Cell cycle phase-dependent effect of retinoic acid on the induction of granulocytic differentiation in HL-60 promyelocytic leukemia cells. Evidence for sphinganine potentiation of retinoic acid-induced differentiation

The application of microeconomic theory to the experimental analysis of behavior has been termed behavioral economics. There has been an increasing interest in applying the concepts of behavioral economics to the study of drug self-administration. In a previously published experiment (Nader and Woolverton, 1992), rhesus monkeys (N = 3) were trained in a discrete-trials choice procedure and allowed to choose between intravenous injections of cocaine (0.03-1.0 mg/kg/injection) and food presentation (1 or 4 pellets; 1 g/pellet) during daily 7-h experimental sessions. When cocaine or food was available under a fixed-ratio (FR) 30 schedule, cocaine intake increased in a dose-related manner for all monkeys. When the response requirement (FR) for cocaine was differentially increased by doubling or quadrupling, the frequency of cocaine choice decreased, shifting the cocaine dose-response function to the right. The present paper is a reanalysis of data from that experiment. Several mathematical models, differentially incorporating the effects of FR, dose and number of food pellets, were compared. When cocaine consumption was analyzed using a multiple linear regression analysis with FR, dose and number of pellets as separate main effects (model I), the R2 was 0.82. When FR and dose were combined into one factor, unit price (UP, responses/mg/kg), and cocaine consumption was analyzed as a linear function of UP (model IIA), the R2 was 0.54. When cocaine consumption was analyzed as a curvilinear, negatively accelerated function of UP (model IIB), the R2 was 0.53. The difference between models I and IIA was statistically significant while models IIA and IIB were not different.(ABSTRACT TRUNCATED AT 250 WORDS)     

AMPA receptors and motivation for drug: effect of the selective antagonist NBQX on behavioural sensitization and on self-administration in mice

A series of experiments was carried out in which the potency of the selective alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionate (AMPA)-receptor antagonist 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) (10-100 mg/kg) on locomotor activity was investigated, in mice. NBQX reduced all forms of activity studied, but its potency to do so varied according to the conditions of the experiment. The smallest dose of NBQX significantly reducing spontaneous or cocaine-induced activity was 100 mg/kg. Mice that had been repeatedly treated with 16 mg/kg cocaine once per week, for 7 weeks, showed a sensitized locomotor response to a challenge dose of cocaine (16 mg/kg). NBQX reversed the sensitized response at 30 and 100 mg/kg. The pattern of results obtained leaves open the role that AMPA-receptors may have in the expression of behavioural sensitization. In two further experiments, mice were trained to self-administer cocaine (30 micrograms per reinforcer) via intravenous catheters, using an operant lever pressing technique. When the amount of cocaine per reinforcer was doubled (to 60 micrograms) or halved (to 15 micrograms) the mice adapted lever pressing rates to maintain some constancy of self-dosing (but not at 7.5 micrograms per reinforcer) and when saline was substituted for cocaine, response rates increased considerably (extinction bursting). NBQX (10 and 30 mg/kg) reduced the self-administration of 30 micrograms reinforcers of cocaine, but only during the first 30 min of the test session. There was no evidence that NBQX specifically antagonized the reinforcing effect of cocaine, as responding was similarly reduced on both the reinforced and the non-reinforced lever, nor did the response to NBQX mimic behaviour seen following changes in the concentration of the reinforcer. The results of the locomotor experiments and the self-administration experiments are discussed together, in terms of current hypotheses about glutamatergic mechanisms involved in motivation for drug.     

Self-administration of smoked cocaine.

Examined methodological issues related to the self-administration of cocaine and the effect of the magnitude of alternative reinforcers on cocaine self-administration. 12 hospitalized male cocaine abusers were involved in an inpatient study in which the between-Ss variable was the monetary value of the alternative reinforcer, and the within-S variable was 3 dose sizes of cocaine. Ss could receive a delivery of cocaine every 30 min in exchange for a token worth a specific amount of money for up to 10 deliveries. Results show that dose-related subjective responses existed, that the extent of subjective responses was related to the amount of cocaine self-administered, and that the amount of cocaine self-administered was reproducible across sessions. In addition, the magnitude of the alternative reinforcer affected the amount of cocaine self-administered. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Evaluation of hepaplastintest for liver disease. Effect of vitamin K administration on values of hepaplastintest (author''s transl)

A procedure for studing intravenous drug self-administration in the cat is described. Ten cats were given 24-h access to methamphetamine reinforcement (0.04 mg/kg/inj). The subjects maintained a significantly higher response rate for drug reinforcement than for saline. The pattern of self-administration over days alternated between periods of high and low drug intake. Six additional cats were used to study the effect of dose per injection on methamphetamine self-administration under conditions of limited access. When methamphetamine was subtituted at various doses per infusion in animals maintained on cocaine reinforcement, response rate was shown to be an inverted U-shaped function of dose. These studies demonstrate that methamphetamine is a reinforcer in the cat and its patterns of intake under conditions of 24-h and limited access resemble other species.     

Regulation of intravenously self-administered nicotine in rats.

Ten male Wistar rats had access to 9 doses of nicotine (0.01–0.10 mg/kg iv) during daily 5-hr sessions. Once responding for nicotine stabilized, nicotine infusions were replaced with either cocaine infusions (0.0–2.4 mg/kg) or saline infusions. Saline substitution results indicate that nicotine functioned as a reinforcer. Regulation of nicotine intake was compared with that of cocaine by obtaining the correlation between mean interdose interval and preceding dose size. Results reveal that although this correlation was significant for both nicotine and cocaine self-administration, nicotine self-administration was less precisely regulated than cocaine self-administration. This procedure suggests that there are differences in regulation among self-administered drugs and that it may serve as a useful baseline for studying differences in vulnerability to drug abuse and potential treatment strategies. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of serotonergic manipulations on cocaine self-administration in rats

Rats were trained to self-administer cocaine (0.5 mg/kg/infusion) and were then pretreated with the 5-HT1A agonist 8-OH-DPAT (0.125, 0.25 or 0.5 mg/kg, SC). 8-OH-DPAT pretreatment produced a decrease in reinforced response rates. When the effect of 8-OH-DPAT (0.5 mg/kg, SC) on responding for a range of cocaine doses was assessed, the drug produced a decrease in response rates when lower doses of cocaine served as the reinforcer. Fluoxetine (10 mg/kg, IV), an indirect 5-HT agonist, also reduced reinforced response rates for a low dose infusion of cocaine. Rates of responding for infusions of higher cocaine doses were not affected by fluoxetine pretreatment during an FR1 schedule of reinforcement. When an FR10 schedule of reinforcement was imposed, reinforced response rates for infusions of higher doses of cocaine were also reduced. Thus, under conditions that produce high rates of responding (low dose infusion or high ratio requirements for an infusion) fluoxetine reduced responding. This effect may be due to the effects at the 5-HT1A receptor, since 8-OH-DPAT produced a similar effect on cocaine self-administration. Given that the effects of these 5-HT agonists are observed only when low doses of cocaine serve as the reinforcer or when task demands are high, it is possible that the suppression of responding reflects an effect that is not specific to the reinforcing impact of cocaine. An alternative explanation for these effects incorporates a concept of unit cost/cocaine infusion that allows for direct comparison across studies that employ different reinforcement schedules.     

Optimization of conformal radiation treatment of prostate cancer: report of a dose escalation study

Under some conditions, stimulant preexposure sensitizes rats to the reinforcing effects of cocaine and other stimulants, whereas under other conditions exposure decreases the reinforcing efficacy of cocaine. This paper reviews the literature on the effects of stimulant preexposure on self-administration, focusing on methodological and interpretative issues. It is concluded that both sensitization and tolerance occur following stimulant preexposure but that these two effects can be dissociated temporally, with sensitization occurring during the development of drug self-administration and tolerance occurring in response to high doses of stimulants administered to experienced self-administering rats. The relative contribution of both of these effects to compulsive drug-taking is discussed, with emphasis on the development of cocaine as a reinforcer, maintenance of self-administration, and relapse to drug-taking.     

Influence of sex, estrous cycle, and drug-onset age on cocaine self-administration in rats (Rattus norvegicus).

The influence of sex, phase of the estrous cycle, and age of drug onset on cocaine self-administration was examined. Adult male, adult female, and adolescent male rats (Rattus norvegicus) were evaluated using low fixed-ratio (FR) schedules of drug delivery with a single fixed cocaine unit dose or a range of cocaine unit doses with a single FR schedule. Sex differences in adults were observed for mg/kg consumption of the 3.0-mg/kg unit dose, with consumption being significantly less in estrus females than in males. Over the estrous cycle, mg/kg consumption of this unit dose was significantly less during estrus than during metestrus-diestrus. Differences due to age of drug onset were also observed, with mg/kg consumption of the 3.0-mg/kg unit dose being significantly less in adolescent males than adult males or adult females during metestrus-diestrus. In contrast, these various groups did not have significantly different mg/kg intakes of cocaine unit doses     

Acquisition, maintenance and reinstatement of intravenous cocaine self-administration under a second-order schedule of reinforcement in rats: effects of conditioned cues and continuous access to cocaine

Second order schedules of IV cocaine reinforcement in rats provide a reliable method for evaluating the effects of conditioned stimuli on cocaine-seeking behaviour, and for measuring the motivational aspects of cocaine reinforcement. In the procedure established here, each infusion of cocaine (0.25 mg/infusion) was initially made contingent on a lever press and was paired with a 20-s light conditioned stimulus (CS). When rats acquired stable rates of cocaine self-administration, the response requirement for cocaine was increased progressively to a second-order schedule of the type FI15 min(FR10:S), whereby the IV cocaine infusion was self-administered following the completion of the first FR10 responses (and CS presentation) after a 15-min fixed interval (FI) had elapsed. Evaluation of the animals' responding during the first, drug-free interval of each daily session provided a measure of cocaine-seeking behaviour, independent of other pharmacological effects of the self-administered drug. Thus, a dose-response study (dose range: 0.083, 0.25 and 0.50 mg/infusion) revealed that responding under this schedule during the initial, drug-free interval changed monotonically with dose, whereas an inverse relationship between cocaine dose and response level tended to appear during the rest of the session, after rats had self-administered the drug. Responding under this schedule was also shown to occur under the control of the CS, which had acquired conditioned reinforcing properties. Thus, a decrease in responding and an increase in the latency to initiate responding followed the omission of the CS for 3 consecutive days. In addition, extinction of cocaine-seeking behaviour was slower when contingent CS presentations occurred compared to extinction when the CS was not present. Furthermore, the reinstatement of responding for cocaine, which followed a brief period of non-contingent CS presentations, was retarded when this conditioned reinforcer had been extinguished together with cocaine. Finally, cocaine-seeking behaviour decreased markedly for the first 6 h that followed a 12-h period of continuous access to cocaine, when compared to responding 6 h after a 90-min session of limited access to the drug. Responding subsequently increased to baseline levels within 72 h. These results emphasise the utility of second-order schedules for studying drug-seeking behaviour and the importance of drug-associated cues in maintaining such responding for cocaine.     

Self-administration of cocaine, alfentanil, and nalbuphine under progressive-ratio schedules: Consumer demand and labor supply analyses of relative reinforcing effectiveness.

Progressive-ratio (PR) schedules of intravenous (IV) drug self-administration are useful for establishing the relationships between reinforcing effectiveness and pharmacological actions of abused drugs. The authors compared the reinforcing effects of the high-efficacy opioid alfentanil, the low-efficacy opioid nalbuphine, and cocaine using a PR schedule of IV drug injection in rhesus monkeys in which the response requirement increased during the experimental session and the initial response requirement (IRR) was varied. Analyses based on either consumer demand or labor supply models of behavioral economics revealed that the relative reinforcing effectiveness of cocaine and alfentanil was greater than that of nalbuphine. These results suggest that PR schedules with varying IRRs can provide meaningful estimates of the relative reinforcing effectiveness of abused drugs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Impulsive choice as a predictor of acquisition of IV cocaine self- administration and reinstatement of cocaine-seeking behavior in male and female rats.

Drug abuse and impulsive choice are related in humans. In female rats, impulsive choice predicted the rate of acquisition of IV cocaine self-administration. The objectives of the present experiments were to: (a) compare impulsive choice in males and females, (b) extend previous research on impulsive choice and acquisition of cocaine self-administration to males, and (c) compare males and females during maintenance, extinction, and reinstatement of cocaine-seeking behavior. Male and female rats were trained on an adjusting delay task in which a response on one of two levers yielded one food pellet immediately, and a response on the other resulted in three pellets after an adjusting delay that decreased after responses on the immediate lever and increased after responses on the delay lever. A mean adjusted delay (MAD) was used as the quantitative measure of impulsivity. In Experiment 1, MADs were analyzed for sex differences. In Experiment 2, acquisition of cocaine self-administration was examined in rats selected for high (HiI; MADs ≤9 seconds) or low (LoI; MADs ≥13 seconds) impulsivity. In Experiment 3, HiI and LoI groups were compared on maintenance and extinction of cocaine self-administration and cocaine-primed reinstatement of drug-seeking behavior. There were no sex differences in impulsive choice; however, HiI male and female rats acquired cocaine self-administration faster than their LoI counterparts. LoI females responded more on a cocaine-associated lever during maintenance and extinction than HiI females, but HiI females showed greater reinstatement of cocaine-seeking behavior than all other groups at the highest dose tested (15 mg/kg). Thus, individual differences in impulsive choice were associated with differences in cocaine-seeking behavior. Impulsive choice and sex may be additive vulnerability factors in certain phases of drug abuse. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Quantification of reinforcing effectiveness: Comment on Meisch (2000).

R. A. Meisch (see record 2000-00465-009) introduces an innovative method for quantifying the reinforcing effectiveness of drugs and other substances. Advantages are that it models the persistence of drug use in humans and its persistence ratios are the same whether responding or consumption is measured. Data indicate that the method is sensitive to factors that affect drug self-administration. The measure's core feature is "the systematic variation of both reinforcer magnitude and schedule size" (Meisch, 2000, p. 347); however, the method may not be widely used with such extensive parametric analysis. Variation of only reinforcer magnitude (or dose/concentration) seems to produce similar results, and this abbreviated analysis is similar to the behavioral economic analysis of demand. When responding is plotted as a function of unit price (responses/milligram), the peak of the curve (where maximum responding occurs) is a measure of persistence. Further work will determine how these and other measures of reinforcing effectiveness agree. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Telepathology diagnosis by means of digital still images: an international validation study

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.     

Effect of VA-045, a novel apovincaminic acid derivative, on closed head injury-induced neurological dysfunction in aged rats

The purpose of the present study was to develop an animal model of nicotine self-administration that more closely approximates the conditions of human nicotine use than do existing models. In most nicotine self-administration models, rats acquire self-administration during brief daily sessions in which rapid injections of a relatively high dose of the drug, 0.03 mg/kg, serve as the reinforcer. The present study examined nicotine self-administration in rats that acquired the behavior while having virtually unlimited access to injections of a relatively low dose of the drug; the rats did not have any prior operant training or shaping. Under these conditions, rats readily acquire nicotine self-administration at doses at least as low as 0.00375 mg/kg per injection, and they self-administer throughout the active portion of their light cycle. The daily nicotine intake of rats, which ranged from 0.18 to 1.38 mg/kg per day, appears to be comparable to that of human smokers.     

Discriminative and reinforcing stimulus effects of nicotine, cocaine, and cocaine + nicotine combinations in rhesus monkeys.

Concurrent cigarette smoking and cocaine use is well documented. However, the behavioral pharmacology of cocaine and nicotine combinations is poorly understood, and there is a need for animal models to examine this form of polydrug abuse. The purpose of this study was twofold: first to assess the effects of nicotine on the discriminative stimulus effects of cocaine, and second, to study self-administration of nicotine/cocaine combinations in a novel polydrug abuse model. In drug discrimination experiments, nicotine increased the discriminative stimulus effects of low cocaine doses in two of three monkeys, but nicotine did not substitute for cocaine in any monkey. Self-administration of cocaine and nicotine alone, and cocaine + nicotine combinations was studied under a second-order fixed ratio 2, variable ratio 16 (FR2[VR16:S]) schedule of reinforcement. Cocaine and nicotine alone were self-administered in a dose-dependent manner. The combination of marginally reinforcing doses of cocaine and nicotine increased drug self-administration behavior above levels observed with the same dose of either cocaine or nicotine alone. These findings indicate that nicotine may increase cocaine's discriminative stimulus and reinforcing effects in rhesus monkeys, and illustrate the feasibility of combining cocaine and nicotine in a preclinical model of polydrug abuse. Further studies of the behavioral effects of nicotine + cocaine combinations will contribute to our understanding the pharmacology of dual nicotine and cocaine dependence, and will be useful for evaluation of new treatment medications. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Stimulus compounding enhances conditioned suppression produced by cocaine-paired stimuli.

When 2 stimuli that occasion cocaine self-administration are presented in compound, their ability to increase cocaine-reinforced operant responding is substantially enhanced. The goal of the present experiment was to determine whether stimulus compounding could produce analogous enhancements of a classically conditioned drug effect. Food-maintained responding in rats was suppressed by a tone and a light that were individually paired with response independent cocaine (3 mg/kg iv). This conditioned suppression was significantly enhanced when the stimuli were presented together in a stimulus-compounding test. The magnitude of this enhancement was similar to that in previous studies in which responding was suppressed by shock-paired stimuli. These results demonstrate that multiple drug-related cues interact in a predictable manner to influence both operant and classically conditioned behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Response requirements and unit dose modify the effects of GBR 12909 on cocaine-maintained behavior.

Previous studies found that GBR 12909 can decrease cocaine-maintained responding at doses that do not affect food-maintained responding. In this study, the effects of GBR 12909 (0.3–3.0 mg/kg) were further examined by varying the response requirement and unit dose of cocaine. Rhesus monkeys earned food or cocaine under a multiple fixed-ratio (FR) schedule. The FR for food was always 30, but the FR for cocaine was varied from 10–130 and the unit dose was varied from 5.6–56.0 μg/kg per injection. Doses of GBR 12909 were tested in an ascending order, for 5 consecutive sessions each. GBR 12909 selectively decreased cocaine maintained responding in all monkeys in at least 1 condition. These effects were enhanced with large response requirements and/or small unit doses. The results demonstrate that environmental variables can influence the selectivity of GBR 12909's effects and contribute to a growing debate concerning the evaluation of potential pharmacotherapies for drug abuse. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Schedule induction conditions not only exaggerate intake but also enhance drug solution choice

In previous research, rats exposed to daily, 3 h sessions of schedule-induced polydipsia (SIP) self-administered high doses of cocaine orally. However, a strong and durable preference for cocaine solution to water requires training in addition to mere oral self-administration exposure. If cocaine is dissolved in a preferred vehicle solution, and the vehicle is subsequently faded to water, then a strong preference for cocaine remains. A similar preference can be instituted for lidocaine solution. Such preferences may develop because the gustatory property of a drug becomes associated with the preferred vehicle and remains to function as a durable conditioned reinforcer after vehicle fading. To determine if drug preference is solely a function of this posited conditioning mechanism, or whether it also depends upon the SIP condition, rats were exposed to daily, 3 h sessions of single-ration feeding, rather than the SIP condition. A preferred vehicle (glucose/saccharin solution) was slowly faded from a 0.19 mg/ml lidocaine solution, which was presented concurrently with a choice for water. Although a preference for lidocaine solution to water could be generated, it occurred for only 5 out of 9 rats, and the preference was relatively unstable. By contrast, in two previous studies using SIP, 26 out of 27 rats maintained a preference for lidocaine solution. Thus, SIP not only exaggerates the amount of drug solution ingested but also contributes to the fixation of the associative drug solution choice.     

Antithrombotic agents in unstable angina. Review of clinical trials

The purpose of this experiment was to investigate the regulation of drug intake in rats (n = 20) self-administering heroin or cocaine during daily 5-hr sessions. Operant chambers were equipped with 2 levers and associated stimulus lights. A response on the lever with stimuli signaling an increase in dose size increased the infusion duration by 3 s, and a response on the lever with stimuli signaling a decrease in dose size decreased the infusion duration by 3 s. Results showed that daily and hourly drug intake for cocaine and heroin groups were relatively constant. Significant correlation coefficients were obtained for heroin and cocaine groups for the relationship between interdose interval (IDI) and infusion duration (dose size). These findings indicate that subjects regulated their drug intake by adjusting IDI throughout drug self-administration sessions.     

Effects of medial prefrontal or anterior cingulate cortex lesions on responding for cocaine under fixed-ratio and second-order schedules of reinforcement in rats

Four experiments examined the effects of excitotoxic, axon-sparing lesions of the medial prefrontal cortex or anterior cingulate cortex in rats on responding under different schedules of intravenous cocaine self-administration and on the locomotor stimulant effects of cocaine. Experiment 1 tested the acquisition and maintenance of cocaine self-administration under a fixed ratio schedule. Rats with medial prefrontal cortex lesions showed facilitated acquisition and enhanced responding for low doses of the drug when lesions were induced before self-administration behaviour was established. Lesions of the anterior cingulate cortex did not affect cocaine self-administration. In experiment 2, rats were trained to respond under a second-order schedule of cocaine reinforcement, where responding during the fixed interval was reinforced by presentation of a cocaine-associated visual stimulus under fixed-ratio contingencies. In control rats, these schedule conditions were found to maintain high rates of responding and a scalloped pattern of responding over time. Omission of conditioned stimulus presentation during the fixed interval significantly disrupted response patterns, confirming that the stimulus served to maintain responding during the fixed interval. By contrast, rats with medial prefrontal cortex lesions showed higher rates and disrupted patterns of responding that were unchanged by stimulus omission. Rats with lesions of the anterior cingulate cortex responded at high rates throughout the fixed interval under all test conditions, indicating that the cocaine-associated stimulus did not serve to maintain temporal patterns of responding in these rats. Experiment 3 demonstrated the lack of effect of either lesion on the acquisition of responding for a non-drug reinforcer, sucrose. In experiment 4, measures of spontaneous and cocaine-induced locomotor activity revealed that rats in both lesion groups were significantly more active than controls regardless of test conditions. These data indicate that facilitated acquisition of cocaine self-administration and disrupted response patterns under second-order schedule contingencies may result from deficits in behavioural inhibition induced by medial prefrontal cortical lesions that contrast with deficits following damage to other limbic cortical regions, such as the basolateral amygdala or anterior cingulate cortex.