Perseverative Responding Research Articles

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.

Synergistic interaction of dopamine D1 and glutamate N-methyl-d-aspartate receptors in the rat dorsal striatum controls attention

The balance between corticostriatal glutamate inputs and mesostriatal dopamine afferents converging onto the same postsynaptic spines of striatal medium spiny neurons in the dorsal striatum is believed to be crucial for regulating executive functions including attention.In the present study we examined the role of dopamine D(1) and glutamate N-methyl-d-aspartate (NMDA) receptors within the medial territory of the dorsal striatum (dm-STR) of the rat during performance of a selective attention task such as the 5-choice serial reaction time (5-CSRT) task, which incorporates a variety of measures including accuracy of visual discrimination (an index of attentional functioning), omissions, premature and perseverative responses (indices of inhibitory response control) and correct response latency (decision time). Infusion of 30 ng/side of the competitive NMDA receptor antagonist 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP) in the dm-STR decreased accuracy and increased the proportion of omission but had no effect on premature or perseverative responding or correct response latency. A lower dose of 10 ng/side CPP only affected omissions. Blockade of D(1) receptors in the dm-STR by SCH23390 (50 and 100 ng/side) had no effect on accuracy but at 100 ng/side SCH23390 decreased anticipatory responding and increased the proportion of omissions. Co-infusion of SCH23390 (50 ng/side) and CPP (10 ng/side), at individually ineffective doses, potently reduced the accuracy of visual discrimination. The effects were highly selective as no changes in response control, decision time and omissions were detected. The data suggest that the synergistic interaction of D(1) and NMDA receptors on the dendritic spines of GABA neurons within the dm-STR may represent a mechanism for the control of attention.

Post-drug consequences of chronic atypical antipsychotic drug administration on the ability to adjust behavior based on feedback in young monkeys

RationaleAtypical antipsychotic drugs are characterized by their affinity for serotonin and dopamine receptors. The dopaminergic system undergoes developmental changes during childhood, making it vulnerable to external influences such as drug administration.ObjectiveThe purpose of this study was to assess the long-term effects of administering risperidone and quetiapine to 12–24-month-old macaque monkeys on cognitive development, a maturational equivalent to 4–8-year-old children.MethodsForty male pigtailed macaques were used in the study (n = 20 placebo, n = 10 risperidone, n = 10 quetiapine). Following a 4-month pre-drug period, animals were orally administered 2 mg/kg of quetiapine and .025 mg/kg of risperidone daily for 4 months, then the dosage was doubled for another 4 months. They were followed up for 4 months after cessation of the drug. Animals were assessed through all phases of the study on two-object discrimination and learning set.ResultsCognitive development was not negatively affected while the animals were being administered the drug. However, the risperidone group had significant decrements in performance on the learning set task after cessation of the drug (p = 0.006, η p2 = 0.59). Analysis of errors showed that the risperidone group had a significant increase in perseverative responding during the post-drug phase (p = 0.002, η p2 = 0.67).ConclusionAs with human studies, neither risperidone nor quetiapine had a negative impact on cognitive development during the drug phases. However, the results show that the risperidone group had behavioral impairment post-drug, suggesting that the drug may have impacted the development of the dopaminergic system.

Delay discounting in C57BL/6J and DBA/2J mice: Adolescent-limited and life-persistent patterns of impulsivity.

Impulsivity is a defining characteristic of adolescence. Compared to adults, for example, adolescents engage in higher rates of drug and alcohol experimentation, risky sexual practices, and criminal activity. Such behavior may reflect reduced sensitivity to long-term consequences of behavior during adolescence. Recently, our lab has attempted to refine mouse procedures to study developmental trends in decision making in the laboratory. In the present experiment, we examined sensitivity to delayed rewards in C57BL/6J (B6) and DBA/2J (D2) mice during adolescence and adulthood using an adaptation of a 2-week delay discounting procedure developed by Adriani and Laviola (2003). During training, mice could choose between a 20- or 100-μl drop of milk delivered after a 1-s delay. During testing, the delay to the large drop of milk was increased from 1 to 100 seconds. As the delay to the larger volume increased, preference shifted to the smaller, more immediate option. In adolescence, both strains showed similar shifts in preference. In contrast, adult B6 mice were less sensitive to increasing delays than were adult D2 mice, who continued to perform much as their adolescent counterparts. A subsequent resistance-to-extinction test ruled out the possibility that the slower change in the adult B6 mice was due to perseverative responding. The present findings suggest that B6 and D2 strains may be differentially suited to uncovering the biological mechanism of short-term and long-term patterns of impulsive behavior.

Sub-optimal performance in the 5-choice serial reaction time task in rats was sensitive to methylphenidate, atomoxetine and d-amphetamine, but unaffected by the COMT inhibitor tolcapone

Prefrontal cortical dopamine (DA) and norepinephrine (NE) are implicated in multiple aspects of cognitive function assessed via the 5-choice serial reaction time task (5-CSRTT) in rodents. The present studies assessed the effects of the NE reuptake inhibitor atomoxetine (0.5–2.0 mg/kg), the mixed DA/NE reuptake inhibitor methylphenidate (0.1–2.0 mg/kg), the catecholamine releaser d-amphetamine (0.1–1.0 mg/kg) and the catecholamine-o-methyl-transferase (COMT) inhibitor tolcapone (3.0–30.0 mg/kg) in rats that exhibited sub-optimal performance (reduced accuracy: <70% correct) in the 5-CSRTT. Increased ITI durations were associated with increased premature responding. Decreased ITI durations resulted in increased percent omissions, increased perseverative responses and increased response latencies, but had no effects on magazine latencies or percent correct. Atomoxetine decreased premature responding at prolonged ITI durations and methylphenidate decreased percent omissions at low doses (0.1 and 0.5 mg/kg). By contrast, d-amphetamine increased premature and perseverative responding in a dose-dependent manner (0.3–1.0 mg/kg). Finally, tolcapone had no effects on sub-optimal performance in the variable ITI 5-CSRTT. These results suggest minimal potential of tolcapone as a therapeutic agent for ADHD and implicate cortical NE, not DA, in impulsive action.

Attentional set shifting in autism spectrum disorder: Differentiating between the role of perseveration, learned irrelevance, and novelty processing

Autism spectrum disorders (ASD) are associated with impaired attentional set shifting, which may reflect enhanced perseverative responding, enhanced learned irrelevance, and/or reduced novelty processing. We assessed the contribution of these potential error sources in ASD adults. A total of 17 ASD and 19 matched comparison individuals first solved a discrimination learning task. Thereafter, the participants faced three types of attentional shift, specifically designed to isolate the effect of the three possible error sources. ASD participants made more errors than comparison individuals in a shift implying a choice between a novel relevant stimulus attribute and a familiar attribute that was previously relevant but now irrelevant. However, they made fewer errors in a shift involving a choice between a novel irrelevant attribute and a familiar, previously irrelevant but now relevant attribute. The results in combination suggest that the performance difference, at least in the present shift task, is caused by reduced novelty processing in ASD participants.

Impaired Error Monitoring and Correction Function in Autism

INTRODUCTION: Error monitoring and correction is one of the executive functions and is important for effective goal directed behavior. Deficient executive functioning, including reduced error monitoring ability, is one of the typical features of such neurodevelopmental disorders as autism, probably related to perseverative responding, stereotyped repetitive behaviors, and an inability to accurately monitor ongoing behavior. Our prior studies of behavioral and event-related potential (ERP) measures during performance on visual oddball tasks in high-functioning autistic (HFA) children showed that despite only minor differences in reaction times HFA children committed significantly more errors. METHODS: This study investigated error monitoring in children with autism spectrum disorder (ASD) with response-locked event-related potentials - the Error-related Negativity (ERN) and Error-related Positivity (Pe) recorded at fronto-central sites. The ERN reflects early error detection processes, while the Pe has been associated with later conscious error evaluation and attention re-allocation. Reaction times (RT) in correct trials and post-error slowing in reaction times were measured. In this study fourteen subjects with ASD and 14 age- and IQ- matched controls received a three-category visual oddball task with novel distracters. RESULTS: ERN had a lower amplitude and longer latency in the ASD group but was localized in the caudal part of anterior cingulate cortex (ACC) in both groups. The Pe component was significantly prolonged in the ASD group but did not reach significance in amplitude differences compared to controls. We found significant post-error slowing in RTs in controls, and post-error acceleration in RTs in the ASD group. CONCLUSIONS: The reduced ERN and altered Pe along with a lack of post-error RT slowing in autism might be interpreted as insensitivity in the detection and monitoring of response errors and a reduced ability of execute corrective actions. This might result in reduced error awareness and failure in adjustment when dealing with situations where erroneous responses may occur. This deficit might be manifested in the perseverative behaviors often seen in individuals with ASD. The results are discussed in terms of a general impairment in self-monitoring and other executive functions underlying behavioral and social disturbances in ASD.

Perseverative responding and neuroanatomical alterations in adult heterozygous reeler mice are mitigated by neonatal estrogen administration

According to the "extreme-male brain" theory, elevated fetal testosterone levels may partly explain the skewed sex ratio found in Autism Spectrum Disorders (ASD). Correcting this testosterone imbalance by increasing estrogen levels may mitigate the abnormal phenotype. Accordingly, while control heterozygous reeler (rl/+) male mice - a putative model of neuroanatomical and behavioral endophenotypes in ASD - show a decreased number of Purkinje cells (PC) compared to control wild-type (+/+) littermates, neonatal estradiol administration has been shown to correct this deficit in the short-term (i.e. on postnatal day 15). Here, we further investigated the neuroanatomical and behavioral abnormalities of rl/+ male mice and the potential compensatory effects of neonatal treatment with estradiol. In a longitudinal study, we observed that: i) infant rl/+ mice showed reduced motivation for social stimuli; ii) adult rl/+ male mice showed reduced cognitive flexibility; iii) the number of amygdalar parvalbumin-positive GABAergic interneurons were remarkably reduced in rl/+ mice; iv) neonatal estradiol administration into the cisterna magna reverted the abnormal profile both at the behavioral and at the neuroanatomical level in the amygdala but did not compensate for the cerebellar abnormalities in adulthood. This study supports the view that an increased excitation-to-inhibition ratio in the cerebellum and in the amygdala during a critical window of development could be crucial to the social and cognitive phenotype of male rl/+ mice, and that acute estradiol treatment during this critical window may mitigate symptoms' severity.

Activation of type 5 metabotropic glutamate receptors attenuates deficits in cognitive flexibility induced by NMDA receptor blockade

Metabotropic glutamate (mGlu) receptors provide a mechanism by which the function of NMDA glutamate receptors can be modulated. As NMDA receptor hypofunction is implicated in the etiology of psychiatric disorders, including schizophrenia, the pharmacological regulation of mGlu receptor activity represents a promising therapeutic approach. We examined the effects of the positive allosteric mGlu 5 receptor modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB), alone and in combination with the NMDA receptor antagonist MK-801, on a task measuring cognitive set-shifting ability. This task measures NMDA receptor-dependent cognitive abilities analogous to those impaired in schizophrenia. Systemic administration of CDPPB (10 and 30 mg/kg i.p) blocked MK-801 (0.1 mg/kg, i.p.)-induced impairments in set-shifting ability. The effect on learning was dose-dependent, with the 30 mg/kg dose having a greater effect than the 10 mg/kg dose across all trials. This ameliorative effect of CDPPB reflected a reduction in MK-801-induced perseverative responding. These results add to the evidence that mGlu 5 receptors interact functionally with NMDA receptors to regulate behavior, and suggest that positive modulators of mGlu 5 receptors may have therapeutic potential in the treatment of disorders, like schizophrenia, characterized by impairments in cognitive flexibility and memory.

Blockade of serotonin 2A receptors prevents PCP-induced attentional performance deficit and CREB phosphorylation in the dorsal striatum of DBA/2 mice

Functional opposition between N-methyl-D-aspartate and 5-HT(2A) receptors may be a neural mechanism supporting cognitive functions. These systems converge on an intracellular signaling pathway that involves protein kinase A-dependent phosphorylation of different proteins including cyclic adenosine monophosphate response element binding (CREB). Thus, we tested whether selective 5-HT(2A) receptor antagonist, M100907, might abolish phencyclidine (PCP)-induced attentional performance deficit by preventing its effects on transduction mechanisms leading to CREB phosphorylation. Using the five-choice serial reaction time task, the ability of subcutaneous injections of 2.5 and 10 microg/kg of M100907 to abolish the effects of an intraperitoneal injection of 1.5 mg/kg PCP on attentional performance as measured by accuracy (percentage of correct responses) and anticipatory and perseverative responding was assessed in DBA/2 mice. The effects of PCP, M100907, and their combination on S(133)-CREB and T(34)-DARPP32 phosphorylation in the dorsal striatum and prefrontal cortex (PFC) of behaviorally naïve mice were examined using Western blotting technique. PCP reduced accuracy and increased anticipatory and perseverative responses as well as it increased S(133)-CREB phosphorylation in the dorsal striatum but not in the PFC. Ten microg/kg M100907 abolished the PCP-induced attentional performance deficits and the increase in S(133)-CREB but not T(34)-DARPP32 phosphorylation. By itself, M100907 had no effect on attentional performance or phospho-S(133)-CREB and phospho-T(34)-DARPP32. Interestingly, the effect of PCP on phospho-S(133)-CREB but not on phospho-T(34)-DARPP32 was dependent on endogenous 5-HT. The data indicate that blockade of 5-HT(2A) receptors may exert beneficial effects on cognitive deficits through a mechanism linked to striatal S(133)-CREB phosphorylation.

Chronic prenatal ethanol exposure increases disinhibition and perseverative responding in the adult guinea pig

Cognitive and behavioural deficits, including increased impulsivity and perseveration, are associated with chronic prenatal ethanol exposure (CPEE) in humans. We tested whether these same deficits occur in the guinea pig after CPEE treatment. Pregnant guinea pigs received oral administration of ethanol (4 g/kg maternal body weight/day), or isocaloric-sucrose/pair-feeding throughout gestation. Young adult offspring were trained in lever-pressing paradigms to work for a sucrose-pellet food reward. CPEE increased No-Go, but not Go, responses in the Go/No-Go paradigm, indicative of a disinhibition deficit in these animals. Perseverative responses in the Cued Alternation task were also increased in CPEE offspring. These data show that CPEE induces behavioural deficits in the guinea pig that are remarkably similar to the executive function deficits that follow prenatal ethanol exposure in humans.

Low-Level Lead Exposure and Contingency-Based Responding in Preschoolers: An Exploratory Study

Two reversal paradigm tasks (spatial reversal and spatial reversal with irrelevant color cues) originally designed to assess contingency-based responding in primates were adapted for use with 139 preschool children with a mean peak blood lead level (BLL) of 4.2 µg/dl (SD = 2.2). Sixty-nine children with BLL ≥5 µg/dl and 70 children with BLL of <5 µg/dl were included. Results indicated that preschool children with low-level lead exposure take longer to learn associations than preschool children with very low levels of lead exposure, and this difference cannot be attributed to increased distractibility or perseverative responding. These results support the use of these measures to assess specific cognitive functions in preschool children.

Response Disengagement on a Spatial Self-Ordered Sequencing Task: Effects of Regionally Selective Excitotoxic Lesions and Serotonin Depletion within the Prefrontal Cortex

Prefrontal cortex (PFC) is critical for self-ordered response sequencing. Patients with frontal lobe damage are impaired on response sequencing tasks, and increased blood flow has been reported in ventrolateral and dorsolateral PFC in subjects performing such tasks. Previously, we have shown that large excitotoxic lesions of the lateral PFC (LPFC) and orbitofrontal cortex FC (OFC), but not global prefrontal dopamine depletion, markedly impaired marmoset performance on a spatial self-ordered sequencing task (SSOST). To determine whether LPFC or OFC was responsible for the previously observed impairments and whether the underlying neural mechanism was modulated by serotonin, the present study compared the effects of selective LPFC and OFC excitotoxic lesions and 5,7-DHT-induced PFC serotonin depletions in marmosets on SSOST performance. Severe and long-lasting impairments in SSOST performance, including robust perseverative responding, followed LPFC but not OFC lesions. The deficit was ameliorated by task manipulations that precluded perseveration. Depletions of serotonin within LPFC and OFC had no effect, despite impairing performance on a visual discrimination reversal task, thus providing further evidence for differential monaminergic regulation of prefrontal function. In the light of the proposed attentional control functions of ventrolateral PFC and the failure of LPFC-lesioned animals to disengage from the immediately preceding response, it is proposed that this deficit may be due to a failure to attend to and register that a response has been made and thus should not be repeated. However, 5-HT does not appear to be implicated in this response inhibitory capacity.

Sustaining Executive Functions During Sleep Deprivation: A Comparison of Caffeine, Dextroamphetamine, and Modafinil

Stimulant medications appear effective at restoring simple alertness and psychomotor vigilance in sleep deprived individuals, but it is not clear whether these medications are effective at restoring higher order complex cognitive capacities such as planning, sequencing, and decision making. After 44 hours awake, participants received a double-blind dose of one of 3 stimulant medications or placebo. After 45-50 hours awake, participants were tested on computerized versions of the 5-Ring Tower of Hanoi (TOH), the Tower of London (TOL), and the Wisconsin Card Sorting Test (WCST). In-residence sleep-laboratory facility at the Walter Reed Army Institute of Research. Fifty-four healthy adults (29 men, 25 women), ranging in age from 18 to 36 years. Participants were randomly assigned to 1 of 3 stimulant medication groups, including caffeine, 600 mg (n=12), modafinil, 400 mg (n=12), dextroamphetamine, 20 mg (n=16), or placebo (n=14). At the doses tested, modafinil and dextroamphetamine groups completed the TOL task in significantly fewer moves than the placebo group, and the modafinil group demonstrated greater deliberation before making moves. In contrast, subjects receiving caffeine completed the TOH in fewer moves than all 3 of the other groups, although speed of completion was not influenced by the stimulants. Finally, the modafinil group outperformed all other groups on indices of perseverative responding and perseverative errors from the WCST. Although comparisons across tasks cannot be made due to the different times of administration, within-task comparisons suggest that, at the doses tested here, each stimulant may produce differential advantages depending on the cognitive demands of the task.

Sustaining Executive Functions During Sleep Deprivation: A Comparison of Caffeine, Dextroamphetamine, and Modafinil

Stimulant medications appear effective at restoring simple alertness and psychomotor vigilance in sleep deprived individuals, but it is not clear whether these medications are effective at restoring higher order complex cognitive capacities such as planning, sequencing, and decision making. After 44 hours awake, participants received a double-blind dose of one of 3 stimulant medications or placebo. After 45-50 hours awake, participants were tested on computerized versions of the 5-Ring Tower of Hanoi (TOH), the Tower of London (TOL), and the Wisconsin Card Sorting Test (WCST). In-residence sleep-laboratory facility at the Walter Reed Army Institute of Research. Fifty-four healthy adults (29 men, 25 women), ranging in age from 18 to 36 years. Participants were randomly assigned to 1 of 3 stimulant medication groups, including caffeine, 600 mg (n = 12), modafinil, 400 mg (n = 12), dextroamphetamine, 20 mg (n = 16), or placebo (n = 14). At the doses tested, modafinil and dextroamphetamine groups completed the TOL task in significantly fewer moves than the placebo group, and the modafinil group demonstrated greater deliberation before making moves. In contrast, subjects receiving caffeine completed the TOH in fewer moves than all 3 of the other groups, although speed of completion was not influenced by the stimulants. Finally, the modafinil group outperformed all other groups on indices of perseverative responding and perseverative errors from the WCST. Although comparisons across tasks cannot be made due to the different times of administration, within-task comparisons suggest that, at the doses tested here, each stimulant may produce differential advantages depending on the cognitive demands of the task.

Contrasting effects of selective lesions of nucleus accumbens core or shell on inhibitory control and amphetamine‐induced impulsive behaviour

The core and shell subregions of the nucleus accumbens receive differential projections from areas of the medial prefrontal cortex that have dissociable effects on impulsive and perseverative responding. The contributions of these subregions to simple instrumental behaviour, inhibitory control and behavioural flexibility were investigated using a ‘forced choice’ task, various parameter manipulations and an omission schedule version of the task. Post-training, selective core lesions were achieved with microinjections of quinolinic acid and shell lesions with ibotenic acid. After a series of behavioural task manipulations, rats were re-stabilized on the standard version of the task and challenged with increasing doses of d-amphetamine (vehicle, 0.5 or 1.0 mg/kg i.p. 30 min prior to test). Neither core- nor shell-lesioned rats exhibited persistent deficits in simple instrumental behaviour or challenges to behavioural flexibility or inhibitory control. Significant differences between lesion groups were unmasked by d-amphetamine challenge in the standard version of the forced task. Core lesions potentiated and shell lesions attenuated the dose-dependent effect of d-amphetamine on increasing anticipatory responses seen in sham rats. These data imply that the accumbens core and shell subregions do not play major roles in highly-trained task performance or in challenges to behavioural control, but may have opposed effects following d-amphetamine treatment. Specifically, they suggest the shell subregion to be necessary for dopaminergic activation driving amphetamine-induced impulsive behaviour and the core subregion for the normal control of this behaviour via conditioned influences.

Chronic cocaine but not chronic amphetamine use is associated with perseverative responding in humans

Chronic drug use has been associated with increased impulsivity and maladaptive behaviour, but the underlying mechanisms of this impairment remain unclear. We investigated the ability to adapt behaviour according to changes in reward contingencies, using a probabilistic reversal-learning task, in chronic drug users and controls. Five groups were compared: chronic amphetamine users (n = 30); chronic cocaine users (n = 27); chronic opiate users (n = 42); former drug users of psychostimulants and opiates (n = 26); and healthy non-drug-taking control volunteers (n = 25). Participants had to make a forced choice between two alternative stimuli on each trial to acquire a stimulus-reward association on the basis of degraded feedback and subsequently to reverse their responses when the reward contingencies changed. Chronic cocaine users demonstrated little behavioural change in response to the change in reward contingencies, as reflected by perseverative responding to the previously rewarded stimulus. Perseverative responding was observed in cocaine users regardless of whether they completed the reversal stage successfully. Task performance in chronic users of amphetamines and opiates, as well as in former drug users, was not measurably impaired. Our findings provide convincing evidence for response perseveration in cocaine users during probabilistic reversal-learning. Pharmacological differences between amphetamine and cocaine, in particular their respective effects on the 5-HT system, may account for the divergent task performance between the two psychostimulant user groups. The inability to reverse responses according to changes in reinforcement contingencies may underlie the maladaptive behaviour patterns observed in chronic cocaine users but not in chronic users of amphetamines or opiates.

Haloperidol and clozapine have dissociable effects in a model of attentional performance deficits induced by blockade of NMDA receptors in the mPFC

Cognitive impairment in schizophrenia is particularly evident in the domains of attention and executive functions. Atypical antipsychotics are somewhat more effective than conventional antipsychotics in improving cognitive functioning in these patients. The aim of this study was to compare the effects of conventional and atypical antipsychotics in a model of attentional performance deficit of schizophrenia induced by blockade of N-methyl-D: -aspartate (NMDA) receptors in the medial prefrontal cortex. Attentional performance was assessed using the five-choice serial reaction time task. The task provides indices of attentional functioning (% correct responses), executive control (measured by anticipatory and perseverative responding), decision time (measured by correct response latency), and omissions. Haloperidol and clozapine were given intraperitoneally (IP) to animals that had received vehicle or a competitive NMDA receptor antagonist, 3-(R)-2-carboxypiperazin-4-propyl-1-phosphonic acid (CPP), directly into the medial prefrontal cortex. Fifty nanograms/side of CPP reduced accuracy (% correct responses) and increased anticipatory and perseverative responding. Haloperidol (0.03 mg/kg IP) reduced the CPP-induced anticipatory and perseverative overresponding but not the impairment in accuracy. In contrast, clozapine (2.5 mg/kg IP) reversed the decrease in accuracy and impulsivity (anticipatory responding) but not perseverative overresponding. CPP increased decision time and omissions, but these effects were not affected by either haloperidol or clozapine. The effects on "impulsivity" and "compulsive perseveration" in a rat model of attentional and executive deficit of schizophrenia might differentiate conventional and atypical antipsychotics. Antagonistic activity at 5-HT(2A) receptors may best explain the facilitatory effects of clozapine on cognition.

Spatial and visual discrimination reversals in adult and geriatric rats exposed during gestation to methylmercury and n − 3 polyunsaturated fatty acids

Fish contain essential long chain polyunsaturated fatty acids (PUFAs), particularly docosahexaenoic acid (DHA), an omega-3 (or n − 3) PUFA, but are also the main source of exposure to methylmercury (MeHg), a potent developmental neurotoxicant. Since n − 3 PUFAs support neural development and function, benefits deriving from a diet rich in n − 3s have been hypothesized to protect against deleterious effects of gestational MeHg exposure. To determine whether protection occurs at the behavioral level, female Long-Evans rats were exposed, in utero, to 0, 0.5, or 5 ppm of Hg as MeHg via drinking water, approximating exposures of 0, 40, and 400 μg Hg/kg/day and producing 0, 0.29, and 5.50 ppm of total Hg in the brains of siblings at birth. They also received pre- and postnatal exposure to one of two diets, both based on the AIN-93 semipurified formulation. A “fish-oil” diet was high in, and a “coconut-oil” diet was devoid of, DHA. Diets were approximately equal in α-linolenic acid and n − 6 PUFAs. As adults, the rats were first assessed with a spatial discrimination reversal (SDR) procedure and later with a visual (nonspatial) discrimination reversal (VDR) procedure. MeHg increased the number of errors to criterion for both SDR and VDR during the first reversal, but effects were smaller or non-existent on the original discrimination and on later reversals. No such MeHg-related deficits were seen when the rats were retested on SDR after 2 years of age. These results are consistent with previous reports and hypotheses that gestational MeHg exposure produces perseverative responding. No interactions between diet and MeHg were found, suggesting that n − 3 PUFAs do not guard against these behavioral effects. Brain Hg concentrations did not differ between the diets, either. In geriatric rats, failures to respond were less common and response latencies were shorter for rats fed the fish-oil diet, suggesting that exposure to a diet rich in n − 3s may lessen the impact of age-related declines in response initiation.

Memory and Perseveration on a Win-Stay, Lose-Shift Task in Rats Exposed Neonatally to Alcohol

It is important to understand the relationship between perseverative responding resulting from perinatal exposure to alcohol and potential underlying causes, including attention, memory, or response-inhibition problems. The present study was designed to examine the relationship between perseveration and memory. Rats exposed neonatally to 6 g/kg/day alcohol from postnatal day (PD) 4 through PD 9 using an artificial rearing technique (n = 8) were compared with an artificially reared gastrostomy control group (n = 8) and a suckle control group (n = 8). Activity levels were assessed from PD 18-21. Beginning on PD 45, subjects were deprived of food and responded for food on a two-lever win-stay, lose-shift task in which reinforcement probability was a function of reinforcement delivery on the previous trial. If reinforcement was delivered, only a response on the same lever (stay) was reinforced. If reinforcement was not delivered, only a response on the opposite lever (shift) was reinforced. Effective responding depended on subjects remembering whether a reinforcer was delivered on the preceding trial. The intertrial interval varied across conditions (5 seconds or 60 seconds). Alcohol-exposed rats showed increased activity during activity testing but did not differ from controls on win-stay, lose-shift accuracy. All groups showed a performance decrease at longer intertrial intervals. Alcohol-exposed rats showed increased lever pressing during the intertrial interval compared with suckle control rats but not with gastrostomy control rats. Choice behavior was comparable for all groups on the win-stay, lose-shift task, indicating that memory, as assessed by this task, was not differentially affected by alcohol exposure. Alcohol-exposed rats responded more during the intertrial interval compared with suckle controls, suggesting increased activity without increased response inhibition. The win-stay, lose-shift procedure is a potentially useful tool for separating simple activity level effects, memory-related effects, and response-inhibition effects. This study also highlights the need for additional research describing the relationship between perseverative responding and underlying mechanisms.