Five-choice Serial Reaction Time Test Research Articles

Preclinical evidence for combining the 5-HT2C receptor agonist lorcaserin and varenicline as a treatment for nicotine dependence.

Varenicline, a nicotinic acetylcholine receptor partial agonist, is used to treat nicotine dependence. Lorcaserin, a 5-HT2C receptor agonist has been approved in some countries to treat obesity. Based on preclinical and preliminary clinical evidence, lorcaserin may have potential to treat nicotine dependence. These experiments examined in rats the effects of combining varenicline (0.5 or 1mg/kg) and lorcaserin (0.3, 0.6 and 1mg/kg) on nicotine self-administration, reinstatement of nicotine seeking, responding for food and impulsive action. Both drugs alone reduced nicotine self-administration. Combining varenicline and 0.6 mg/kg lorcaserin reduced responding to a greater extent than either drug alone. In a relapse model, extinguished nicotine seeking was reinstated by a priming injection of nicotine and nicotine-associated cues. Reinstatement was reduced by varenicline (1mg/kg) and by lorcaserin (0.3mg/kg). Combining lorcaserin (0.3mg/kg) with varenicline (0.5 or 1mg/kg) reduced reinstatement to a greater degree than either drug alone. Both drugs had minimal effects on responding for food, alone or in combination. In the five-choice serial reaction time test, varenicline (0.5 or 1mg/kg) increased impulsivity, measured as increased premature responding. This effect was reduced by lorcaserin (0.3mg/kg). Plasma levels of varenicline or lorcaserin were not altered by co-administration of the other drug. Varenicline and lorcaserin have additive effects on nicotine self-administration, and on nicotine seeking. Lorcaserin prevents impulsivity induced by varenicline. This pattern of effects suggests that co-administration of varenicline and lorcaserin has potential as a treatment for nicotine dependence that may exceed the value of either drug alone.

Stimulation of nicotinic acetylcholine alpha7 receptors rescue schizophrenia-like cognitive impairments in rats

Alpha7 nicotinic acetylcholine receptor (α7 nAChR) dysfunction plays an important role in schizophrenia. Positive allosteric modulators of α7 nAChR have emerged as a promising therapeutic approach to manage cognitive deficits that are inadequately treated in schizophrenic patients. The aim of the present study was to evaluate the ability of type I (CCMI) and type II (PNU120596) α7 nAChR positive allosteric modulators to counteract MK-801-induced cognitive and sensorimotor gating deficits. The activity of these compounds was compared with the action of the α7 nAChR agonist A582941. CCMI, PNU120596 and A582941 reversed the sensorimotor gating impairment evoked by MK-801 based on the prepulse inhibition of the startle response. Additionally, no MK-801-evoked working memory deficits were observed with α7 nAChR ligand pretreatment as assessed in a discrete paired-trial delayed alternation task. However, these compounds did not affect the rats' attentional performances in the five-choice serial reaction time test. The α7 nAChR agents demonstrated a beneficial effect on sensorimotor gating and some aspects of cognition tested in a rat model of schizophrenia. Therefore, these results support the use of α7 nAChR positive allosteric modulators as a potential treatment strategy in schizophrenia.

Developmental Ethanol Exposure Leads to Long-Term Deficits in Attention and Its Underlying Prefrontal Circuitry.

Chronic prenatal exposure to ethanol can lead to a spectrum of teratogenic outcomes that are classified in humans as fetal alcohol spectrum disorders (FASD). One of the most prevalent and persistent neurocognitive components of FASD is attention deficits, and it is now thought that these attention deficits differ from traditional attention deficit hyperactivity disorder (ADHD) in their quality and response to medication. However, the neuronal mechanisms underlying attention deficits in FASD are not well understood. We show here that after developmental binge-pattern ethanol exposure, adult mice exhibit impaired performance on the five-choice serial reaction time test for visual attention, with lower accuracy during initial training and a higher rate of omissions under challenging conditions of high attention demand. Whole-cell electrophysiology experiments in these same mice find dysregulated pyramidal neurons in layer VI of the medial prefrontal cortex, which are critical for normal attention performance. Layer VI neurons show decreased intrinsic excitability and increased responses to stimulation of both nicotinic acetylcholine receptors and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors. Moreover, although nicotinic acetylcholine responses correlate with performance on the five-choice task in control mice, these relationships are completely disrupted in mice exposed to ethanol during development. These findings demonstrate a novel outcome of developmental binge-pattern ethanol exposure and suggest that persistent alterations to the function of prefrontal layer VI neurons play an important mechanistic role in attention deficits associated with FASD.

Effects of the selective 5-HT7 receptor antagonist SB-269970 on premature responding in the five-choice serial reaction time test in rats

The antagonists of serotonin 5-HT7 receptors have been demonstrated to ameliorate cognitive impairments in pharmacological animal models of schizophrenia that involve blockade of N-methyl-d-aspartate receptors (NMDARs). The administration of NMDAR antagonists evokes a broad range of cognitive deficits, including a loss of impulse control. The involvement of 5-HT7 receptors in the modulation of impulsivity has been recently suggested but has not been studied in great detail.The aim of the present study was to examine the effect of a selective 5-HT7 receptor antagonist SB-269970 on a measure of impulsive action, i.e., premature responding on the five-choice serial reaction time task (5-CSRTT) in rats. The antagonist of 5-HT2A receptor M100,907 was used as a positive control. The efficacies of both compounds were assessed in conditions of increased impulsivity that were produced by the administration of the NMDAR antagonist MK-801 or/and non-drug stimuli, i.e., using variable inter-trial intervals (vITIs). To examine the general ability of SB-269970 to counteract the MK-801-induced impairments, a discrete paired-trial delayed alternation task in a T-maze was employed.MK-801 significantly increased the number of premature responses in 5-CSRTT, and this effect was abolished by the administration of M100,907 (0.5mg/kg) and SB-269970 (1mg/kg). In addition, M100,907, but not SB-269970, reduced premature responding in the prolonged ITI trials. Both M100,907 and SB-269970 attenuated MK-801-induced working memory impairment in a T-maze.The present study demonstrated the efficacy of SB-269970 against MK-801-induced premature responding in the 5-CSRTT. This anti-impulsive action may offer additional benefits to the cognitive-enhancing effects of pharmacological blockade of 5-HT7 receptors.

Hyperactivity, increased nicotine consumption and impaired performance in the five-choice serial reaction time task in adolescent rats prenatally exposed to nicotine

Prenatal exposure to nicotine has been linked to accelerated risk for different psychiatric disorders, including conduct disorder, attention deficit hyperactivity disorder (ADHD) and drug abuse. We examine a potential link between prenatal nicotine exposure, hyperactivity, anxiety, nicotine consumption, and cognitive performance in rats. Adolescent offspring of females exposed during pregnancy to 0.06 mg/ml nicotine solution as the only source of water and of a group of pair-fed females, used as a control for anorexic effects of nicotine, were evaluated in a battery of tests, including locomotor activity, the elevated plus maze, two-bottle free-choice nicotine solution consumption, the five-choice serial reaction time test (5-CSRTT) and a delay-discounting test. All tests were conducted between postnatal day (PND) 25 and PND 50. Nicotine-exposed animals expressed hyperactivity, increased number of open arms entries in the elevated plus maze and increased numbers of anticipatory responses in the 5-CSRTT. Decreased aversion for nicotine solution in the free-choice test and decreased numbers of omission errors in the 5-CSRTT were observed both in nicotine-exposed and pair-fed offspring. Neither nicotine exposure nor pair-feeding had an effect on impulsive choice in a delay-discounting test. Our study confirms deleterious effects of prenatal nicotine exposure on important aspects of behaviour and inhibitory control in adolescent rats and supports epidemiological findings that show increased levels of symptoms of ADHD and related disorders among those whose mothers smoked during their pregnancy. It also suggests a link between food restriction during pregnancy and addiction-related behaviours in offspring.

Intact attentional processing but abnormal responding in M1 muscarinic receptor-deficient mice using an automated touchscreen method

Cholinergic receptors have been implicated in schizophrenia, Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. However, to better target therapeutically the appropriate receptor subsystems, we need to understand more about the functions of those subsystems. In the current series of experiments, we assessed the functional role of M1 receptors in cognition by testing M1 receptor-deficient mice (M1R−/−) on the five-choice serial reaction time test of attentional and response functions, carried out using a computer-automated touchscreen test system. In addition, we tested these mice on several tasks featuring learning, memory and perceptual challenges. An advantage of the touchscreen method is that each test in the battery is carried out in the same task setting, using the same types of stimuli, responses and feedback, thus providing a high level of control and task comparability. The surprising finding, given the predominance of the M1 receptor in cortex, was the complete lack of effect of M1 deletion on measures of attentional function per se. Moreover, M1R−/− mice performed relatively normally on tests of learning, memory and perception, although they were impaired in object recognition memory with, but not without an interposed delay interval. They did, however, show clear abnormalities on a variety of response measures: M1R−/− mice displayed fewer omissions, more premature responses, and increased perseverative responding compared to wild-types. These data suggest that M1R−/− mice display abnormal responding in the face of relatively preserved attention, learning and perception.

The Nicotinic Acetylcholine Receptor 5 Subunit Plays a Key Role in Attention Circuitry and Accuracy

Stimulation of the prefrontal cortex by acetylcholine is critical for attention; however, the cellular mechanisms underlying its influence on attention pathways within the brain are not well understood. Pyramidal neurons in layer VI of the prefrontal cortex are believed to play an important role in this process because they are excited by acetylcholine and provide a major source of feedback projections to the thalamus. Here, we show using whole-cell electrophysiology that the relatively rare alpha5 subunit of the nicotinic acetylcholine receptor powerfully enhances nicotinic currents in layer VI pyramidal neurons in prefrontal cortical brain slices from adult mice. In addition, behavioral experiments using the five-choice serial reaction time test show that the presence of the nicotinic receptor alpha5 subunit also increases the accuracy of adult mice on this visual attention task under highly demanding conditions. Together, these findings demonstrate a novel and important role for the nicotinic receptor alpha5 subunit in adult brain circuitry required for attentional performance.

Dopaminergic modulation of the orbitofrontal cortex affects attention, motivation and impulsive responding in rats performing the five-choice serial reaction time task

Understanding the neurobiological factors underlying individual differences in impulsivity may provide valuable insight into vulnerability to impulse control disorders. Recent data implicate both the orbitofrontal cortex (OFC) and the dopaminergic system in psychiatric disorders associated with high levels of impulsivity, including substance abuse, mania and obsessive–compulsive disorder. However, the consequences of modulating dopaminergic activity within the OFC on impulsive behaviour are largely unknown. The effects of direct intra-OFC infusions of agonists and antagonists at the dopamine D 1 and D 2 receptors were therefore assessed in rats performing the five-choice serial reaction time test (5CSRT) of attention and motor impulsivity. Intra-OFC administration of SCH23390, a D 1 receptor antagonist, decreased impulsive responding in highly impulsive (HI) rats, but did not affect behaviour in less impulsive (LI) animals. Furthermore, the D 2 agonist quinpirole caused significant deficits in task performance, impairing accuracy, increasing omissions and decreasing the number of trials completed, which resembled the effects of systemic administration. In contrast, the D 1 agonist SKF 81297 had little effect on behaviour. Neither agonist increased impulsivity. These data provide partial support for the suggestion that high levels of impulsivity are associated with increased dopamine levels within the OFC, but further indicate that simulating dopamine's actions selectively at the D 1 or D 2 receptor cannot reproduce a highly impulsive phenotype. Dopaminergic activity within the OFC may therefore modulate impulsivity indirectly, perhaps in conjunction with other neurotransmitter systems. Furthermore, D 2-mediated neurotransmission within the OFC could make a more fundamental contribution to cognitive behaviour.

Yohimbine Increases Impulsivity Through Activation of cAMP Response Element Binding in the Orbitofrontal Cortex

Stress can increase impulsivity and has a negative impact on psychiatric outcome. Norepinephrine is heavily implicated in responses to stress, and the alpha(2) antagonist yohimbine is used clinically to study this aspect of the stress response. Yohimbine induces mild anxiety and increases impulsivity in healthy volunteers but has more detrimental effects in some psychiatric populations, triggering mania in bipolar patients and drug craving in substance-dependent individuals. Understanding the mechanism by which yohimbine affects brain function could provide insight into the heightened reaction to stress in these patients. Yohimbine's effects were assessed in rats using the five-choice serial reaction time test of attention and impulse control. We then examined whether yohimbine altered activity of cyclic adenosine monophosphate response element binding (CREB) protein-a transcription factor implicated in the stress response-in brain areas that regulate impulsivity. The behavioral consequences of any changes in CREB activity were subsequently assessed using viral-mediated gene transfer to regionally overexpress CREB or the dominant negative antagonist mCREB. Yohimbine increased impulsive responding in rats and selectively increased CREB phosphorylation within the orbitofrontal cortex but not medial prefrontal cortex or nucleus accumbens. Overexpressing mCREB within the orbitofrontal cortex blocked yohimbine's effects on impulsivity, whereas overexpressing CREB in this region increased impulsive responding and potentiated the proimpulsive actions of yohimbine. These data suggest a novel molecular mechanism contributing to impulsivity that may be sensitive to stress. Such findings may improve our understanding of the neurobiological pathways linking the response to stress and impulsivity in both healthy and psychiatric populations.

Comparative study of five antiepileptic drugs on a translational cognitive measure in the rat: relationship to antiepileptic property

Antiepileptic drugs (AEDs) have been available for many years; yet, new members of this class continue to be identified and developed due to the limitations of existing drugs, which include a propensity for cognitive impairment. However, there is little preclinical information about the cognitive effects they produce, which clinically include deficits in attention and slowing of reaction time. The purpose of this study was to profile two first-generation AEDs, phenytoin and valproate, and three second-generation AEDs, levetiracetam, pregabalin and lacosamide. Initially, each drug was examined across a range of well characterised preclinical seizure tests, and then each drug was evaluated in the five-choice serial reaction time test (5-CSRTT) based on efficacious doses from the seizure tests. Each AED was tested for anti-seizure efficacy in either (1) the maximal electroshock seizure test, (2) s.c. PTZ seizure test, (3) amygdala-kindled seizures and (4) the genetic absence epilepsy rat of Strasbourg model of absence seizures. On completion of these studies, each drug was tested in rats trained to asymptotic performance in the 5-CSRTT (0.5 s SD, 5 s ITI, 100 trials). Male rats were used in all studies. Each AED was active in at least one of the seizure tests, although only valproate was active in each test. In the 5-CSRT test, all drugs with the exception of levetiracetam, significantly slowed reaction time and increased omissions. Variable effects were seen on accuracy. The effect on omissions was reversed by increasing stimulus duration from 0.5 to 5 s, supporting a drug-induced attention deficit. Levetiracetam had no negative effect on performance; indeed, reaction time was slightly increased (i.e. faster). These results highlight somewhat similar effects of phenytoin, valproate, pregabalin and lacosamide on attention and reaction time, and comparison to efficacious doses from the seizure tests support the view that there may be a better separation with the newer AEDs. Levetiracetam had no detrimental effect in the 5-CSRTT, which may be consistent with clinical experience where the drug is considered to be well tolerated amongst the AED class.

ADX47273 [S-(4-Fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone]: A Novel Metabotropic Glutamate Receptor 5-Selective Positive Allosteric Modulator with Preclinical Antipsychotic-Like and Procognitive Activities

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) enhance N-methyl-d-aspartate receptor function and may represent a novel approach for the treatment of schizophrenia. ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone], a recently identified potent and selective mGlu5 PAM, increased (9-fold) the response to threshold concentration of glutamate (50 nM) in fluorometric Ca(2+) assays (EC(50) = 170 nM) in human embryonic kidney 293 cells expressing rat mGlu5. In the same system, ADX47273 dose-dependently shifted mGlu5 receptor glutamate response curve to the left (9-fold at 1 microM) and competed for binding of [(3)H]2-methyl-6-(phenylethynyl)pyridine (K(i) = 4.3 microM), but not [(3)H]quisqualate. In vivo, ADX47273 increased extracellular signal-regulated kinase and cAMP-responsive element-binding protein phosphorylation in hippocampus and prefrontal cortex, both of which are critical for glutamate-mediated signal transduction mechanisms. In models sensitive to antipsychotic drug treatment, ADX47273 reduced rat-conditioned avoidance responding [minimal effective dose (MED) = 30 mg/kg i.p.] and decreased mouse apomorphine-induced climbing (MED = 100 mg/kg i.p.), with little effect on stereotypy or catalepsy. Furthermore, ADX47273 blocked phencyclidine, apomorphine, and amphetamine-induced locomotor activities (MED = 100 mg/kg i.p.) in mice and decreased extracellular levels of dopamine in the nucleus accumbens, but not in the striatum, in rats. In cognition models, ADX47273 increased novel object recognition (MED = 1 mg/kg i.p.) and reduced impulsivity in the five-choice serial reaction time test (MED = 10 mg/kg i.p.) in rats. Taken together, these effects are consistent with the hypothesis that allosteric potentiation of mGlu5 may provide a novel approach for development of antipsychotic and procognitive agents.

Opposing effects of 5-HT2A and 5-HT2C receptor antagonists in the rat and mouse on premature responding in the five-choice serial reaction time test

Serotonin (5-HT) has been linked to impulsivity with recent data suggesting that different receptor sub-types exert opposing influences on this behaviour. This work characterised the effects of 5-HT(2A) (ketanserin, (+/-)2,3-dimethoxyphenyl-1-[2-4-(piperidine)-methanol] [M100907]), 5-HT(2B) (6-chloro-5-methyl-1-(5-quinolylcarbamoyl) indoline [SB215505]) and 5-HT(2C) (6-chloro-5-methyl-1-[2-(2-methylpyridyl-3-oxy)-pyrid-5-yl carbomyl] indoline [SB242084]) receptor antagonists on impulsive behaviour, measured in the five-choice serial reaction time test (5CSRTT), in rats and mice. The effects of (+/-)-2,5-dimethoxy-4-iodoamphetamine (DOI) and (S)-2-(chloro-5-fluoro-indol-1-yl)-1-methylethylamine 1:1 C4H4O4 (Ro60-0175), two compounds that have been used extensively as agonists for the 5-HT(2A) and 5-HT(2C) receptor, were also measured. Rats and mice were trained on the 5CSRTT in which reinforcement is earned for detecting and correctly responding to brief presentations of a stimulus light. Impulsivity in this task is measured as premature responding, before stimulus presentation. Several variants of the task were used in which the inter-trial interval (ITI) length was manipulated to alter basal levels of premature responding. In the rat, ketanserin and M100907 reduced and SB242084 enhanced premature responding. SB215505 had no effect. DOI generally disrupted responding, while Ro60-0175 reduced premature responding when a long ITI was used. In mice, M100907 reduced and SB242084 increased premature responding when the ITI was lengthened. The effects of these drugs on other aspects of performance were less robust. M100907 and ketanserin did not affect response accuracy but tended to slow speed of responding; SB242084 occasionally increased speed of responding and slightly reduced accuracy. Serotonin exerts both excitatory and inhibitory influences on motor impulsivity via 5-HT(2A) and 5-HT(2C) receptors in both rats and mice.

Assessment of modafinil on attentional processes in a five-choice serial reaction time test in the rat

It is well known that modafinil is an effective wake-promoting agent, but there is growing evidence to suggest that modafinil may also enhance some aspects of cognition. In man, modafinil has been shown to enhance vigilance in sleep-deprived and/or narcoleptic subjects and also to improve executive-type functioning (predominantly inhibitory response control processes) across a variety of human patient population groups. Preclinically, a delay-dependent improvement has been reported with modafinil in a mouse T-maze test of working memory. To investigate further the role of modafinil as a potential cognition enhancer, the effects of modafinil on attentional processes were assessed in the rat. The aim of the present study was to evaluate the potential of modafinil to enhance five-choice serial reaction time test (5-CSRT) performance. Lister Hooded rats received 32-128 mg/kg modafinil and 5-CSRT performance was assessed under standard and test parametric conditions in which the attentional load was increased, and also under conditions of scopolamine pre-treatment. Modafinil failed to significantly enhance 5-CSRT performance under standard conditions. Similarly, modafinil was unable to reverse the deficits in accuracy and/or increased omission errors induced by either parametric or pharmacological manipulations. Indeed, at higher doses, modafinil caused an increase in premature responding under certain test conditions, suggestive of increased impulsivity. The present findings suggest that, although modafinil may enhance vigilance in sleep-deprived human subjects, attentional processes in normal awake rats remain unaffected. No evidence was found to support a modafinil-induced improvement in response control; rather, under conditions of increased attentional load, modafinil appeared to facilitate impulsive responding. Finally, the failure of modafinil to improve a scopolamine-induced performance deficit suggests that modafinil does not act on the cholinergic system directly.

Effects of scopolamine on a novel choice serial reaction time task

Rats were trained on a novel attentional task adapted from the five-choice serial reaction time test first developed by Carli et al. [1983; Behav. Brain. Res., 9, 361-80]. The novel task required rats to detect the occurrence of brief light flashes in one of two spatial locations following trial initiation by a lever press. Blank trials were interleaved with stimulus trials and the rat had to make a different response to indicate the absence of a light. Occasional light-alone trials were also presented in which the visual stimulus appeared without forewarning. Pre-exposure to food for 60 min prior to test increased response omissions for all trials and slowed correct response latency, but failed to significantly alter accuracy. A decrease in light-stimulus duration (1-0.4 s) decreased accuracy, increased the reporting of blank trials and the number of light-alone trial omissions. Scopolamine (0.03-0.1 mg/kg) and scopolamine methylbromide (0.1 mg/kg) failed to affect accuracy, but increased light-alone trial omissions and lengthened correct response latency. The results confirm that the novel task is able to distinguish between motivational and attentional manipulations, and imply that scopolamine affected performance via nonattentional mechanisms.

Doubly dissociable effects of median- and dorsal-raphé lesions on the performance of the five-choice serial reaction time test of attention in rats

Six experiments examined the effects of selective median (MRN)- and dorsal (DRN)-raphé nucleus lesions on the performance of the five-choice serial reaction time task. In this test rats are required to localize brief visual stimuli presented randomly in one of five locations in approximately 30 min sessions of 100 trials. Both accuracy and latency to respond are measured, as well as the incidence of premature and perseverative responding. Selective 5-HT lesions were induced by intra-raphé infusions of 5,7-dihydroxytryptamine following pretreatment with both a noradrenergic and a dopaminergic re-uptake inhibitor. Analysis of tissue monoamine content demonstrated that the MRN lesion profoundly depleted hippocampal 5-HT (by about 90%) without affecting noradrenaline and dopamine, whereas the DRN lesion primarily depleted (by about 80%) nucleus accumbens and caudate-putamen 5-HT. Rats with 5-HT lesions of the MRN performed the task with a similar degree of accuracy to that exhibited by sham-operated controls. Although the MRN lesion did not affect the latency to respond correctly to the visual targets the lesioned animals collected the food reward significantly faster than the controls. A transient increase in the number of premature responses also resulted from this lesion. In contrast the DRN lesion produced a transient but significant increase in the accuracy of performance, and increased both the speed and the probability of responding. The similarity of the effects following global forebrain 5-HT depletion and the selective DRN lesion suggests that the 5-HT projections of the DRN rather than the MRN may play an important role in impulsive behaviour following 5-HT depletion.