Karen G. Anderson

Effects of clomipramine on self-control choice in Lewis and Fischer 344 rats

Rates of delay discounting (impulsive choice) have been shown to vary among individuals, particularly people who abuse drugs relative to those who do not, but factors that may contribute to these differences have not been identified. To explore a role for possible genetic and neurochemical determinants, Lewis (n = 8) and Fischer 344 (n = 8) rats were allowed to choose between one food pellet delivered immediately and three food pellets delivered after increasing delays. The delays to the large reinforcer (0, 10, 20, 40, 60 s) were increased across five blocks of trials in daily experimental sessions. For both groups of rats, choice for the larger reinforcer decreased as the delay to presentation increased. However, the Lewis rats were more likely to choose the smaller, immediate reinforcer earlier in the session, i.e., at shorter large-reinforcer delays, than the Fisher 344 rats. This difference in choice was statistically significant. Repeated administration of 3.0 mg/kg, i.p. clomipramine (mean of last five sessions) did not significantly alter choice, relative to baseline, for either strain. The present findings suggest that differences in delay discounting/impulsive choice may involve genetic, e.g., neurochemical, differences.

Effects of variable training, signaled and unsignaled delays, and d-amphetamine on delay-discounting functions.

One common procedure for obtaining delay-discounting functions consists of a choice between a larger reinforcer that is presented after an increasing delay and a smaller reinforcer that is always presented immediately within session. Repeating the same context of delay presentation (e.g. ascending delay order) in a discrete-choice paradigm, however, may lead to a perseverative response pattern when rats are used as subjects. The purpose of this study was to increase the variability in delay presentation (i.e. ascending and descending delays) in an attempt to reduce a perseverative response pattern and gain tighter control over choice by reinforcer amount and delay. For one group of rats (n = 8), delays to reinforcer presentation were differentially signaled by a flashing houselight and for one group of rats (n = 8) the delays were unsignaled. Effects of delay signal and d-amphetamine on choice were evaluated in both groups. Similar rates of delay discounting and area under the curve (AUC) were observed with both ascending and descending delay presentations and with signaled and unsignaled delays to reinforcement. Increasing the variability in delay order resulted in differences in the choice pattern during 0-s probe sessions. d-Amphetamine had little or no effect on AUC at low doses, but decreased AUC at the highest doses tested, that is, 1.0 and 1.7 mg/kg. Some of the changes in AUC after d-amphetamine administration may have been because of disruption in discrimination of the different food amounts.

Effects of acute and repeated nicotine administration on delay discounting in Lewis and Fischer 344 rats.

Biological differences may underlie individual differences in impulsive behavior, such as choice for a smaller, more immediate reinforcer over a larger, more delayed reinforcer. Repeated exposure to drugs of abuse may have different effects on such behavior. To evaluate the acute and repeated effects of nicotine on impulsive choice, two strains of rats that have been shown to differ in impulsive choice were tested in a delay-discounting paradigm. Eight Lewis and eight Fischer 344 rats were allowed to choose between one food pellet delivered immediately and three food pellets delivered after a delay. The delay systematically increased in blocks of trials within each session, and the delay value at which the choice for the two alternatives was equal (i.e. the indifference point) was interpolated. Effects of nicotine (0.1–1.0 mg/kg, subcutaneous) on percent choice and indifference points were determined during the acute-testing phase and during the redetermination of effects of each dose after at least 30 sessions of repeated 1.0 mg/kg nicotine exposure. The Lewis rats had shorter indifference points (i.e. made fewer larger-reinforcer choices) compared with the Fischer 344 rats. Acute nicotine administration increased the mean larger-reinforcer choices at the 0.3 mg/kg dose in the Lewis rats and at the 1.0 mg/kg dose in the Fischer 344 rats. After repeated exposure to nicotine, indifference points returned to near-baseline (predrug) levels for both the strains. Strain differences were observed in the rates of delay discounting, and nicotine may decrease the impulsive choice acutely, but this effect does not seem to be long lasting.

Sex differences in schedule-induced alcohol consumption

Six female and five male Wistar rats obtained food by pressing a lever on a fixed-interval (FI) 60-s schedule in the presence of a sipper tube which allowed access to an alcohol solution. Systematic manipulation of the alcohol concentration revealed that male rats consumed higher alcohol concentrations (v/v) than female rats to obtain maximum alcohol intake (g ETOH/kg) during an experimental session. Males also reached higher blood alcohol levels (BALs) than females. Individual lick rates varied over a small range when the FI schedule parameter was manipulated (20 s and 180 s) during probe sessions. Very few licks were observed when all pellets were presented at the beginning of the session, during extinction, or during sessions in which only a few pellets were presented. Reduction of the solutions alcohol concentration to half the maximum concentration or presentation of distilled water resulted in increased lick rates at most values of the FI schedule in four of the five male subjects, but not in female subjects. Alcohol intake during sessions in which half the maximum alcohol concentration was available was lower than that observed during sessions in which subjects consumed the maximum alcohol concentration. The lick rate data in conjunction with those on alcohol intake suggest that male rats, but not female rats, maintained blood alcohol concentrations at levels which they had also reached during sessions in which the maximum alcohol concentration was available from the sipper tube.

GTS-21, a mixed nicotinic receptor agonist/antagonist, does not affect the nicotine cue

Identification of nicotinic receptor subtypes involved in nicotine dependence is required for guiding the design of more selective antagonists capable of blocking the nicotine cue and nicotine self-administration. Due to the multiplicity of nicotinic receptors in the mammalian brain, selective agonists and antagonists are needed to assess the functional involvement of a particular subtype in vivo. Only recently have a few nicotinic receptor subtype-selective antagonists and agonists been identified. GTS-21 (also known as DMBX-anabaseine) is the only agent so far reported that selectively stimulates the alpha7 nicotinic receptor. Here GTS-21 was used to assess the possible mediation of the nicotine cue by this receptor subtype. Long-Evans rats were trained to discriminate between presession administration of 0.10 or 0.40 mg/kg (-)-nicotine bitartrate and its vehicle. GTS-21 did not substitute for nicotine, as all subjects consistently chose the vehicle lever after GTS-21 substitution. In another experiment, different doses of GTS-21 were administered prior to nicotine administration to investigate whether GTS-21 would antagonize the nicotine cue. Such was not the case. The lack of effect of GTS-21 upon the nicotine cue is consistent with the notion that the cue is mediated by nicotinic receptors other than the alpha7 receptor.

Behavioral effects of acute and chronic cocaine administration in male and female rats: Effects of fixed-ratio schedule parameters.

Intact and gonadectomized male and female rats pressed a lever to obtain food on different fixed-ratio (FR) schedules in a three-component multiple schedule. The values of a small, intermediate and large FR schedule were individually determined and were higher for intact male rats than for most subjects in the other groups. Acute cocaine administration (1.0–30.0 mg/kg) dose-dependently decreased response rates maintained by all three schedules, but responding maintained by the large FR schedule was more sensitive to the rate-decreasing effects of acute cocaine administration. Response rates of intact male rats were less sensitive to the rate-decreasing effects of cocaine than those of the other groups, at least at higher doses during the small and intermediate FR schedules. Cocaines dose-effect curve was redetermined after chronic administration of a behaviorally active dose of cocaine. Differences between groups of subjects were not evident. Behavioral tolerance was consistently observed when responding was maintained by the small FR schedule. Effects varied between subjects within groups when responding was maintained by the intermediate FR schedule, but behavioral tolerance was frequently observed. Behavioral sensitization was evident during the large FR schedule, but these data were difficult to interpret because of a considerable shift in response rates after vehicle administration. The data suggest that the comparison of drug effects in male and female rats requires a systematic analysis of the contribution of behavioral parameters. They also provide additional evidence for the notion that reference to reinforcement-loss alone is not sufficient to explain the development of tolerance to the behavioral effects of cocaine.

Concurrent variable-interval drug self-administration and the generalized matching law: a drug-class comparison.

It has previously been shown that self-administration of cocaine under concurrent variable-interval schedules is well described by the generalized matching law. That is, choice between two cocaine-maintained options was apportioned in accordance with relative frequency of reinforcement. However, the generality of this conclusion to drugs of other pharmacological classes has not been determined. In the present study, four male rhesus monkeys (Macaca mulatta) lever pressed under various pairs of concurrent variable-interval schedules with drug injection as the maintaining event. An opioid (alfentanil, 0.001 or 0.004 mg/kg/injection), a barbiturate (methohexital, 0.25 or 0.5 mg/kg/injection), and a psychomotor stimulant (cocaine, 0.05 mg/kg/injection) were selected as representatives of major classes of abused drugs and because of their relatively short duration of action. As has been found for cocaine, choice was well accounted for by the generalized matching law. There were no systematic differences in matching-law parameters across drugs and/or doses. As in earlier studies with drug and nondrug reinforcers, undermatching was a consistent finding. Therefore, the conclusion that relative reinforcement frequency is a crucial determinant of choice, as proposed by the generalized matching law, can be extended to behavior maintained by drugs from a variety of pharmacological classes.

Effects of acute and repeated administration of caffeine on temporal discounting in rats.

Delay to presentation is one variable that can weaken the reinforcing efficacy of an outcome in a choice situation and drugs have been shown to modify such choices. A growing body of literature has examined effects of stimulant drugs on temporal (delay) discounting, but effects of caffeine, the most widely used stimulant in the world, have not previously been assessed. In the present experiment, effects of caffeine (administered acutely and repeatedly) on temporal discounting were analyzed. Male Sprague-Dawley rats (n=7) chose between a single food pellet delivered immediately after a lever press and three food pellets delivered after a delay. The delay to the three pellets increased within each session, from 0 to 16 s. High doses of caffeine increased large-reinforcer choice relative to control conditions. With repeated caffeine exposure, percent choice for the large reinforcer decreased relative to acute administration, but was still greater than pre-drug baseline. Following withdrawal of drug administration, choice returned to levels seen during pre-drug baseline. Reintroduction of caffeine increased the percent choice for a larger, delayed reinforcer to near acute levels. The results from the present study are consistent with previous research in which stimulant drugs have decreased temporal (delay) discounting.

Effects of acute and chronic methylphenidate on delay discounting.

Methylphenidate (MPH) is one of the most common therapeutics used for the treatment of attention-deficit/hyperactivity disorder (ADHD), which consists of symptoms of inattention, and/or impulsivity and hyperactivity. Acute administration of MPH has been found to decrease impulsive choice in both humans and nonhuman animals, however, little is known about potential long-term changes in impulsive choice due to chronic administration of MPH. In the present experiment, effects of acute and chronic MPH (1.0-10.0mg/kg) were assessed on impulsive choice in the adult male Spontaneously Hypertensive Rat (SHR) to determine the extent of behavioral changes after chronic MPH exposure. Subjects chose between an immediate single food pellet and three food pellets delivered after a delay that increased within session (0 to 16s). At relatively higher doses during acute and chronic administration, choice maintained by the larger reinforcer was disrupted when there was no delay to either outcome, suggesting that MPH may be affecting stimulus control under the current delay-discounting task. When this disruption was not observed, however, MPH effects were selective in that only one intermediate dose (3.0mg/kg) decreased mean impulsive choice at one delay (8s) following acute administration. The same effect was observed following chronic MPH administration except that the dose was higher (5.6 mg/kg) and the delay was shorter (4s). Chronic administration of MPH did not show any negative indicators (e.g., an increase in impulsive choice) when administration was discontinued.

Cocaine discrimination and time-course effects in male and female Wistar rats.

Previously, sex differences have been observed in the behavioral effects of acute and chronic cocaine administration. In the present experiment, male and female rats were trained to discriminate intraperitoneal injections of 10.0 mg/kg cocaine from its vehicle. It was hypothesized that the subjective effects of cocaine might differ between male and female rats. It was further hypothesized that generalization gradients between male and female rats might differ as a function of the time since cocaine administration. In addition, we were interested to see whether multiple generalization gradients could be determined within the same experimental session. For that purpose, two different types of generalization tests were conducted in extinction, one in which subjects were tested both 10 min and 30 min following cocaine administration (vehicle, 1.0, 3.0, 5.6, 10 or 17 mg/kg) and one in which subjects were only tested 30 min after cocaine administration. The generalization gradients obtained 30 min following drug administration were shifted to the right of the gradient obtained 10 min following drug administration. The two 30-min gradients were not different from one another, showing that multiple generalization gradients can be obtained within the same experimental session.