The effect of repeated nicotine administration on the performance of drug-naive rats in a five-choice serial reaction time task

Nicotine improves cognitive performance both in animals and in humans, particularly in tests involving attentional processes. The five-choice serial reaction time task (5-CSRTT) is widely used as a model of attentional performance in rats, and previous studies have demonstrated effects of nicotine in this task on measures such as improved reaction time. Using a modified version of this task (in which rats were required to respond to the disappearance of one of five stimulus lights), we evaluated the effects of repeated nicotine administration (0.3 mg/kg, intraperitoneally, on three occasions over 7 days) in drug-naive rats. After the first administration, nicotine increased accuracy and reduced inappropriate responding (anticipatory responses and responses during time-out) compared to performance following vehicle administration on the preceding day. However, with repeated administration the improvement in accuracy disappeared, and other effects became apparent. Thus, after the third administration the main effects of nicotine were to increase inappropriate responding and to reduce reaction times. A fourth administration 1-2 weeks later produced similar results to the third administration, suggesting that the effects of nicotine were now constant. Despite the general increase in inappropriate responding, there was no impairment in accuracy. In contrast to the response to repeated nicotine, the performance of the rats on the 3 vehicle days remained constant. These data demonstrate that the administration of nicotine to drug-naive subjects improves performance in the 5-CSRTT but that with repeated administration this effect disappears and is replaced by a profile in which inappropriate and impulsive responding predominate.     

Serotonin antagonists in the five-choice serial reaction time task and their interactions with nicotine

Much research has implicated the serotonin (5-HT) system in cognitive functioning and psychomotor stimulant abuse, but its role depends on the subtypes of 5-HT receptors involved and the nature of the behavioural task. Here we aimed to extend previous studies by examining the role of 5-HT1A and 5-HT2C receptors in attentional performance. The effects of the selective 5-HT antagonists WAY-100635 and SB-242084 were assessed alone and for interactions with nicotine in the five-choice serial reaction time task in rats. The effects of several doses of WAY-100635 were tested in combination with a fixed dose of nicotine, and then various doses of nicotine were tested in combination with SB-242084. Systemic administration of WAY-100635 and SB-242084 induced opposing effects on speed-related measures in the five-choice serial reaction time task, with antagonism at 5-HT1A receptors increasing omission errors and response latency, and antagonism at 5-HT2C receptors reducing both omissions and latency, and also increasing anticipatory responses; neither drug affected accuracy. Nicotine itself improved all main indices of attention, and there was preliminary evidence that the detrimental effects of WAY-100635 on response latency were weakened by nicotine. Conversely, treatment with SB-242084 enhanced all speed-related indices of performance to above the levels seen under the influence of nicotine alone, thus suggesting that 5-HT2C antagonists might be useful to decrease reaction times if used as an add-on therapy to treat attentional decline.     

Characterisation of the effects of nicotine in the five-choice serial reaction time task in rats: antagonist studies

Rationale: Nicotine has been shown to decrease reaction time and increase anticipatory responses in a five-choice serial reaction time task (5-CSRTT) in rats, but the receptor mechanisms mediating this effect remain unknown. Objectives: To evaluate further the effects of nicotine in this task and to characterise the receptors mediating these effects. Methods: Using a standard 5-CSRTT protocol, rats were trained to respond to a 0.5-s visual stimulus, which was reduced to 0.25 s for experimental sessions to induce a performance decrement. The effects of acute (0.03–0.3 mg/kg IP) and repeated (0.1 and 0.3 mg/kg IP for 5 days) nicotine were studied, as was the ability of mecamylamine (1 mg/kg IP), hexamethonium (5 mg/kg IP), dihydro-β-erythroidine (6 mg/kg IP) and methyllycaconitine (10 mg/kg IP) to antagonise the effects of acute nicotine. Results: Nicotine had no effect on accuracy, but decreased response latencies, improved performance in the less-well attended stimulus locations and increased inappropriate responding after both acute and repeated treatment. The data suggest that nicotine improves readiness to respond and improves target scanning, and decreases the ability to withhold premature responses (i.e. increased impulsivity). Except for the reduction in error latency, all of the effects of nicotine were antagonised by the non-selective, centrally acting antagonist mecamylamine, whereas the peripheral antagonist hexamethonium had no effect, demonstrating that nicotine’s actions are central in origin. Dihydro-β-erythroidine, a competitive nicotinic antagonist, antagonised all of the effects of nicotine. In contrast, the α₇ antagonist methyllycaconitine had no significant effects against nicotine. Conclusions: These results demonstrate that the α₇ receptor subtype is not involved in the effects of nicotine in the 5-CSRTT and that its effects are more likely to be mediated by a receptor(s) such as α₄β₂, α₄β₄ and/or α₃β₂ which is sensitive to antagonism by dihydro-β-erythroidine. Received: 12 October 1999 / Final version: 9 December 1999     

Nicotine-induced enhancements in the five-choice serial reaction time task in rats are strain-dependent

RATIONALE: Clinically, nicotine improves attention, but this has proven difficult to demonstrate preclinically. We tested nicotine in Sprague-Dawley (SD) and Lister hooded (LH) rats in the five-choice serial reaction time task. Since SD rats demonstrate lower asymptotic performance than LH rats, we surmised that nicotine would only improve performance in this strain. METHODS: Rats were placed in operant chambers 10 min after nicotine treatment (0.001-0.2 mg/kg). RESULTS: Nicotine dose-dependently increased correct responses only in SD rats (approximately 20% at the highest dose). By contrast, nicotine dose-dependently increased omission errors and reduced trials completed in both strains of rat, and dose-dependently reduced tray responses in SD rats. CONCLUSION: The magnitude of improvement in accuracy seen with nicotine in SD rats is greater than previously demonstrated using lesion or parametric manipulation models in other strains of rat in this test of attention. Although this suggests that the SD strain may be a useful "tool" for future studies, other task parameters, such as stimulus duration, may have to be optimum to demonstrate the magnitude of improvement observed presently.     

Measuring impulsivity in mice: the five-choice serial reaction time task

Rationale  

Mice are useful tools for dissecting genetic and environmental factors in relation to the study of attention and impulsivity. The five-choice serial reaction time task (5CSRTT) paradigm has been well established in rats, but its transferability to mice is less well documented.     

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 α7 receptors in attentional performance of mice and in effects of nicotine.Materials and methods Mice with targeted deletion of the gene coding for the α7 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 α7^−/− (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 α7^−/− 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 α7^−/− and wild-type mice.Conclusions α7 nicotinic receptor knockout mice are impaired in performance of the 5-CSRTT, suggesting a possible role for α7 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.     

The effects of acute and repeated administration of ketamine on attentional performance in the five-choice serial reaction time task in rats

Ketamine, the non-competitive antagonist of the N-methyl-d-aspartate receptors, is used in clinical and preclinical studies to produce schizophrenia-like cognitive impairments. However, the impact of ketamine on attentional functions remains poorly characterised. In the present study, we further examine the effects of ketamine on attentional processes assessed in the five-choice serial reaction time task (5-CSRTT) in rats. The applied schedules of ketamine administration have been previously demonstrated to evoke frontal-dependent set-shifting impairments. Rats were trained to reach a stable baseline performance. Afterwards, animals received a single injection of ketamine (0, 3 and 10 mg/kg, IP) 45 min before the 5-CSRTT session (experiment 1). In experiment 2, ketamine (0 and 30 mg/kg, IP) was administered after the daily test session for 10 consecutive days. The rats׳ performance was assessed at 22 h following ketamine administration and for 4 days after the last dose. Acute and repeated administration of ketamine disrupted rats׳ performance on the 5-CSRTT. Reduced speed of responding and an increased number of omissions were noted in the absence of reduced food motivation. The within-session pattern of responding differed between rats treated acutely and repeatedly with ketamine. Specifically, repeated drug administration evoked an increase in omissions toward the end of the session, and this effect was not secondary to the reduced motivation. Ketamine affected performance during the withdrawal period only when testing with variable inter-trial intervals. The repeated administration of ketamine can impair rats׳ ability to sustain attention over the course of session, suggesting some utility for modelling attentional disturbances.     

Effects of atipamezole, an alpha 2-adrenoceptor antagonist, on the performance of rats in a five-choice serial reaction time task.

The present study investigates whether pharmacological activation of the noradrenergic system improves attention. The effects of atipamezole, a potent alpha 2-adrenoceptor antagonist, on the performance of adult male rats in the five-choice serial reaction time task were studied. Before drug testings, food-deprived rats were trained to detect and respond to brief flashes of light presented randomly by the computer in one of five spatially diverse locations until a stable level of performance had been reached (about 3 months). Single-dose administration of atipamezole (0.03-3.0 mg/kg) slightly increased the number of premature and perseverative responses during the intertrial interval and slightly decreased the reaction times to incorrect responses, indicating increased behavioral activation. Atipamezole did not affect discriminative accuracy. However, in a subpopulation of rats with the poorest discriminative accuracy according to pretest performance seven of eight rats improved their discriminative accuracy when treated with 0.3 mg/kg atipamezole as compared to controls. At the other doses tested, no improvement was found. The present results suggest that acute administration of atipamezole, and alpha 2-adrenoceptor antagonist, slightly increases behavioral activation, although the effects on baseline performance in the task measuring selective attention are modest.     

Serotonin2 receptor agonists and serotonergic anorectic drugs affect rats’ performance differently in a five-choice serial reaction time task

A five-choice serial reaction time task was used to study the effects of serotonin (5-HT) receptor agonists and antagonists on accuracy of performance and food-motivated behaviour. Lysergic acid diethylamide (LSD), 0.1 mg/kg IP and quipazine, 2.5 mg/kg IP significantly reduced the percentage of correct responses and increased the percentage of omissions with no effect on other measures such as latency to collect the reinforcement or to respond correctly. The effects of LSD and quipazine were reversed by 1–2 mg/kg ritanserin, a potent 5-HT₂ and 5-HT_1C receptor antagonist. Metachlorophenylpiperazine (mCPP) 2.5 mg/kg IP, an agonist at 5-HT_1B and 5-HT_1C receptors, andd-fenfluramine (DF) 1.25 mg/kg IP, a releaser of 5-HT from nerve terminals and inhibitor of 5-HT uptake, increased the percentage of omissions and the latency to respond correctly or to collect the reinforcement with no effects on the correct responses. Effects similar to those of mCPP and DF were obtained by 60 min access to food before testing. Haloperidol, 0.1 mg/kg IP, did not affect the percentage of correct responses or the latency to collect the reinforcement, but significantly increased the proportion of errors of omission and the latency to respond correctly. The results show that 5-HT₂ receptor agonists cause attentional disturbances at doses that have no marked effect on motivation for food or speed. An increase in the latency to collect the reinforcement was found only with prefeeding and drugs supposed to cause satiety such as mCPP and DF. An increase in latency to respond correctly and in the percentage of omissions seemed related to haloperidol-induced motor retardation and reduced level of arousal. The five-choice serial reaction time task seems useful for separating effects on attentional processes from those on food-motivated behaviour or motor activity.     

Chronic nicotine administration improves attention while nicotine withdrawal induces performance deficits in the 5-choice serial reaction time task in rats

Nicotine appears to enhance attention, while nicotine withdrawal leads to attentional deficits in humans that are ameliorated with nicotine administration. However, there has been much debate as to whether nicotine improves performance under baseline conditions, or only ameliorates attentional deficits. Thus, we studied the effects of acute and chronic nicotine administration and nicotine withdrawal on attentional performance in the 5-choice serial reaction time task (5-CSRTT) in Wistar and Sprague Dawley (SD) rats under baseline conditions. Wistar rats performed with higher accuracy compared to SD rats. Acute nicotine administration induced small increases in accuracy and correct responses, impulsivity and speed of responding, and decreases in omission errors. These effects were more pronounced in less accurate rats or after task modifications were implemented to disrupt the rats' performance. Chronic nicotine administration via minipumps consistently increased accuracy during days 4-6 of nicotine infusion after the effect of nicotine on impulsivity during days 1-3 dissipated. By contrast, nicotine withdrawal induced decreases in correct responses, and increases in omissions and latencies to respond, but had no effect on accuracy. These results provide evidence that chronic, but not acute, nicotine administration induced accuracy improvement under baseline conditions, while nicotine withdrawal produced some limited performance deficits.     

Psychopharmacological approaches to modulating attention in the five-choice serial reaction time task: implications for schizophrenia

Rationale In schizophrenia, attentional disturbance is a core feature which may not only accompany the disorder, but may precede the onset of psychiatric symptoms.Objectives The five-choice serial reaction time task (5CSRTT) is a test of visuo-spatial attention that has been used extensively in rats for measuring the effects of systemic and central neurochemical manipulations on various aspects of attentional performance, including selective attention, vigilance and executive control. These findings are relevant to our understanding of the neural systems that may be compromised in patients with schizophrenia.Methods The 5CSRTT is conducted in an operant chamber that has multiple response locations, in which brief visual stimuli can be presented randomly. Performance is maintained using food reinforcers to criterion levels of accuracy. Various aspects of performance are measured, including attentional accuracy and premature responding, especially under different attentional challenges.Results The effects of systemic and intra-cerebral infusions of selective dopamine, serotonin and cholinergic receptor agents on the 5CSRTT are reviewed with a view to identifying attention-enhancing effects that may be relevant to the treatment of cognitive deficits in schizophrenia. In addition, some novel agents such as modafinil and histamine receptor agents are also considered. Examining the effects of selective neurochemical lesions helped define the neural locus of attentional effects. Similarly, findings from microdialysis studies helped identify the extracellular changes in neurotransmitters and their metabolites in freely moving rats during performance of the 5CSRTT.Conclusions The monoaminergic and cholinergic systems have independent but complementary roles in attentional function, as measured by the 5CSRTT. These functions are predominantly under the control of the prefrontal cortex and striatum. These conclusions are considered in the context of their application towards therapeutic approaches for attentional disturbances that are typically observed in schizophrenic patients.     

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.     

Attention,impulsivity, and cognitive flexibility in adult male rats exposed to ethanol binge during adolescence as measured in the five-choice serial reaction time task: the effects of task and ethanol challenges

Rationale  

Alcohol abuse is prevalent in adolescent humans, but the long-term behavioral consequences of binge alcohol drinking are unknown.     

Effects of transient inactivation of the subthalamic nucleus by local muscimol and APV infusions on performance on the five-choice serial reaction time task in rats

Within the basal ganglia circuitry, recent conceptions of the subthalamic nucleus are that it fulfils integrative functions. We have previously shown that bilateral excitotoxic lesions of the subthalamic nucleus induce behavioural deficits in a five-choice serial reaction time task in the rat, consistent with attentional impairments and suggesting important roles of this basal ganglia structure in mechanisms of behavioural control. In the present study, we tested the effects of (i) blocking its excitatory inputs (originating mainly in the cerebral cortex and the parafascicular nucleus of the thalamus) via the NMDA receptors and (ii) stimulating its GABA receptors to mimick the influence of its inhibitory inputs (mainly from the globus pallidus). Bilateral microinfusions of APV (NMDA receptor antagonist) or muscimol (GABA-A receptor agonist) into the subthalamic nucleus were administered to rats trained in the same five-choice serial reaction time task. Both APV (0.125–0.5 μg) and muscimol (1–3 ng) reduced choice accuracy, slowed correct responses and increased omissions and perseverative responses. Premature responses tended to increase after APV but decrease after muscimol. Increased perseverations at the food magazine occurred only after muscimol infusions. These results reproduce many of the effects of lesions of the STN and are consistent with an integrative role for this structure in pallidal and thalamo-cortical processing. Received: 19 February 1998/Final version: 12 May 1998     

Activation of 5-HT2A receptors impairs response control of rats in a five-choice serial reaction time task

The present experiments investigated the effects of agents acting at serotonin (5-HT)-2 receptors on the performance of rats in a choice serial reaction time (5-CSRT) task in order to examine the role of 5-HT2 receptors in the modulation of attention and response control. The results indicate that DOI, [(+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride; 0.05, 0.1 and 0.2 mg/kg, subcutaneously], a 5-HT(2A/2C) agonist, slightly impaired the choice accuracy of the well performing rats and markedly increased their premature responding. DOI (0.05 and 0.1 mg/kg) had no effect on the latency to collect earned food pellets or to respond correctly, indicating that these lower doses of DOI did not reduce motivation for the food reward in this task. The selective effect of a low dose of DOI (0.1 mg/kg) on premature responding was completely blocked by ketanserin (0.2 mg/kg), a 5-HT2A antagonist, and ritanserin (0.3 mg/kg), a 5-HT(2A/2C) antagonist, but only partially blocked by a high dose of SER082 (1.0 mg/kg), a 5-HT2C antagonist. In contrast to DOI, mCPP, [1-(3-phenyl)piperazine; 0.05 and 0.15 mg/kg], a 5-HT2C agonist, had no effect on choice accuracy or premature responding, but it reduced behavioral activity and/or arousal as indicated by the decreased number of trials completed and increased the probability of omissions. SER082 (1.0 mg/kg) blocked the effects of mCPP on performance. These data suggest that the overactivation of 5-HT2A receptors impairs response control in a 5-CSRT task, whereas the overactivation of 5-HT2C receptors can affect behavioral activity and/or arousal state of the animals for this food rewarded task.     

Intra-prefrontal 8-OH-DPAT and M100907 improve visuospatial attention and decrease impulsivity on the five-choice serial reaction time task in rats

Rationale. The central serotonergic systems are a major target for drugs used to treat neuropsychiatric disorders such as depression and schizophrenia in which disruption of frontal cortex function has been implicated. However, it is not known precisely how serotonin (5-HT) modulates the medial prefrontal cortex (mPFC) to affect cognitive function and behaviour. Objective. To investigate the roles of 5-HT_1A and 5-HT_2A receptors in mPFC on performance of the five-choice serial reaction time task (5CSRT), which assesses visuospatial attention, impulsivity and motivational processes. Methods. Following training on the 5CSRT, rats were implanted with bilateral guide cannulae aimed at the mPFC. Rats received intra-mPFC infusions of either 8-OH-DPAT (10, 30 and 100 ng) or M100907 (30, 100 and 300 ng) according to a Latin square design. Results. Both 8-OH-DPAT and M100907 selectively enhanced accuracy of target detection. When the stimulus duration was shortened, infusions of 8-OH-DPAT continued to improve accuracy, whereas M100907 decreased premature responding and omissions, thus partly dissociating the effects of these two compounds. Similar effects were obtained following systemic administration of M100907 and 8-OH-DPAT. The effects of 8-OH-DPAT were blocked by the 5-HT_1A antagonist WAY 100635, at a dose that itself had no significant effects on behaviour. Conclusions. These results indicate that modulation of 5-HT function within the mPFC via distinct receptors can enhance performance on the 5CSRT. These findings suggest a mechanism by which serotonergic agents improve cognitive function, which may be relevant to their therapeutic benefit in the treatment of neuropsychiatric disorders. Electronic Publication     

Differential roles of dopamine D1 and D2 receptors in the nucleus accumbens in attentional performance on the five-choice serial reaction time task.

Nucleus accumbens (NAC) dopamine may play a role in attentional and executive processes, as it modulates cortico-limbic inputs, including afferents from the prefrontal cortex. The present study examined the role of NAC dopamine D1 and D2 receptors in visual attentional processes and response control in rats as assessed in the five-choice serial reaction time task (5CSRT). Rats were trained to detect the location of brief (0.5 s) visual targets presented randomly in an array of five apertures to receive food reward. They were tested after bilateral infusions of a D1 receptor antagonist (SCH 23390) and agonist (SKF 38393) and a D2 receptor antagonist (sulpiride) and agonist (quinpirole) into the NAC. While intra-NAC SCH 23390 decreased accurate responding and increased response omissions, SKF 38393 improved accuracy and decreased omissions at the lowest dose (0.1 microg/side). At higher doses, SKF 38393 increased premature 'impulsive' responding. Sulpiride impaired the attentional accuracy of responding and slowed the latency to collect the earned food reward. By contrast, intra-NAC infusions of quinpirole did not significantly affect attentional accuracy, but increased perseverative responding. Optimal performance on the 5CSRT depends on both D1 and D2 receptors in the NAC, but they modulate different aspects of performance. D1 receptor agents had more selective effects on attentional accuracy while D2 receptor stimulation did not affect accuracy or premature responses, but enhanced perseverative responding. The data are discussed in terms of the different functions of NAC dopamine receptors in the processing of information from its different cortico-limbic inputs.     

A study of the nicotinic agonist SIB-1553A on locomotion, and attention as measured by the five-choice serial reaction time task

SIB-1553A is a novel ligand with reputed agonist selectivity at nicotinic receptors containing the β₄ subunit. As such, it represents an interesting pharmacological tool with which to probe the function of nicotine receptor subtypes. In the present studies, we compared SIB-1553A with nicotine in its ability to stimulate locomotion and to enhance attention in rats as assessed using the five-choice serial reaction time task (5-CSRTT). In nicotine-naive rats, SIB-1553A (10–40 mg/kg) induced a comparable increase in locomotion to nicotine (0.4 mg/kg), whereas in nicotine-sensitised rats, an enhanced locomotor response was seen to nicotine (0.4 mg/kg) but not to SIB-1553A (10–80 mg/kg). Similarly, chronic treatment with either SIB-1553A or nicotine did not lead to a cross-sensitised locomotor response. Unlike nicotine, SIB-1553A-induced locomotion was insensitive to antagonism by either mecamylamine (1 mg/kg) or DHβE (3 mg/kg), suggesting a non-nicotinic mechanism. In young and aged rats, nicotine (0.4 mg/kg) enhanced attention as demonstrated by an increase in response accuracy and speed. SIB-1553A (3–10 mg/kg) did not mimic any of these changes and at the highest dose tended to disrupt performance. These results lend further support to the involvement of a high affinity site, possibly α₄β₂, in the locomotor and attentional-enhancing properties of nicotine.     

Double dissociation of serotonergic and dopaminergic mechanisms on attentional performance using a rodent five-choice reaction time task

Abstract Rationale. Converging evidence suggests that dopaminergic and serotonergic mechanisms affect distinct aspects of cognitive performance. Experiments using the rodent five-choice reaction time task have established a critical role for dopaminergic mechanisms in the rat medial prefrontal cortex (mPFC), but have yielded only incomplete evidence regarding the specific functions of serotonin receptors. Objectives. To contrast the effects of systemic or intra-mPFC administration of dopamine or serotonin agents on performance of the five-choice reaction time task. Methods. Two groups of rats trained on the five-choice reaction time task received systemic administration of either the dopamine D₁ receptor partial agonist SKF 38393 (0, 1, 3 or 10 mg/kg IP) or the serotonin 5-HT_2A/C receptor antagonist ketanserin (0, 0.3, 0.6 or 1 mg/kg SC) prior to testing; a further group was implanted with chronic guide cannulae and received ketanserin (0, 0.025, 0.1 or 0.4 μg/side) infused into the mPFC prior to testing. Results. SKF 38393 affected aspects of accuracy and vigour of responding, while regardless of the route of administration ketanserin reduced premature responding without any effect on choice accuracy. Conclusions. Together with our previous findings of increased choice accuracy following intra-mPFC SKF 38393 (Granon et al. 2000), the present results support the notion that the functions of dopamine and serotonin receptors in the mPFC relate to two distinct domains of executive control. Dopamine D₁ receptors are critical to optimise response selection in skilled non-automatic tasks, while serotonin 5-HT_2A receptors regulate the execution of primed responses. Electronic Publication     

ABT-594 improves performance in the 5-choice serial reaction time task under conditions of increased difficulty, sub-chronic dosing, and in poorly-performing subjects

Several studies have tested nicotinic receptor ligands in the 5-Choice Serial Reaction Time Task (5-CSRTT) with varying results. Some investigators have increased attentional demands by modifying task parameters or using aged or poor performing rats to observe treatment effects. This study examined the α4β2 nicotinic agonist ABT-594 in the 5-CSRTT using a variety of manipulations to determine optimal conditions for observing enhancement. ABT-594 had no effect in drug-naïve adult rats that self-initiated trials. Constant trial presentation decreased accuracy and omissions, with the latter significantly attenuated by acute administration of ABT-594 (0.019-0.062 μmol/kg). Sub-chronic treatment (0.019 μmol/kg) initially impaired drug-naïve subjects, but significant improvements in accuracy and decreased omissions were observed after 5 days of dosing. In 18-22 month-old rats, attentional demands were altered by interspersing blocks of trials with different stimulus durations. Acute ABT-594 (0.062 μmol/kg) enhanced accuracy performance in poor performing rats (< 70% accuracy) but not in those that performed well (> 80% accuracy), while omissions were decreased in both groups. Sub-chronic treatment with (0.019 μmol/kg) decreased omissions in all rats, but enhanced accuracy primarily in poor performing rats. These experiments demonstrate that an α4β2 nicotinic agonist can enhance attention, but accuracy effects may only be observed under specific conditions. Moreover, a reduction in omissions was more reliably observed than improvements in accuracy, resulting in a net increase in signals successfully detected.