RESUMO
The rapid serial visual presentation (RSVP) task and continuous performance tasks (CPT) are used to assess attentional impairments in patients with psychiatric and neurological conditions. This study developed a novel touchscreen task for rats based on the structure of a human RSVP task and used pharmacological manipulations to investigate their effects on different performance measures. Normal animals were trained to respond to a target image and withhold responding to distractor images presented within a continuous sequence. In a second version of the task, a false-alarm image was included, so performance could be assessed relative to two types of nontarget distractors. The effects of acute administration of stimulant and nonstimulant treatments for ADHD (amphetamine and atomoxetine) were tested in both tasks. Methylphenidate, ketamine, and nicotine were tested in the first task only. Amphetamine made animals more impulsive and decreased overall accuracy but increased accuracy when the target was presented early in the image sequence. Atomoxetine improved accuracy overall with a specific reduction in false-alarm responses and a shift in the attentional curve reflecting improved accuracy for targets later in the image sequence. However, atomoxetine also slowed responding and increased omissions. Ketamine, nicotine, and methylphenidate had no specific effects at the doses tested. These results suggest that stimulant versus nonstimulant treatments have different effects on attention and impulsive behaviour in this rat version of an RSVP task. These results also suggest that RSVP-like tasks have the potential to be used to study attention in rodents.
Assuntos
Anfetamina , Cloridrato de Atomoxetina , Atenção , Estimulantes do Sistema Nervoso Central , Ketamina , Metilfenidato , Nicotina , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/administração & dosagem , Cloridrato de Atomoxetina/farmacologia , Cloridrato de Atomoxetina/administração & dosagem , Atenção/efeitos dos fármacos , Atenção/fisiologia , Masculino , Ratos , Metilfenidato/farmacologia , Metilfenidato/administração & dosagem , Nicotina/farmacologia , Nicotina/administração & dosagem , Anfetamina/farmacologia , Anfetamina/administração & dosagem , Ketamina/farmacologia , Ketamina/administração & dosagem , Estimulação Luminosa/métodos , Inibidores da Captação Adrenérgica/farmacologia , Inibidores da Captação Adrenérgica/administração & dosagem , Aprendizagem Seriada/efeitos dos fármacos , Aprendizagem Seriada/fisiologia , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Percepção Visual/efeitos dos fármacos , Percepção Visual/fisiologia , Ratos Sprague-DawleyRESUMO
This study investigated whether adolescent nicotine exposure in one generation of rats would impair the cognitive capacity of a subsequent generation. Male and female rats in the parental F0 generation were given twice-daily i.p. injections of either 1.0mg/kg nicotine or an equivalent volume of saline for 35days during adolescence on postnatal days 25-59 (P25-59). After reaching adulthood, male and female nicotine-exposed rats were paired for breeding as were male and female saline control rats. Only female offspring were used in this experiment. Half of the offspring of F0 nicotine-exposed breeders and half of the offspring of F0 saline control rats received twice-daily i.p. injections of 1.0mg/kg nicotine during adolescence on P25-59. The remainder of the rats received twice-daily saline injections for the same period. To evaluate transgenerational effects of nicotine exposure on complex cognitive learning abilities, F1 generation rats were trained to perform a highly structured serial pattern in a serial multiple choice (SMC) task. Beginning on P95, rats in the F1 generation were given either 4days of massed training (20patterns/day) followed by spaced training (10 patterns/day) or only spaced training. Transgenerational effects of adolescent nicotine exposure were observed as greater difficulty in learning a "violation element" of the pattern, which indicated that rats were impaired in the ability to encode and remember multiple sequential elements as compound or configural cues. The results indicated that for rats that received massed training, F1 generation rats with adolescent nicotine exposure whose F0 generation parents also experienced adolescent nicotine exposure showed poorer learning of the violation element than rats that experienced adolescent nicotine exposure only in the F1 generation. Thus, adolescent nicotine exposure in one generation of rats produced a cognitive impairment in the next generation.
Assuntos
Disfunção Cognitiva/induzido quimicamente , Epigênese Genética/efeitos dos fármacos , Nicotina/administração & dosagem , Animais , Comportamento de Escolha/efeitos dos fármacos , Feminino , Masculino , Ratos , Ratos Long-Evans , Aprendizagem Seriada/efeitos dos fármacosRESUMO
The long-term effects of adolescent exposure to methylphenidate (MPD) on adult cognitive capacity are largely unknown. We utilized a serial multiple choice (SMC) task, which is a sequential learning paradigm for studying complex learning, to observe the effects of methylphenidate exposure during adolescence on later serial pattern acquisition during adulthood. Following 20.0mg/kg/day MPD or saline exposure for 5 days/week for 5 weeks during adolescence, male rats were trained to produce a highly structured serial response pattern in an octagonal operant chamber for water reinforcement as adults. During a transfer phase, a violation to the previously-learned pattern structure was introduced as the last element of the sequential pattern. Results indicated that while rats in both groups were able to learn the training and transfer patterns, adolescent exposure to MPD impaired learning for some aspects of pattern learning in the training phase which are learned using discrimination learning or serial position learning. In contrast adolescent exposure to MPD had no effect on other aspects of pattern learning which have been shown to tap into rule learning mechanisms. Additionally, adolescent MPD exposure impaired learning for the violation element in the transfer phase. This indicates a deficit in multi-item learning previously shown to be responsible for violation element learning. Thus, these results clearly show that adolescent MPD produced multiple cognitive impairments in male rats that persisted into adulthood long after MPD exposure ended.
Assuntos
Estimulantes do Sistema Nervoso Central/toxicidade , Comportamento de Escolha/efeitos dos fármacos , Deficiências da Aprendizagem/induzido quimicamente , Metilfenidato/toxicidade , Aprendizagem Seriada/efeitos dos fármacos , Análise de Variância , Animais , Animais Recém-Nascidos , Masculino , Ratos , Ratos Long-Evans , Transferência de Experiência/efeitos dos fármacosRESUMO
Nicotine exposure in adolescent rats has been shown to cause learning impairments that persist into adulthood long after nicotine exposure has ended. This study was designed to assess the extent to which the effects of adolescent nicotine exposure on learning in adulthood can be accounted for by adolescent injection stress experienced concurrently with adolescent nicotine exposure. Female rats received either 0.033 mg/h nicotine (expressed as the weight of the free base) or bacteriostatic water vehicle by osmotic pump infusion on postnatal days 25-53 (P25-53). Half of the nicotine-exposed rats and half of the vehicle rats also received twice-daily injection stress consisting of intraperitoneal saline injections on P26-53. Together these procedures produced 4 groups: No Nicotine/No Stress, Nicotine/No Stress, No Nicotine/Stress, and Nicotine/Stress. On P65-99, rats were trained to perform a structurally complex 24-element serial pattern of responses in the serial multiple choice (SMC) task. Four general results were obtained in the current study. First, learning for within-chunk elements was not affected by either adolescent nicotine exposure, consistent with past work (Pickens, Rowan, Bevins, and Fountain, 2013), or adolescent injection stress. Thus, there were no effects of adolescent nicotine exposure or injection stress on adult within-chunk learning typically attributed to rule learning in the SMC task. Second, adolescent injection stress alone (i.e., without concurrent nicotine exposure) caused transient but significant facilitation of adult learning restricted to a single element of the 24-element pattern, namely, the "violation element," that was the only element of the pattern that was inconsistent with pattern structure. Thus, adolescent injection stress alone facilitated violation element acquisition in adulthood. Third, also consistent with past work (Pickens et al., 2013), adolescent nicotine exposure, in this case both with and without adolescent injection stress, caused a learning impairment in adulthood for the violation element in female rats. Thus, adolescent nicotine impaired adult violation element learning typically attributed to multiple-item learning in the SMC task. Fourth, a paradoxical interaction of injection stress and nicotine exposure in acquisition was observed. In the same female rats in which violation-element learning was impaired by adolescent nicotine exposure, adolescent nicotine experienced without adolescent injection stress produced better learning for chunk-boundary elements in adulthood compared to all other conditions. Thus, adolescent nicotine without concurrent injection stress facilitated adult chunk-boundary element learning typically attributed to concurrent stimulus-response discrimination learning and serial-position learning in the SMC task. To the best of our knowledge, the current study is the first to demonstrate facilitation of adult learning caused by adolescent nicotine exposure.
Assuntos
Comportamento de Escolha/efeitos dos fármacos , Nicotina/toxicidade , Aprendizagem Seriada/efeitos dos fármacos , Estresse Psicológico , Fatores Etários , Animais , Feminino , Injeções , Ratos , Ratos Long-EvansRESUMO
This study was designed to determine whether deficits in adult serial pattern learning caused by adolescent nicotine exposure persist as impairments in asymptotic performance, whether adolescent nicotine exposure differentially retards learning about pattern elements that are inconsistent with "perfect" pattern structure, and whether there are sex differences in rats' response to adolescent nicotine exposure as assessed by a serial multiple choice task. The current study replicated the results of our initial report (Fountain et al., 2008) using this task by showing that adolescent nicotine exposure (1.0mg/kg/day nicotine for 35days) produced a specific cognitive impairment in male rats that persisted into adulthood at least a month after adolescent nicotine exposure ended. In addition, sex differences were observed even in controls, with additional evidence that adolescent nicotine exposure significantly impaired learning relative to same-sex controls for chunk boundary elements in males and for violation elements in females. All nicotine-induced impairments were overcome by additional training so that groups did not differ at asymptote. An examination of the types of errors rats made indicated that adolescent nicotine exposure slowed learning without affecting rats' cognitive strategy in the task. This data pattern suggests that exposure to nicotine in adolescence may have impaired different aspects of adult stimulus-response discrimination learning processes in males and females, but left abstract rule learning processes relatively spared in both sexes. These effects converge with other findings in the field and reinforce the concern that adolescent nicotine exposure poses an important threat to cognitive capacity in adulthood.
Assuntos
Transtornos Cognitivos/induzido quimicamente , Nicotina/toxicidade , Aprendizagem Seriada/efeitos dos fármacos , Caracteres Sexuais , Animais , Condicionamento Operante/efeitos dos fármacos , Feminino , Masculino , RatosRESUMO
RATIONALE: Overactivation of serotonin (5-hydroxytryptamine, 5-HT)(2A) receptors causes impulsivity and attentional deficits. Since 5-HT(2A) receptors are known to entertain antagonistic interactions with metabotropic glutamate (mGlu)2/3 receptors, this interaction may provide an alternative target for a novel class of antipsychotics. OBJECTIVES/METHODS: The study characterizes interactions between 5-HT(2A) and mGlu2/3 receptors implicated in impulse control. Hooded Lister rats were trained in a 5-choice serial reaction time task (5-CSRTT) and treated with the 5-HT(2A/2C) receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropan hydrochloride (DOI, 0.1 mg/kg) and the mGlu2/3 receptor agonist LY379268 (1 mg/kg). In addition, associated drug-induced changes in neuronal activity were assessed via c-Fos immunoreactivity (Fos IR), and co-localization of c-Fos and GABAergic markers was detected using double immunofluorescence labeling. RESULTS: Systemic DOI caused impulsive overresponding that was attenuated in animals pre-treated with LY379268. LY379268 itself had no significant effect on the rats' performance in the 5-CSRTT. DOI enhanced Fos IR within fronto-cortical and limbic brain structures, and this effect was blocked by LY379268 pre-treatment. Double immunofluorescence labeling showed a specific co-localization of DOI-elicited Fos IR with GABAergic (GAD(67)-positive) cells lacking the calcium-binding protein parvalbumin while LY379268 increased Fos IR in GABAergic and non-GABAergic cells. CONCLUSION: Our results suggest that impulsivity is possibly due to a primary increase in Glu transmission mediated via 5-HT(2A) receptor activation. Thus, mGlu2/3 receptor agonists might have some potential for treating motor impulsivity-related impairments while their cognitive enhancing effects were not confirmed in this study.
Assuntos
Aminoácidos/farmacologia , Anfetaminas/antagonistas & inibidores , Encéfalo/fisiologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Comportamento Impulsivo/induzido quimicamente , Comportamento Impulsivo/tratamento farmacológico , Receptores de Glutamato Metabotrópico/agonistas , Aminoácidos/uso terapêutico , Anfetaminas/farmacologia , Animais , Animais não Endogâmicos , Encéfalo/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Comportamento de Escolha/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Neurônios GABAérgicos/efeitos dos fármacos , Neurônios GABAérgicos/fisiologia , Genes fos/fisiologia , Comportamento Impulsivo/fisiopatologia , Imagem Molecular/métodos , Imagem Molecular/psicologia , Ratos , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Aprendizagem Seriada/efeitos dos fármacos , Aprendizagem Seriada/fisiologia , Agonistas do Receptor de Serotonina/farmacologia , Agonistas do Receptor de Serotonina/fisiologiaRESUMO
RATIONAL AND OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Assuntos
Atenção/efeitos dos fármacos , Corpo Estriado/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Fluorbenzenos/farmacologia , Fenciclidina/farmacologia , Piperidinas/farmacologia , Antagonistas do Receptor 5-HT2 de Serotonina , Animais , Corpo Estriado/metabolismo , Relação Dose-Resposta a Droga , Injeções Intraperitoneais , Injeções Subcutâneas , Masculino , Camundongos , Camundongos Endogâmicos DBA , Fosforilação , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Tempo de Reação/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/metabolismo , Aprendizagem Seriada/efeitos dos fármacosRESUMO
RATIONALE: Nicotine-induced cognitive enhancement may be a factor maintaining tobacco smoking, particularly in psychiatric populations suffering from cognitive deficits. Schizophrenia patients exhibit higher smoking rates compared with the general population, suggesting that attempts to self-medicate cognitive schizophrenia deficits may underlie these high smoking levels. OBJECTIVES: The present study explored pro-cognitive effects of nicotine in a model of schizophrenia-like cognitive dysfunction to test this self-medication hypothesis. MATERIALS AND METHODS: We investigated whether chronic nicotine (3.16 mg/kg/day, base) would attenuate the performance disruption in the five-choice serial reaction time task (5-CSRTT, a task assessing various cognitive modalities, including attention) induced by repeated administration of phencyclidine (PCP), an N-methyl-D-aspartate receptor antagonist that induces cognitive deficits relevant to schizophrenia. RESULTS: Chronic nicotine administration shortened 5-CSRTT response latencies under baseline conditions. Nicotine-treated rats also made more correct responses and fewer omissions than vehicle-treated rats. Replicating previous studies, repeated PCP administration (2 mg/kg, 30 min before behavioral testing for two consecutive days followed 2 weeks later by five consecutive days of PCP administration) decreased accuracy and increased response latencies, premature responding, and timeout responding. Chronic nicotine did not attenuate these PCP-induced disruptions. CONCLUSIONS: Chronic nicotine had pro-cognitive effects by itself, supporting the hypothesis that cognitive enhancement may contribute to tobacco smoking. At the doses of nicotine and PCP used, however, no support was found for the hypothesis that the beneficial effects of nicotine on cognitive deficits induced by repeated PCP administration, assessed in the 5-CSRTT, are larger than nicotine effects in the absence of PCP.
Assuntos
Atenção/efeitos dos fármacos , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/psicologia , Cognição/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Fenciclidina , Animais , Transtornos Cognitivos/induzido quimicamente , Interpretação Estatística de Dados , Implantes de Medicamento , Masculino , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Desempenho Psicomotor/efeitos dos fármacos , Ratos , Ratos Wistar , Tempo de Reação/efeitos dos fármacos , Aprendizagem Seriada/efeitos dos fármacosRESUMO
5-HT4 agonists are currently being developed for the treatment of Alzheimer's disease and have previously been demonstrated to improve cognitive performance in a variety of tests but none that specifically test attention. Here we characterise the 5-HT4 partial agonist SL65.0155 compared to the reference drug, nicotine, in a test that is used to measure attention in rats, the five-choice serial reaction time task (5CSRTT). SL65.0155 (0.1 or 1 mg/kg s.c) and nicotine (0.2 mg/kg s.c.) were tested in protocols using fixed or variable stimulus durations. SL65.0155 improved performance by virtue of reducing incorrect responses and increasing % correct trials. Perseverative responses were reduced by SL65.0155, and latency during incorrect trials was increased following treatment with 0.1 mg/kg SL65.0155. Nicotine, as previously reported, improved performance in several parameters in the 5CSRTT, including response latencies, errors of omission and correct responses in both the baseline and variable stimulus protocol. These data suggest 5-HT4 agonists may have beneficial effects on attention and thereby may be useful for the treatment of cognitive deficits.
Assuntos
Comportamento de Escolha/efeitos dos fármacos , Dioxanos/farmacologia , Oxidiazóis/farmacologia , Tempo de Reação/efeitos dos fármacos , Aprendizagem Seriada/efeitos dos fármacos , Animais , Atenção/efeitos dos fármacos , Atenção/fisiologia , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Comportamento de Escolha/fisiologia , Dioxanos/administração & dosagem , Injeções Subcutâneas , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Nicotina/administração & dosagem , Nicotina/farmacologia , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/farmacologia , Oxidiazóis/administração & dosagem , Ratos , Tempo de Reação/fisiologia , Receptores 5-HT4 de Serotonina/fisiologia , Aprendizagem Seriada/fisiologia , Agonistas do Receptor 5-HT4 de SerotoninaRESUMO
In the present study investigating the effects of adolescent nicotine exposure on adult serial pattern learning, adolescent rats received daily i.p. injections of either 1.0 mg/kg nicotine or saline for 5 days per week for 5 weeks beginning on postnatal day 25 (P25), then were allowed 35 days drug free. Rats then began training on P95 as adults on a 24-element serial pattern composed of eight 3-element chunks. Adolescent exposure to 1.0 mg/kg nicotine produced persistent retardation of learning for the first element of each 3-element chunk of the pattern, that is, for chunk boundary elements, and transient retardation of learning for elements 2 and 3 of each chunk of the pattern, that is, for the within-chunk elements. Deficits at chunk boundaries were interpreted as deficits of phrasing cue discrimination learning whereas deficits for learning responses for elements within-chunks (elements 2 and 3 of chunks) were interpreted as deficits of rule learning. These results indicate that the effects of adolescent nicotine exposure on adult learning and cognitive capacity deserve further scrutiny.
Assuntos
Deficiências da Aprendizagem/induzido quimicamente , Nicotina , Aprendizagem Seriada/fisiologia , Análise de Variância , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Masculino , Ratos , Ratos Long-Evans , Aprendizagem Seriada/efeitos dos fármacosRESUMO
BACKGROUND: There is emerging evidence from behavioural studies in humans for nicotinic modulation of inhibitory control. Administration of nicotine, however, also increases general arousal, and this may be responsible for the cognitive enhancing effects of nicotine. DISCUSSION: To test an arousal explanation of nicotine's effects on cognitive inhibition, this study compared the separate and combined effects of an acute dose of nicotine and an arousal manipulation on inhibitory processes associated with the retrieval-induced forgetting (RIF) paradigm. RESULTS: In a double blind placebo controlled design, 1.0 mg of nicotine delivered via nasal spray to non-smoking healthy young adults significantly increased the retrieval-induced forgetting observed in episodic list learning, relative to the placebo condition. In contrast, negative arousal evoked by an unsolvable anagram task had no effect either separately or in combination with nicotine. CONCLUSION: This result argues against the attribution of nicotine-induced changes in RIF performance to non-specific arousal effects. It suggests, furthermore, that pharmacological manipulation of the RIF produces effects that are qualitatively distinct from mood-induced effects. We consider these changes to relate to the direct modulation of information processing by nicotine.
Assuntos
Nível de Alerta/efeitos dos fármacos , Atenção/efeitos dos fármacos , Estimulantes Ganglionares/farmacologia , Inibição Psicológica , Rememoração Mental/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Retenção Psicológica/efeitos dos fármacos , Administração Intranasal , Adolescente , Adulto , Afeto/efeitos dos fármacos , Método Duplo-Cego , Feminino , Humanos , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Aprendizagem por Associação de Pares/efeitos dos fármacos , Resolução de Problemas/efeitos dos fármacos , Desempenho Psicomotor/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacos , Aprendizagem Seriada/efeitos dos fármacosRESUMO
The tremendous increase in the use of mouse inbred strains and mutant mice to study the molecular basis of psychiatric disorders urges for a better understanding of attentional performance in mice. To this aim, we investigated possible strain differences in performance and cholinergic modulation of visuospatial attention in three widely used mouse inbred strains (129S2/SvHsd, C57BL/6JOlaHsd and DBA/2OlaHsd) in the five-choice serial reaction time task. Results indicated that after extended training, performance of 129S2/SvHsd mice was superior to that of C57BL/6JOlaHsd and DBA/2OlaHsd mice in terms of attention, omission errors, inhibitory control and latencies to correct choice. Increasing the attentional load resulted in comparable decrements in attention in all strains and inhibitory control impairments that were most pronounced in DBA/2OlaHsd mice. Further pharmacological evaluation indicated that all strains showed attentional impairments after treatment with the muscarinic and nicotinic antagonists scopolamine and mecamylamine, respectively. 129S2/SvHsd mice were less sensitive, whereas DBA/2OlaHsd mice appeared more sensitive to the detrimental effects of mecamylamine. In addition, subchronic, but not acute, nicotine treatment slightly improved attentional performance in all strains to the same extent. In conclusion, our data indicate strain specificity with particularly good performance of 129S2/SvHsd mice and strong cholinergic involvement in visuospatial attention in mice.
Assuntos
Atenção/fisiologia , Comportamento de Escolha/fisiologia , Fibras Colinérgicas/fisiologia , Aprendizagem em Labirinto/fisiologia , Receptores Colinérgicos/fisiologia , Aprendizagem Seriada/fisiologia , Animais , Atenção/efeitos dos fármacos , Comportamento de Escolha/efeitos dos fármacos , Colinérgicos/farmacologia , Fibras Colinérgicas/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Mecamilamina/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Endogâmicos , Nicotina/farmacologia , Receptores Colinérgicos/efeitos dos fármacos , Escopolamina/farmacologia , Aprendizagem Seriada/efeitos dos fármacos , Percepção Espacial/efeitos dos fármacos , Percepção Espacial/fisiologia , Comportamento Espacial/efeitos dos fármacos , Comportamento Espacial/fisiologia , Especificidade da EspécieRESUMO
RATIONALE: Nicotinic receptors have been implicated in attentional performance. Nicotine can improve attention in animals and humans, but knowledge about relevant receptor subtypes is very limited. OBJECTIVES: The aim was to examine the role of alpha7 receptors in attentional performance of mice and in effects of nicotine. MATERIALS AND METHODS: Mice with targeted deletion of the gene coding for the alpha7 subunit of nicotinic receptors and wild-type controls were trained on a five-choice serial reaction time task with food reinforcers presented under varying parametric conditions. Nicotine was administered in a range of doses (0.001-1.0 mg/kg sc), including those reported to enhance attentional performance. RESULTS: Initially the alpha7(-/-) (knockout) mice responded less accurately and made more anticipatory responses. After task parameters were altered so that the time allowed for responding was reduced and anticipatory (impulsive) responses were punished by a time-out, the pattern of performance deficits changed; there were increased omission errors in alpha7(-/-) mice but normal levels of accuracy and anticipatory responding. Nicotine did not improve any measure of performance, either with the original training parameters or after retraining; the largest dose used (1.0 mg/kg) produced a general impairment of responding in alpha7(-/-) and wild-type mice. CONCLUSIONS: alpha7 nicotinic receptor knockout mice are impaired in performance of the 5-CSRTT, suggesting a possible role for alpha7 receptors in attentional processing. However, identification of a protocol for assessing attention-enhancing effects of nicotine in mice may require further modifications of test procedures or the use of different strains of animal.
Assuntos
Condicionamento Operante/fisiologia , Desempenho Psicomotor/fisiologia , Receptores Nicotínicos/fisiologia , Animais , Atenção/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Relação Dose-Resposta a Droga , Estimulantes Ganglionares/administração & dosagem , Estimulantes Ganglionares/farmacologia , Genótipo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nicotina/administração & dosagem , Nicotina/farmacologia , Desempenho Psicomotor/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacos , Receptores Nicotínicos/genética , Reforço Psicológico , Aprendizagem Seriada/efeitos dos fármacos , Receptor Nicotínico de Acetilcolina alfa7RESUMO
Impaired attention is evident in several neurological and psychiatric disorders. In the present study, attentional capabilities were measured in the operant five-choice serial reaction time task (5-CSRTT) in male (C57BL/6Jx129Sv)F2 hybrid (B6129F2) mice. Main aims were to validate and standardize the test in these mice: to setup procedures, measure potential beneficial effects of sub-chronic nicotine in degraded versions of the 5-CSRTT (by decreasing stimulus duration, inducing white noise and making the stimuli unpredictable) and study disruptive effects of additional administration of the muscarinic antagonist scopolamine. During the baseline pre-nicotine sessions, the B6129F2 mice attained a very good performance in the test (95% accuracy). As stimulus duration was reduced from 2 s to 1 s, response accuracy of the mice decreased. Mice treated with nicotine (0.16 mg/kg) attained significantly higher response accuracy and had a lower percentage of incorrect responses in comparison with the solvent-treated animals. No further beneficial effects of nicotine were found. Reduced response accuracy was also obtained when stimulus duration was reduced from 1 s to 0.5 s and when a variable intertrial interval was introduced. Noise interpolation between trials did not impair performance. Finally, scopolamine (0.16 mg/kg) disrupted attentional functioning. Although most studies have been performed in rats, these results add to the existing evidence that the 5-CSRTT can also be used to assess attentional performance in mice. This offers the opportunity to test transgenic and knockout mice with similar background as the B6129F2 as animal models of psychiatric and neurological diseases.
Assuntos
Atenção/fisiologia , Comportamento de Escolha/fisiologia , Desempenho Psicomotor/fisiologia , Tempo de Reação/fisiologia , Aprendizagem Seriada/fisiologia , Análise de Variância , Animais , Atenção/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Comportamento de Escolha/efeitos dos fármacos , Relação Dose-Resposta a Droga , Camundongos , Camundongos Endogâmicos C57BL , Antagonistas Muscarínicos/farmacologia , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Desempenho Psicomotor/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/genética , Escopolamina/farmacologia , Aprendizagem Seriada/efeitos dos fármacosRESUMO
OBJECTIVE: Behavioural consequences of spontaneous and antagonist-precipitated withdrawal from nicotine upon performance of rats were compared alongside non-nicotinic antagonists in the 5-choice serial reaction time task (5-CSRTT). METHODS: Male hooded Lister rats were trained to detect and respond to brief flashes of light presented every 15 s in one of five holes until a stable level of performance was achieved. RESULTS: Surgical removal of osmotic minipumps from rats having received nicotine (3.16 mg/kg per day base SC) chronically for 7 days produced marked deficits in performance. Compared to saline-treated controls, deficits were apparent 10 h and 16 h following nicotine abstinence; the percentage of omission errors increased concomitantly with modest decreases in response accuracy. Tests conducted 34 h and 106 h post-withdrawal indicated a progressive and complete recovery in attention performance, respectively. In another experiment, following the exposure to the same nicotine regime, administration of the competitive nicotine receptor antagonist dihydro-beta-erythroidine precipitated immediate deficits in performance that were greater than those observed in saline-treated subjects. Methyllycaconitine, an alpha(7) nicotinic receptor antagonist failed to precipitate attention deficits in nicotine-treated rats. Tests with SCH23390 and raclopride produced impairments that were similar in profile to nicotine withdrawal contrasting with non-specific effects of dizocilpine. CONCLUSIONS: These results provide evidence of a cognitive impairment resulting from nicotine deprivation in rodents. Specifically, blockade of D(1) receptors by SCH23390 produced decrements in performance that were qualitatively similar but greater in magnitude to the alterations observed following nicotine withdrawal. Overall, assessing nicotine withdrawal in the 5-CSRTT presents an animal model that exhibits robust construct and face validity.
Assuntos
Atenção/efeitos dos fármacos , Nicotina/toxicidade , Síndrome de Abstinência a Substâncias/fisiopatologia , Animais , Atenção/fisiologia , Comportamento de Escolha/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Masculino , Ratos , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/antagonistas & inibidores , Aprendizagem Seriada/efeitos dos fármacos , Aprendizagem Seriada/fisiologiaRESUMO
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.
Assuntos
Atenção/efeitos dos fármacos , Nicotina/farmacologia , Aprendizagem Seriada/efeitos dos fármacos , Análise de Variância , Animais , Masculino , Ruído , Ratos , Análise e Desempenho de TarefasRESUMO
This study assessed the effects of prenatal cocaine exposure on cognitive functioning, using an intravenous (IV) rodent model that closely mimics the pharmacokinetics seen in humans after smoking or IV injection and that avoids maternal stress and undernutrition. Cocaine-exposed males were significantly impaired on a 3-choice, but not 2-choice, olfactory serial reversal learning task. Both male and female cocaine-exposed rats were significantly impaired on extradimensional shift tasks that required shifting from olfactory to spatial cues; however, they showed no impairment when required to shift from spatial to olfactory cues. In-depth analyses of discrete learning phases implicated deficient selective attention as the basis of impairment in both tasks. These data provide clear evidence that prenatal cocaine exposure produces long-lasting cognitive dysfunction, but they also underscore the specificity of the impairment.
Assuntos
Atenção/efeitos dos fármacos , Cocaína/toxicidade , Efeitos Tardios da Exposição Pré-Natal , Reversão de Aprendizagem/efeitos dos fármacos , Aprendizagem Seriada/efeitos dos fármacos , Animais , Aprendizagem por Discriminação/efeitos dos fármacos , Feminino , Masculino , Rememoração Mental/efeitos dos fármacos , Orientação/efeitos dos fármacos , Gravidez , Ratos , Ratos Long-Evans , Fatores Sexuais , Olfato/efeitos dos fármacosRESUMO
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.
Assuntos
Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Desempenho Psicomotor/efeitos dos fármacos , Tempo de Reação/efeitos dos fármacos , Aprendizagem Seriada/efeitos dos fármacos , Animais , Nível de Alerta/efeitos dos fármacos , Masculino , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Estimulação Luminosa , Ratos , Ratos Sprague-Dawley , Esquema de ReforçoRESUMO
A temporal order discrimination task was performed by 20 regular smokers who were tested with and without a pre-test cigarette in a repeated measures design following overnight abstinence. Subjects were asked to discriminate the temporal order of the rapid sequential illumination of two lights positioned equidistant from a central fixation point. None of the measures of performance in this task were significantly affected by smoking.
Assuntos
Aprendizagem por Discriminação , Aprendizagem Seriada , Fumar/psicologia , Percepção Visual , Adulto , Atenção/efeitos dos fármacos , Aprendizagem por Discriminação/efeitos dos fármacos , Feminino , Humanos , Masculino , Nicotina/administração & dosagem , Psicofísica , Aprendizagem Seriada/efeitos dos fármacos , Fumar/efeitos adversos , Percepção Visual/efeitos dos fármacosRESUMO
INTRODUCTION: The aim of this study was to determine the effect of routine withdrawal of antiepileptic drugs (AEDs) during preoperative evaluation on cognitive functions and also to clarify whether short-term withdrawal of AED would help to lateralize the epileptic focus and to highlight focal dysfunction of memory in patients with temporal lobe epilepsy. MATERIAL & METHODS: Cognitive function was evaluated in 25 patients on full medication and after 1-week during the ongoing AED withdrawal. Six additional patients without AED withdrawal were studied during the same time interval and served as controls. The effect of AED withdrawal on memory tests was evaluated in a subgroup of 11 patients with temporal lobe epilepsy (TLE group). RESULTS: In the TLE group, verbal recurrent-sequences learning tasks deteriorated significantly in patients with left-sided foci during AED withdrawal. In the whole group, attention, concentration and mental flexibility improved both in patients and in controls; the improvement was interpreted as being the result of the practice effect. During AED withdrawal, the number of errors in these tests decreased or remained unchanged. CONCLUSION: We suggest that preoperative neuropsychological testing can be scheduled at any time in patients referred for epilepsy surgery. In patients with temporal lobe epilepsy, the lateralizing results of selective memory tests may be most reliable if the testing is performed during AED withdrawal.