PubMed Health⌕ Search

Biomedical subjects

I P Stolerman

Publications and source records attributed to I P Stolerman.

At least 19 recordsLinked to original sources
PubMed2006

Impaired performance of alpha7 nicotinic receptor knockout mice in the five-choice serial reaction time task.

RATIONALE: Nicotinic receptors have been implicated in attentional performance. Nicotine can improve attention in animals and humans, but knowledge about relevant receptor subtypes is very limited. OBJECTIVES: The aim was to examine the role of alpha7 receptors in attentional performance of mice and in effects of nicotine. MATERIALS AND METHODS: Mice with targeted deletion of the gene coding for the alpha7 subunit of nicotinic receptors and wild-type controls were trained on a five-choice serial reaction time task with food reinforcers presented under varying parametric conditions. Nicotine was administered in a range of doses (0.001-1.0 mg/kg sc), including those reported to enhance attentional performance. RESULTS: Initially the alpha7(-/-) (knockout) mice responded less accurately and made more anticipatory responses. After task parameters were altered so that the time allowed for responding was reduced and anticipatory (impulsive) responses were punished by a time-out, the pattern of performance deficits changed; there were increased omission errors in alpha7(-/-) mice but normal levels of accuracy and anticipatory responding. Nicotine did not improve any measure of performance, either with the original training parameters or after retraining; the largest dose used (1.0 mg/kg) produced a general impairment of responding in alpha7(-/-) and wild-type mice. CONCLUSIONS: alpha7 nicotinic receptor knockout mice are impaired in performance of the 5-CSRTT, suggesting a possible role for alpha7 receptors in attentional processing. However, identification of a protocol for assessing attention-enhancing effects of nicotine in mice may require further modifications of test procedures or the use of different strains of animal.

Animals↗
PubMed2006

Attentional performance of C57BL/6 and DBA/2 mice in the 5-choice serial reaction time task.

C57BL/6 and DBA/2 were compared in the 5-choice serial reaction time task for differences in performance related to attention and impulsivity. The goal was to examine behavioural processes in mice that may relate to ADHD in humans. Groups of male mice were trained to nose-poke in response to a stimulus light presented randomly in one of five holes; correct responses were reinforced with food. During training the stimulus duration (SD) was reduced progressively from 60 to 0.5s. The C57BL/6 and DBA/2 mice did not differ during early stages of training when attentional demands were low (SD of 60, 10 or 5s). As task demands increased, strain differences emerged; C57BL/6 mice were more accurate than DBA/2 mice with stimuli of 2, 1 and 0.5s. DBA/2 mice also made more anticipatory (impulsive) responses during inter-trial intervals than C57BL/6 mice at SD of 5, 2, 1 and 0.5s. The ability to carry out the task was present in both strains of mice but they differed significantly in the levels of performance that were achieved. It is argued that the differences in accuracy and anticipatory responding were closely related and that the primary difference between the strains may be in impulsivity.

Analysis of Variance↗
PubMed2006

Cocaine self-administration in rats with histories of cocaine exposure and discrimination.

RATIONALE: Interrelationships between the discriminative stimulus and reinforcing properties of psychoactive drugs and the way in which they may interact to control drug intake are unclear. Studies have shown that drug history can influence the expression of drug-produced behavioral effects. OBJECTIVE: The present study examined the acquisition and maintenance of intravenous cocaine self-administration in rats with a history of drug discrimination. METHODS: Two groups of male hooded rats (n=12 each) were successfully trained in a single-lever food-reinforced procedure to discriminate cocaine (10 mg/kg) from saline. Control groups (n=12 each) received drug injections and/or saline injections only and lever-pressed for food reinforcers with no discrimination training. Subsequently, all subjects were implanted with chronic jugular catheters and allowed to nose-poke for infusions of cocaine (0.2 mg/kg per infusion). RESULTS: Initial rates of responding were similar for all groups. Acquisition of self-administration on a FR-10 schedule of drug delivery was significantly faster for cocaine-exposed rats in comparison to all other groups (P<0.02). There were no differences between groups in the breaking points of cocaine and saline on a progressive ratio schedule of self-administration. Dose-response functions were obtained by two methods and were similar for all groups. CONCLUSION: These results are consistent with earlier studies demonstrating weakly sensitized primary reinforcing properties of cocaine in preexposed rats. Previous learning to discriminate cocaine impaired this sensitization.

Animals↗
PubMed2005

Tolerance to nicotine in mice lacking alpha7 nicotinic receptors.

RATIONALE: Previous studies have suggested that a knockout of the gene coding for alpha7 nicotinic receptor subunits influences the behaviour of undrugged mice but not the acute effect of nicotine on locomotor activity. OBJECTIVES: The present studies extend these observations to nicotine tolerance assessed by means of schedule-controlled behaviour. METHODS: Groups of alpha7-/- and alpha7+/+ mice were trained to press levers under an FR20 schedule of food reinforcement. The acute response rate-depressant effects of nicotine were determined in both genotypes and the mice were then subdivided into groups treated daily with nicotine (1.2 mg/kg/day) or saline. After 39 days of exposure to this regimen, the dose-response curves were re-determined. RESULTS: Knockout of the alpha7 gene had no consistent effect on the lever-pressing behaviour of undrugged mice and did not influence the acute, dose-related, response rate-depressant effect of nicotine (0.2-1.2 mg/kg). When dose-response curves for nicotine (0.4-2.0 mg/kg) were re-determined after daily dosing with the drug, both wild-type and knockout mice developed similar tolerance to nicotine, as shown by approximately 2.5-fold shifts to the right of the dose-response curves. CONCLUSIONS: Nicotinic receptors containing the alpha7 subunit do not play a significant role in the regulation of the lever-pressing behaviour studied or in the acute behavioural depressant effect of nicotine and the development of tolerance to that effect. Such results contrast with previous reports suggesting profound impairments in sensitivity to nicotine in nicotinic receptor beta2-/- mice.

Animals↗
PubMed2004

The role of nicotinic receptor alpha 7 subunits in nicotine discrimination.

The subtypes of nicotinic receptors at which the behavioural effects of nicotine originate are not fully understood. The experiments described here use mice lacking the alpha7 subunit of nicotinic receptors to investigate the role of alpha7-containing receptors in nicotine discrimination. Wild-type and alpha7-knockout mice were trained in a two-lever nicotine discrimination procedure using a tandem schedule of food reinforcement. Mutant mice exhibited baseline rates of lever-pressing as low as 52.2% of rates in wild-type controls (n=21-24). Mutant and wild-type mice acquired discrimination of nicotine (0.4 or 0.8 mg/kg) at a similar rate (n=10-12) and reached similar final levels of accuracy (71.9 +/- 4.4% and 90.8 +/- 3.1% after 60 training sessions for 0.4 and 0.8 mg/kg training doses, respectively, in mutant mice, as compared with 75.0 +/- 6.5% and 87.6 +/- 4.8% for wild types). The genotypes exhibited similar steep dose-response curves for nicotine discrimination. In both genotypes, dose-response curves for mice trained with 0.8 mg/kg of nicotine were displaced three- to four-fold to the right as compared with those for the mice trained with the smaller dose. The predominant effect of nicotine on the overall rate of responding was a reduction at the largest doses tested and there was no difference between the genotypes. The results suggest that nicotinic receptors containing the alpha7 subunit do not contribute to the discriminative stimulus or response-rate-depressant effects of nicotine, although they may regulate baseline rates of operant responding.

Animals↗
PubMed2004

Differential effects of psychomotor stimulants on attentional performance in rats: nicotine, amphetamine, caffeine and methylphenidate.

Nicotine can improve attentional performance in the rat as assessed by a modified five-choice serial reaction time task (5-CSRTT), but it is not known if the effect is shared with other psychomotor stimulants. This study compared the effects of nicotine, amphetamine, caffeine and methylphenidate on performance in the 5-CSRTT and determined whether presenting stimuli at unpredictable times by using variable inter-trial intervals (ITI) influenced the sensitivity of the task to the drugs. One group of male hooded rats was trained to obtain food reinforcers by nose-poking in response to 1 s light stimuli presented randomly in one of five apertures, with fixed ITI; for a second group of rats, ITI varied randomly (n=12 per group). As observed previously, nicotine (tested in doses of 0.05-0.2 mg/kg) produced dose-related improvements in accuracy, reduced omission errors and response latencies, but increased anticipatory responding. Amphetamine (0.1-0.8 mg/kg) and methylphenidate (2.5-10 mg/kg) increased accuracy and reduced response latency, and decreased anticipatory responding. Caffeine (2.5-20 mg/kg) did not improve performance except at a small dose that decreased omission errors only. Training at different levels of stimulus predictability influenced performance in the undrugged state but had little impact on profiles of responses to the drugs. The findings with methylphenidate support the potential value of the 5-CSRTT for testing drugs that may be useful in the treatment of attention deficit hyperactivity disorder.

Amphetamine↗
PubMed2003

Comprehensive deficits in performance of an attentional task produced by co-administering alcohol and nicotine to rats.

BACKGROUND: Nicotine can improve and alcohol can impair attentional performance in rats, but little is known about the effects of mixtures of the two drugs with respect to attention. AIMS: The aims were to investigate the effects of alcohol and nicotine alone and when co-administered on performance of a five-choice serial reaction time task, and to examine the impact of task difficulty by varying durations of the limited hold (LH) for availability of the reinforcer. METHODS: Male hooded rats were trained to respond (nose-poke) to a 0.5 s light stimulus presented randomly in one of five apertures to obtain food reinforcers. Three groups of rats trained with different LH values were used (n = 10). RESULTS: The first experiment showed that training at different LH values had little effect on performance when the LH value during testing was held constant. Experiment 2 showed that alcohol (0.4-1.6 g/kg, i.p.) had no effect on the percentage of correct responses (accuracy) but it impaired all speed-related indices. In the third experiment, the effects of nicotine (0.1 and 0.2 mg/kg, s.c.) were determined alone and on the dose-response curve for alcohol (0.4-1.2 g/kg, i.p.). Nicotine alone produced small improvements in performance whereas co-administration of nicotine and alcohol produced large decrements at doses of alcohol that themselves only slightly impaired performance. These decrements included impairments of accuracy as well as of anticipatory responding, omission errors, response latencies and reinforcers earned. There were no marked or consistent interactions of drug effects with LH values. CONCLUSIONS: Task performance was disrupted to a much greater extent by co-administration of alcohol and nicotine than by alcohol alone; therefore, it seems unlikely that an ability of nicotine to reverse the effects of alcohol can account for associations between the use of the two substances.

Animals↗
PubMed2003

Attentional effects of nicotine and amphetamine in rats at different levels of motivation.

RATIONALE: The effects of drugs on performance of tasks used to assess attention might be confounded with changes in motivation. Few studies have investigated the role of motivational factors in such situations. OBJECTIVES: To determine how changes in motivation for food influence performance of the 5-choice serial reaction time task and whether the effects of nicotine and amphetamine can be explained by motivational changes. METHODS: Male hooded Lister rats were trained to respond to a 1-s light stimulus presented randomly in one of five apertures in order to obtain food reinforcers. For three groups of rats (n=9-10), access to food was restricted to maintain body weights at 80, 90 or 95% of control weights. Saline and nicotine (0.025-0.2 mg/kg) were tested in each group, with and without pre-feeding (5 g). In a second experiment, saline and amphetamine (0.03-0.9 mg/kg s.c.) were tested without pre-feeding. RESULTS: High levels of motivation for food were associated with increases in anticipatory responses, fewer omission errors, shorter response latencies and completion of more trials, without change in accuracy. Nicotine, but not amphetamine, increased accuracy and the number of trials completed; whereas amphetamine, but not nicotine, increased omission errors. Both drugs decreased anticipatory responding at the largest doses tested. There were few interactions of motivational level with drug effects. CONCLUSIONS: The improvements in performance produced by nicotine did not resemble the effect of increased motivation, but some effects of amphetamine resembled those of reducing the level of motivation for food. Motivational levels did not confound assessments of the attentional effects of the drugs in terms of response accuracy.

Amphetamine↗
PubMed2003

Nicotine trace discrimination in rats with midazolam as a mediating stimulus.

It was shown previously that effects of drugs present prior to training sessions could serve as discriminative stimuli. Further experiments have aimed to determine whether a second drug can serve as a mediating stimulus that increases the strength of stimulus control by such pre-session drug effects. Rats were trained in a two-lever discrimination procedure with food reinforcers presented on a tandem variable-interval fixed-ratio (VI-FR) schedule. Injections of nicotine (0.6 mg/kg) or saline were followed after 5 min by administration of midazolam (0.2 mg/kg) as a putative mediating stimulus. The nicotine antagonist mecamylamine (1.0 mg/kg) was administered 5 min after midazolam, to block effects of nicotine during training sessions, as in previous work on pre-session drug effects. Stimulus control was acquired slowly and to an accuracy of only 75%. Midazolam did not facilitate the acquisition or magnitude of nicotine-induced stimulus control. However, extinction tests showed that the presence of midazolam was required for expression of stimulus control by pre-session effects of the training dose of nicotine. The response to nicotine (0.075-0.6 mg/kg) was dose-related, but the dose-response relationship was not dependent upon the presence of midazolam. In a group of rats trained with nicotine and midazolam as above, but without mecamylamine, stimulus control by nicotine was not dependent upon the presence of midazolam. In all cases, overall rates of responding were very low when tests were carried out without midazolam, suggesting the presence of state-dependent learning. The results imply that under appropriate conditions the discriminative stimulus effects of one drug (nicotine) can be mediated by the action of a second substance (midazolam). This finding can be conceptualized in terms of occasion setting, with nicotine serving as the feature and midazolam as the target stimulus. Furthermore, it appears that even when rates of responding show drug-state dependence, this is not necessarily the case for discriminative stimulus effects.

Animals↗
PubMed2002

Nicotine-induced enhancement of attention in the five-choice serial reaction time task: the influence of task demands.

RATIONALE: Beneficial effects of nicotine on cognitive processes including attention have potential therapeutic uses and have been proposed as incentives for tobacco smoking. OBJECTIVES: To establish task conditions under which the effects of nicotine on attention are obtained reliably and to characterise such effects further. METHODS: Rats were trained in a modified version of the five-choice serial reaction time task (5-CSRTT) to detect 1-s light stimuli with greater than 70% accuracy and fewer than 20% omission errors. Nicotine was tested under different task requirements by varying signal event rate, stimulus duration and stimulus predictability, and by introducing white-noise distractors. RESULTS: Nicotine (0.05-0.2 mg/kg, s.c.) repeatedly improved accuracy and reduced omission errors and reaction times, leading to increases in numbers of reinforcers earned. Anticipatory responding was increased. Parametric modifications intended to increase demands on sustained attention did not affect performance in a manner suggesting that this subtype of attention was being taxed, and the effects of nicotine were not more marked under such conditions. Shorter stimulus durations impaired performance, but this manipulation weakened the effect of nicotine on accuracy. In contrast, the presence of noise distractors facilitated the effects of nicotine to the extent that distractor-induced impairments were abolished by the drug. CONCLUSIONS: The 5-CSRTT can provide a sensitive rodent model for the attention-enhancing effects of nicotine. Changes made to the procedure may have increased its sensitivity to nicotine, particularly with respect to accuracy. There were indications that the effects of nicotine were largest on processes of selective attention or on disengaging attention from irrelevant events and shifting it to behaviourally significant stimuli.

Analysis of Variance↗
PubMed2002

The role of nicotinic receptor beta-2 subunits in nicotine discrimination and conditioned taste aversion.

The subtypes of nicotinic receptors at which the behavioural effects of nicotine originate are not fully understood. These experiments use mice lacking the beta2 subunit of nicotinic receptors to investigate its role in nicotine discrimination and conditioned taste aversion (CTA). Wild-type and mutant mice were trained either in a two-lever nicotine discrimination procedure using a tandem schedule of food reinforcement, or in a counterbalanced two-flavour CTA procedure. Rates of lever-pressing of wild-type and mutant mice did not differ. Wild-type mice acquired discrimination of nicotine (0.4 or 0.8 mg/kg) rapidly and exhibited steep dose-response curves. Mutant mice failed to acquire these nicotine discriminations and exhibited flat dose-response curves. Both wild-type and mutant mice acquired discrimination of nicotine (1.6 mg/kg) although discrimination performance was weak in the mutants. Nicotine initially reduced response rates in wild-type and mutant mice, and tolerance developed to this effect in each genotype. Both genotypes acquired discrimination of morphine (3 mg/kg) with similar degrees of accuracy, and dose-response curves for morphine discrimination in the two genotypes were indistinguishable. Nicotine produced dose-related CTA in both genotypes, but the magnitude of the effect was less in the mutants than in the wild-type controls. It is concluded that nicotinic receptors containing the beta2 subunit play a major role in the discriminative stimulus and taste aversion effects of nicotine that may reflect psychological aspects of tobacco dependence. Such receptors appear to have a less crucial role in the response-rate, reducing effects of nicotine and in nicotine tolerance.

Animals↗
PubMed2002

Nicotine-induced attentional enhancement in rats: effects of chronic exposure to nicotine.

Consistent with human literature, previous studies identified attention-enhancing effects of nicotine in rats, using a 5-choice task. The present study addressed the influence of repeated exposure to nicotine on these effects. Over six weeks, the effects of nicotine (0.0, 0.05 and 0.2 mg/kg) given ten min before sessions were tested each week. In addition, rats were injected daily two hours after sessions. In the first week, when these post-session injections were of saline for all rats, pre-session nicotine had profound rate-disruptive effects at the larger dose. In weeks 2-6, when half the rats received post-session injections of saline and the other half of nicotine (0.4 mg/kg), the disruptive effects of pre-session nicotine had disappeared and it enhanced attentional performance on all response indices. These effects did not differ significantly between post-session treatment groups or weeks, although they appeared less pronounced in the last two weeks. When tested under modified task parameters in weeks 9 and 10, nicotine (0.1 mg/kg) robustly enhanced performance in both groups despite continuing daily post-session administration of nicotine or saline. These studies provide evidence that, following tolerance to initial disruptive effects, the nicotine-induced attentional enhancement is stable across lengthy periods of chronic exposure. This is important for potential therapeutic applications of the drug and indicates that these effects can be a continuous motive for smoking behavior.

Animals↗
PubMed2002

Drug trace discrimination with nicotine and morphine in rats.

In typical drug discrimination experiments, subjects are exposed to psychoactive substances both prior to and during training sessions. The present experiments aimed to determine whether pre-session effects of drugs could serve as discriminative stimuli. Rats were trained in a two-lever discrimination procedure with food reinforcers presented on a tandem variable interval-fixed ratio (VI-FR) schedule. Injections of nicotine (0.6mg/kg 20 min pre-session) or saline were followed by administration of the nicotine antagonist mecamylamine (1.0 mg/kg 10 min pre-session) to block effects of nicotine during training sessions. Similarly, the action of morphine (10 mg/kg 30 min pre-session) was terminated by administering naloxone (0.1 mg/kg 10 min pre-session). These drug discriminations were acquired slowly to an accuracy of only 70-75% (n=10-12). Extinction tests confirmed stimulus control by nicotine in the presence of mecamylamine and by morphine in the presence of naloxone. The antagonists attenuated the response-rate reducing effects of the training doses of their respective agonists. The results are interpreted in terms of stimulus control by pre-session effects of the training drugs, but other explanations are considered. Stimulus control by pre-session drug states may be weak due to the time elapsed between termination of drug effects and training (trace conditioning).

Animals↗
PubMed2002

Effects of dopamine receptor antagonists on nicotine-induced attentional enhancement.

An understanding of the neuropharmacological mechanisms mediating attentional enhancement by nicotine would indicate whether these effects could be dissociated pharmacologically from other behavioural effects of nicotine. The aim of the present study was to examine the involvement of dopamine neurotransmission in the effects of nicotine on different response indices of an attentional paradigm. The effects of the D2-type dopamine receptor antagonist raclopride (0.025-0.1 mg/kg) and the D1-type receptor antagonist SCH23390 (0.006-0.024 mg/kg) were tested, in both the presence and absence of nicotine (0.1 mg/kg), in rats trained in a modified version of the five-choice serial reaction time task (5-CSRTT). Nicotine robustly enhanced the accuracy of signal detection, reduced omission errors and shortened response latencies. Neither raclopride nor SCH23390 altered the effects of nicotine on accuracy and omissions, but raclopride augmented accuracy and SCH23390 increased omissions when given alone. By contrast, raclopride, but not SCH23390, reversed the nicotine-induced reductions in response latencies, at doses that had no effect on their own. In the presence of nicotine, both antagonists had rate-disruptive effects at the highest dose. Both antagonists also reduced responding in the intertrial interval, and this effect was additive to the nicotine-induced decrease in this measure. The data indicate that D2-type dopamine receptors may be involved in the effects of nicotine on response speed. Neither the D1- nor the D2-type dopamine receptor antagonist affected nicotine-induced improvements in signal detection, at doses that reversed dependence-related behavioural effects of nicotine in previous studies. Thus these effects may be pharmacologically dissociable.

Animals↗
PubMed2001

Generalisation of ethanol with drug mixtures containing a positive modulator of the GABA(A) receptor and an NMDA antagonist.

Ethanol is thought to produce its discriminative stimulus effect by actions on two or more neurotransmitter systems. To test this idea further, rats were trained to discriminate mixtures of two drugs from vehicle in two-lever procedures with food reinforcers presented on a tandem variable-interval fixed ratio schedule. After drug-appropriate responding with the training mixtures reached 85%, generalisation to ethanol was examined in extinction tests. Rats trained to discriminate a mixture of chlordiazepoxide (5.0 mg/kg, s. c.) plus dizocilpine (0.08 mg/kg, i.p.) yielded a mean of 76% drug-appropriate responding when tested with ethanol (3.0 g/kg, i.g. ). However, when rats were trained with an 8.0 mg/kg dose of pentobarbitone in a mixture with 0.08 mg/kg of dizocilpine, the same dose of ethanol produced only 33% drug-appropriate responding. After retraining with pentobarbitone (12 mg/kg) plus dizocilpine (0.04 mg/kg), ethanol (3.0 g/kg, i.g.) produced 75% drug-appropriate responding. Pentobarbitone and dizocilpine administered alone produced full, dose-related generalisation, but there was no generalisation to (+)-amphetamine (0.025-0.8 mg/kg, s.c.). Thus, ethanol substituted for mixtures in which the GABA(A)-modulatory component had equal or greater salience than the NMDA-antagonist component. Doses of ethanol that generalised with the drug mixtures always reduced overall rates of responding as compared with control rates. Nevertheless, these data provide further support for the hypothesis that ethanol produces a compound stimulus comprised of elements resembling the effects of positive modulators of GABA(A) receptors and those of NMDA antagonists.

Amphetamine↗
PubMed2000

Nicotine in an animal model of attention.

Studies in smokers have suggested that at least part of the improved psychomotor performance produced by nicotine is the result of an effect on attention. Many animal experiments have assessed the effects of nicotine and its antagonists on diverse types of learning and memory but relatively few have looked at it in tasks designed to assess attention. In a five-choice serial reaction time task (5-CSRTT), rats with restricted access to food were presented with an array of five holes; illumination of a randomly selected hole signalled that a nose-poke into it would be reinforced by food presentation. Initially, signal length and the inter-trial interval (ITI) were varied and the procedure was demonstrated to satisfy some criteria for a vigilance task. The effects of nicotine on deficits in performance induced by varying signal length and ITI were assessed. Under appropriate conditions, small doses of nicotine increased the percentage of correct responses (accuracy), decreased omission errors and reaction time, and increased anticipatory responses. Subsequently, the effects of varying the ITI were examined more extensively in a slightly modified task. Here, nicotine produced small but robust, highly significant dose-related increases in accuracy, as well as decreases in omission errors and reaction times. Nicotine also increased accuracy when light stimuli were presented in an unpredictable manner. The nicotine antagonist mecamylamine produced a modest deficit in reaction time only. It is concluded that appropriate doses of nicotine can produce robust improvements in performance of normal rats in an attentional task. The effect cannot be attributed easily to changes in sensory or motor capability, learning or memory and may provide the measures needed to investigate the neuropharmacological and neuroanatomical bases of the elusive attentional effect of nicotine.

Animals↗