, these data raise the possibility of a species difference between non-human primates and rats in the pentobarbital-like discriminative stimulus effects of zolpidem.

Animals↗
PubMed1997

Discriminative stimulus effects of zolpidem in pentobarbital-trained subjects: II. Comparison with triazolam and caffeine in humans.

In the present study, four non-drug-abusing humans were trained to discriminate between a hypnotic dose of pentobarbital, 100 mg, and placebo. After acquiring the pentobarbital-placebo discrimination, a range of doses of zolpidem, triazolam, pentobarbital and caffeine were tested to determine whether they shared discriminative stimulus effects with the training dose of pentobarbital, Zolpidem, a rapid-onset, short-duration, quickly eliminated imidazopyridine hypnotic agent, was tested because its discriminative stimulus effects have been shown to differ from those of classic sedative/hypnotic compounds in rodents, but not in nonhuman primates. Triazolam and caffeine were included as positive and negative controls, respectively. The subject-rated and performance-impairing effects of zolpidem, triazolam, pentobarbital and caffeine were assessed concurrently. These four subjects met the discrimination criterion (> or = 80% correct drug identifications on four consecutive seasions) in 4 to 18 (mean = 8.5) sessions, and the pentobarbital-placebo discrimination was well maintained during a test-of-novel-doses and test-of-novel-drugs phase (i.e., placebo and 100 mg pentobarbital occasioned 0-35% [mean = 17%] and 75-100% [mean = 85%] drug-appropriate responding, respectively). Zolpidem, triazolam and pentobarbital generally produced dose-related increases in pentobarbital-appropriate responding and sedative-like, subject-rated drug effects. Caffeine on average produced low levels of pentobarbital-appropriate responding, although some doses of caffeine produced maximal pentobarbital-appropriate responding in some subjects. Caffeine produced some stimulant-like (e.g., jittery, motivated, nervous and stimulated) subject-rated drug effects. Zolpidem and triazolam, and to a much lesser extent pentobarbital, but not caffeine, impaired performance. These results suggest that humans can acquire and maintain a pentobarbital-placebo discrimination, and this discrimination is pharmacologically specific. These results also suggest that despite the somewhat unique biochemical profile of zolpidem, its discriminative stimulus, subject-rated and performance-pairing effects are similar to those of classic sedative/hypnotic compounds like the barbiturates and benzodiazepines. Finally, the results observed in the present study with zolpidem, triazolam and caffeine demonstrate that the discriminative stimulus effects of drugs observed with nonhuman primates can be systematically replicated in humans.

Adult↗
PubMed1997

The relationship between reinforcing effects and in vitro effects of D1 agonists in monkeys.

The reinforcing effects of many psychomotor stimulants have been related to increased dopaminergic neurotransmission and stimulation of central nervous system (CNS) dopamine (DA) receptors. Consistent with this notion, some drugs that directly stimulate DA receptors have been found to function as positive reinforcers. The present experiments were designed to examine why some, but not all, D1 receptor agonists can function as reinforcers in rhesus monkeys by comparing behavioral and CNS in vitro measures of potency and efficacy. Seven rhesus monkeys were allowed to self-administer cocaine under a progressive-ratio (PR) schedule until stable responding was established. Various doses of D1 agonists, previously reported to function as positive reinforcers, were then made available for self-administration. Stimulation of cAMP production in rhesus and rat striatal tissue was studied for these compounds and for D1 agonists previously reported not to function as positive reinforcers in monkeys (SKF 38393, SKF 77434 and S(-)-6-BrAPB). Blockade of DA uptake in rat striata was also examined for all compounds. SKF 81297, SKF 82958 and R(+)-6-BrAPB maintained responding under the PR schedule and did not differ significantly in efficacy as positive reinforcers; SKF 81297 was less potent than the other two agonists. SKF 81297, SKF 82958 and R(+)-6-BrAPB stimulated higher levels of cAMP production in rhesus striata than did SKF 38393, SKF 77434 and S(-)-6-BrAPB. In contrast, all compounds blocked DA uptake. Thus, reinforcing efficacy among D1 agonists increases with efficacy in stimulating D1 receptors.

Animals↗
PubMed1996

Parametric analysis of cocaine self-administration under a progressive-ratio schedule in rhesus monkeys.

The present study was designed to investigate parameters and quantitative analysis of cocaine self-administration under a progressive-ratio (PR) schedule of reinforcement, with the goal of enhancing the resolution of PR schedules for measuring reinforcing efficacy. Six rhesus monkeys were prepared with chronic intravenous catheters and trained to self-administer cocaine under a PR schedule. The schedule consisted of five components, each made up of four trials (i.e., 20 trials total). Each trial within a component had the same response requirement. Three initial response requirements were tested: fixed-ration (FR) 60, FR 120 and FR 240. The response requirements doubled in successive components to a maximum of FR 960, FR 1920 or R 3840, respectively, in the fifth component. A trial ended with an injection or the expiration of a 12- or 24-min limited hold (LH). The inter-trial interval (ITI) was 15 or 30 min. Four dependent measures were assessed: break point (last FR completed), injections/session, responses/session and response rate (responses/s). For the three initial FRs, the break point, number of injections/session, responses/session and rate increased with dose of cocaine (0.013-0.1 mg/kg per injection) at both ITI/LH values. At the ITI15/LH12, responding decreased at higher doses, i.e., the dose-response functions were biphasic. In contrast, at the ITI30/LH24, responding reached an asymptote at higher doses. In general, cocaine maintained significantly higher break points, injections/session, responses/session and rate at ITI30/LH24 than at ITI15/LH12. However, at both ITI/LHs, as initial FR was increased, injections/session at the higher doses decreased while break point, total responses/session and rate did not change. A ceiling on performance, as assessed by break point, total responses/session and response rate, may have limited the number of cocaine injections an animal could take in a session. The results of this study indicate that optimal conditions for measuring the reinforcing efficacy of cocaine were obtained at the longer ITI/LH and at initial FRs above 60.

Animals↗
PubMed1996

Assessment of benzodiazepine receptor heterogeneity in vivo: apparent pA2 and pKB analyses from behavioral studies.

The purpose of this review was to establish in vivo apparent pA2 and pKB values for antagonism of the discriminative stimulus effects of benzodiazepine ligands, and to compare these values to those obtained from other behavioral procedures. Articles were chosen from the Medline data base from January 1976 to August 1995. This literature consisted of studies with flumazenil (Ro 15-1788) as the antagonist, as well as other benzodiazepine ligands (beta-carbolines, CGS 9896, CGS 8216). The dose which occasioned 50% of the maximal response (ED50) was obtained from values estimated from the graphs presented in each article. These ED50 values were used to conduct apparent pKB and apparent pA2 analyses. Apparent pA2 values for antagonism of the discriminative stimulus effects of diazepam in rats were the following (antagonist, pA2, slope): flumazenil, 4.7, -1.5; beta-CCE, 4.0, -3.0; beta-CCtB, 5.0, -2.2. The apparent pA2 value for CGS 8216 antagonism of the discriminative stimulus effects of diazepam in rats was 5.74, -2.22 (reported in Shannon and Davis 1984). The mean apparent pA2 value for flumazenil antagonism of the discriminative stimulus effects of diazepam in rhesus monkeys was 6.55, with a mean slope of -1.42. Analysis of baboon data from Ator and Griffiths (1986) revealed apparent pKB values for flumazenil antagonism of the discriminative stimulus effects of lorazepam that were lower than the pKB values for either zopiclone or CL 218,872. Analyses of the pKB data also revealed the following: no effect of route of administration (rat, PO versus IP; baboon, PO versus IM), no effect of pretreatment time (grouped into two categories: 10-20 min and 40-70 min, in rats and non-human primates), and a species effect (pKB values for rats were reliably lower than either non-human primates or pigeons, rhesus monkeys were lower than baboons). The apparent pA2 and pKB values obtained in the present review were similar across behavioral assays, except that, in squirrel monkeys, flumazenil pKB values for antagonism of benzodiazepine-induced decreases in schedule-controlled behavior were lower than pKB values obtained from drug discrimination studies. This review provides apparent pA2 values for antagonism of the discriminative stimulus effects of benzodiazepine ligands and provides evidence from pKB analyses consistent with functional heterogeneity of benzodiazepine receptors in vivo.

Animals↗
PubMed1996

Effects of exposure regimen on changes in sensitivity to the effects of cocaine on schedule-controlled behavior in rhesus monkeys.

It has been reported that conditions of drug exposure can influence changes in sensitivity to cocaine upon repeated administration. In the present experiment, the behavioral effects of prolonged exposure to continuous or intermittent infusion of cocaine were compared in rhesus monkeys responding under a multiple component fixed-ratio (FR) schedule of food presentation. In order to quantify changes in sensitivity to cocaine, cumulative dose-response functions for acute cocaine were determined using a multiple schedule comprised of six 10-minute components separated by time-out periods of 3 minutes. Initially, cocaine decreased responding in a dose-related manner. Continuous infusion of cocaine (4 mg/kg per day) for a period of 4 weeks resulted in a 2- to 4-fold shift to the right in the cocaine dose-response function, i.e., tolerance developed. In contrast, when the same daily dose of cocaine was injected intermittently (1.0 mg/kg per injection) four times/day to different monkeys, there was no change in the effects of cocaine on responding. The present results support the notion that the dosing regimen is an important determinant of changes in sensitivity to the behavioral effects of cocaine. Additionally, since sensitization failed to develop upon intermittent administration of cocaine, behavioral baseline may play a role in changes in sensitivity to cocaine.

Animals↗
PubMed1996

Zipeprol: preclinical assessment of abuse potential.

Zipeprol was evaluated in a number of in vitro and in vivo assays predictive of stimulant, depressant, or opioid abuse potential. Zipeprol had affinity for mu and kappa opioid binding sites as well as sigma binding sites. However, it failed to exert opioid-like agonist actions in rodents, and did not attenuate withdrawal signs in morphine- or pentobarbital-dependent rats. Zipeprol did not substitute for either amphetamine or pentobarbital in drug discrimination assays in rhesus monkeys. On the other hand, it suppressed morphine withdrawal signs in rhesus monkeys in two assays, and it acted as a quadazocine-sensitive reinforcer in monkeys trained to self-inject alfentanil. Zipeprol also acted as a reinforcer in monkeys trained to self-inject methohexital. In a dose range of 10-18 mg/kg, zipeprol induced convulsions in monkeys. Zipeprol appears to have abuse potential and a novel spectrum of action involving both opioid and non-opioid effects.

Animals↗
PubMed1996

Intravenous self-administration of cocaine under concurrent VI schedules of reinforcement.

Under concurrent VI (conc VI) schedules of reinforcement, organisms match the proportion of responses to the proportion of reinforcers obtained from the available options. This result is the basis of the matching law, a major theoretical view of the control of choice between and among available reinforcers. The present experiment examined the extent to which i.v. cocaine self-administration by monkeys under conc VI schedules of reinforcement was predicted by the matching law. One group of rhesus monkeys (n = 4) was prepared with chronic indwelling i.v. catheters and allowed to respond in a two-lever situation under conc VI schedules of reinforcement for cocaine injections. Three doses of cocaine (0.025, 0.05 and 0.1 mg/kg per injection) were made available under various conc VI schedules with an average inter-injection interval of 3 min. The same injection was available for each response, the difference between the options being the schedule of reinforcement. Each dose and schedule condition was in effect for at least ten consecutive sessions and until responding was stable. In a second group of monkeys (n = 3), a comparable experiment was conducted with responding maintained by the delivery of 1-g food pellets. Overall response rate maintained by cocaine was inversely related to dose. In addition, response rate decreased over the course of a session, apparently due to accumulation of cocaine. With regard to choice, more responding was maintained by the schedule that arranged more frequent injections. Choice was well predicted by the matching law, with a consistent tendency toward undermatching but no consistent bias toward one or the other option. Results were similar for behavior maintained by food, though two of three monkeys showed an unexplained bias toward the left lever. With regard to drug self-administration, these results demonstrate that in a choice situation, with all other variables being equal, injections that are available more frequently in time maintain behavior more strongly than less frequently available injections. Undermatching implies that the relative proportion of behavior maintained by the two options is somewhat less than the relative proportion of injections obtained. The finding that choice maintained by cocaine under conc VI schedules was comparable to choice maintained by food extends the generality of the conclusion that drugs and non-drug reinforcers control behavior by similar mechanisms.

Animals↗