Decision-making and frontoparietal resting-state functional connectivity among impulsive-compulsive diagnoses. Insights from a Bayesian approach.

The Iowa Gambling Task (IGT) is one of the most widely used paradigms for assessing decision-making. An impairment in this process may be linked to several psychopathological disorders, such as obsessive-compulsive disorder (OCD), substance abuse disorder (SUD) or attention-deficit/hyperactivity disorder (ADHD), which could make it a good candidate for being consider a transdiagnostic domain. Resting-state functional connectivity (rsFC) has been proposed as a promising biomarker of decision-making. In this study, we aimed to identify idiosyncratic decision-making profiles among healthy people and impulsive-compulsive spectrum patients during the IGT, and to investigate the role of frontoparietal network (FPN) rsFC as a possible biomarker of different decision-making patterns. Using functional near-infrared spectroscopy (fNIRS), rsFC of 114 adults (34 controls; 25 OCD; 41 SUD; 14 ADHD) was obtained. Then, they completed the IGT. Hybrid clustering methods based on individual deck choices yielded three decision-makers subgroups. Cluster 1 (n = 27) showed a long-term advantageous strategy. Cluster 2 (n = 25) presented a maladaptive decision-making strategy. Cluster 3 (n = 62) did not develop a preference for any deck during the task. Interestingly, the proportion of participants in each cluster was not different between diagnostic groups. A Bayesian general linear model showed no credible differences in the IGT performance between diagnostic groups nor credible evidence to support the role of FPN rsFC as a biomarker of decision-making under the IGT context. This study highlights the importance of exploring in depth the behavioral and neurophysiological variables that may drive decision-making in clinical and healthy populations.

Dietary tryptophan depletion alters the faecal bacterial community structure of compulsive drinker rats in schedule-induced polydipsia.

RATIONALE: Compulsive behaviour, present in different psychiatric disorders such as obsessive-compulsive disorder, schizophrenia and drug abuse, is associated with altered levels of serotonin (5-hydroxytryptamine, 5-HT). The gut microbiota regulates tryptophan (TRP) metabolism and may affect global 5-H synthesis in the enteric and central nervous systems, suggesting a possible involvement of gut microbiota in compulsive spectrum disorders. OBJECTIVES: The present study investigated whether chronic TRP depletion by diet alters the faecal bacterial community profiles of compulsive versus non-compulsive rats in schedule-induced polydipsia (SIP). Peripheral plasma 5-HT and brain-derived neurotrophic factor (BDNF) levels were evaluated. METHODS: Wistar rats were selected as High Drinkers (HD) or Low Drinkers (LD) according to their SIP behaviour and were fed for 14 days with either a TRP-free diet (T-) or a TRP-supplemented diet (T+). The faecal bacterial community structure was investigated with 16S rRNA gene-targeted denaturing gradient gel electrophoresis (DGGE) fingerprinting analysis. RESULTS: Compulsive HD rats showed a lower bacterial diversity than LD rats, irrespectively of the diet. The TRP-depleted HD rats, the only group increasing compulsive licking in SIP, showed a reduction of bacterial evenness and a highly functionally organized community compared with the other groups, indicating that this bacterial community is more fragile to external changes due to the dominance of a low number of species. The chronic TRP depletion by diet effectively reduced peripheral plasma 5-HT levels in both HD and LD rats, while plasma BDNF levels were not altered. CONCLUSIONS: These results highlight the possible implication of reduced microbial diversity in compulsive behaviour and the involvement of the serotonergic system in modulating the gut brain-axis in compulsive spectrum disorders.

Transcranial direct current stimulation improves risky decision making in women but not in men: A sham-controlled study.

Behavioral and anatomical sex-related differences have been traditionally found in decision-making processes assessed by Iowa Gambling Task (IGT). So far, the administration of transcranial direct current stimulation (tDCS) over orbitofrontal regions has shown an enhancing effect over decision-making. However, it is unknown whether there is a sex-dependent effect of stimulation in decision-making, a key question considering previous differences between men and women in IGT and the influence of individual differences in tDCS. The present study examines, at first time, the interaction between sex and tDCS in decision-making. For that aim, in a first experimental phase, ninety-two healthy participants performed the IGT. In a second phase, sixty-one participants received 20 min of anodal or sham tDCS over the right orbitofrontal cortex (rOFC) in a single-session pre-post sham-controlled study. To support the focality of the montage, a Stop Signal Task (SST) was used as a control task and also a numerical simulation of current flow distribution was performed. According to literature, in the first phase, results showed that men outperformed women in the IGT. In the second phase, the stimulation varied the IGT performance according to a sex specific manner: anodal tDCS increased the IGT performance in women, while in men; the stimulation did not produce any effect. Results were mediated by sex-specific morphological differences. These results highlight the necessity to consider the interaction of sex with the effect of the stimulation in future tDCS protocols, specifically in future clinical studies.

tDCS recovers depth perception in adult amblyopic rats and reorganizes visual cortex activity.

Amblyopia or lazy eye is a neurodevelopmental disorder that arises during the infancy and is caused by the interruption of binocular sensory activity before maturation of the nervous system. This impairment causes long-term deterioration of visual skills, particularly visual acuity and depth perception. Although visual function recovery has been supposed to be decreased with age as consequence of reduced neuronal plasticity, recent studies have shown that it is possible to promote plasticity and neurorestoration in the adult brain. Thus, transcranial direct current stimulation (tDCS) has been shown effective to treat amblyopia in the adulthood. In the present work we used postnatal monocular deprivation in Long Evans rats as an experimental model of amblyopia and the cliff test task to assess depth perception. Functional brain imaging PET was used to assess the effect of tDCS on cortical and subcortical activity. Visually deprived animals ability to perceive depth in the cliff test was significantly reduced in comparison to their controls. However, after 8 sessions of tDCS applied through 8 consecutive days, depth perception of amblyopic treated animals improved reaching control level. PET data showed 18F-FDG uptake asymmetries in the visual cortex of amblyopic animals, which disappeared after tDCS treatment. The possibility of cortical reorganization and stereoscopy recovery following brain stimulation points at tDCS as a useful strategy for treating amblyopia in adulthood. Furthermore, monocular deprivation in Long Evans rats is a valuable research model to study visual cortex mechanisms involved in depth perception and neural restoration after brain stimulation.

Behavioral and biological markers for predicting compulsive-like drinking in schedule-induced polydipsia.

Schedule-induced polydipsia (SIP), characterized by the development of persistent and excessive drinking under intermittent food-reinforcement schedules, is an animal model of compulsive behavior that can differentiate two populations: high drinkers (HD) and low drinkers (LD). The aim of the present study was to identify behavioral and biological markers to predict the vulnerability to developing compulsive-like drinking in SIP. Adult male Wistar rats were first trained in a spatial-discrimination serial reversal-learning task and in a reinforcer devaluation task to measure behavioral flexibility and habit formation, respectively. Subsequently, the rats were tested using the SIP protocol and identified as HD or LD based on their drinking rates. The performance of HD and LD rats in the two previous tasks was then analyzed. Before and after SIP exposure, blood glucose and plasma corticosterone (CORT) levels were measured. Additionally, serum electrolyte levels, including sodium, potassium, and chloride, were analyzed after SIP. HD rats showed higher behavioral inflexibility by exhibiting increased perseverative responses in the reversal-learning task and insensitivity to reinforcer devaluation during extinction under selective satiation. After SIP exposure, HD rats exhibited increased basal plasma CORT levels, indicating that this vulnerable group might have a dysregulation of the HPA axis. Although HD and LD rats had blood glucose levels within normal range, the HD group showed lower levels. The HD group did not exhibit hyponatremia (i.e., reduced serum sodium levels) when compared to LD rats after 20 daily SIP sessions. The results of the present study demonstrated that HD rats exhibit behavioral inflexibility and greater habitual-like behavior before SIP. Moreover, these results highlight the importance of measuring different behavioral and biological markers for predicting the vulnerability to developing compulsivity, and for enhancing the understanding of the pathophysiology of compulsive spectrum disorders.

Excessive habit formation in schedule-induced polydipsia: Microstructural analysis of licking among rat strains and involvement of the orbitofrontal cortex.

Schedule-induced polydipsia (SIP) is an animal model of compulsive drinking that selects for individual differences and varies across rat strains. The aim of this study was to investigate excessive habit formation by analyzing the SIP licking microstructure among rat strains, and to compare the brain areas activated by SIP in different populations. Wistar, Long Evans and Roman High- and Low-Avoidance rat strains were compared using a cluster analysis of 2 main variables, that is, frequency of licking (percentage of interpellet intervals with drinking episodes) and intensity of licking (mean number of licks per interpellet interval), and were found to exhibit high intensity and frequent licking (compulsive drinkers, CD), low intensity but frequent licking (habitual drinkers, HD), and low intensity and low-frequency licking (low drinkers, LD). The Wistar strain showed a higher frequency and intensity of licking, and had the largest group of CD rats when compared with the other strains. Regarding the acquisition of SIP, CD rats showed a higher intensity of licking when compared with the HD and LD rats. Moreover, c-Fos quantification revealed that rats in the CD group showed hyperactivity in the lateral orbitofrontal cortex and basolateral amygdala when compared with the LD group. Analyzing the SIP microstructure could be a valuable tool for understanding the role of excessive habit formation in the development of compulsive drinking and its underpinning neurobiological mechanisms.

Transcranial direct-current stimulation (tDCS) improves detection of simple bright stimuli by amblyopic Long Evans rats in the SLAG task and produces an increase of parvoalbumin labelled cells in visual cortices.

In this work visual functional improvement of amblyopic Long Evans rats treated with tDCS has been assessed using the "slow angled-descent forepaw grasping" (SLAG) test. This test is based on an innate response that does not requires any memory-learning component and has been used before for measuring visual function in rodents. The results obtained show that this procedure is useful to assess monocular but not binocular deficits, as controls and amblyopic animals showed significant differences during monocular but not during binocular assessment. On the other hand, parvoalbumin labelling was analysed in three areas of the visual cortex (V1M, V1B and V2L) before and after tDCS treatment. No changes in labelling were observed after monocular deprivation. However, tDCS treatment significantly improved vision through the amblyopic eye, and a significant increase of parvoalbumin-positive cells was observed in the three areas, both in the stimulated hemisphere but also in the non-stimulated hemisphere. This effect occurred both in control and amblyopic animals. Thus, tDCS induced changes are similar in controls and amblyopic animals, although only the last one showed a functional improvement.

Transcranial direct current stimulation improves visual acuity in amblyopic Long-Evans rats.

Transcranial direct current stimulation (tDCS) has proved to increase brain cortex plasticity and different models of brain damage. In this work, we have analyzed the effects of tDCS in an experimental model of amblyopia using Long-Evans rats. Animals were monocularly deprived between 12 and 75 postnatal days and visual cortex contralateral to the deprived eye was stimulated using anodal tDCS during 8days (20min/day). The effects of tDCS treatment on the visual function were evaluated by using the optomotor reflex of the animals as a measure of visual acuity. Results obtained indicate that monocular occlusion during the critical period lead to a reduction of visual acuity in monocular and binocular conditions. Stimulation with anodal tDCS produced a nearly full recovery in visual acuity of amblyopic animals. However, same stimulation protocol in healthy control animals produced a decrease of binocular visual acuity. These data indicate that tDCS can reverse the effects of monocular deprivation on visual acuity, although it is essential to use this technique in a controlled way due to the possible adverse effects on healthy individuals.

Impulsivity as long-term sequelae after chlorpyrifos intoxication: time course and individual differences.

Chlorpyrifos (CPF) is a common organophosphate (OP) insecticide that has been widely used in agriculture as a pesticide. The primary mechanism of acute toxic action of OPs is initiated by acetylcholinesterase (AChE) inhibition. However, non-AChE targets have also been proposed as alternative that contributes to the acute lethal action and side effects of short or long-term exposure. Recently, we have found that a single dose of 250 mg/kg CPF produces acceleration in acquisition on schedule-induced polydipsia (SIP) procedure 6 months after its administration. Moreover, CPF animals show a higher level of impulsivity in a delay-discounting task 1 year after acute administration, and these effects are potentiated when animals are divided into high (HD) and low (LD) drinkers in SIP. In the present study, rats were injected with a subcutaneous (sc) dose of 250 mg/kg of CPF, and 10 weeks later its effect on delay-discounting task was evaluated. Consequently, these animals were evaluated based on SIP, and divided into two populations (HD and LD) according to their rates of drinking in this task. One year after OP administration, these animals were re-evaluated in a delay-discounting task. Results revealed that the CPF-administered rats prefer immediate reward and show a more impulsive choice, 10 weeks after CPF administration. Furthermore, 1 year after it administration, only animals treated with CPF that are high drinkers on SIP are more impulsive than the rest of the groups Therefore, these data suggest that some individuals are more sensitive to OP intoxication than the others, at least in terms of durability of sequelae.

Acute high dose of chlorpyrifos alters performance of rats in the elevated plus-maze and the elevated T-maze.

Chlorpyrifos (CPF) is a broad spectrum organophosphate (OP) pesticide widely used in agriculture, industry and household. Several animal studies indicate emotional disturbances after CPF exposure, although the results are sometimes puzzling. Thus, both anxiolytic and anxiogenic effects of CPF have been reported in different animal models of anxiety [Sánchez-Amate MC, Flores P, Sánchez-Santed F. Effects of chlorpyrifos in the plus-maze model of anxiety. Behav Pharmacol 2001;12:285-92; Sánchez-Amate MC, Dávila E, Cañadas F, Flores P, Sánchez-Santed F. Chlorpyrifos shares stimulus properties with pentilenetetrazol as evaluated by and operant drug discrimination task. Neurotoxicology 2002;23:795-803; López-Crespo G, Carvajal F, Flores P, Sánchez-Santed F, Sánchez-Amate MC. Time-course of biochemical and behavioural effects of a single high dose of chlorpyrifos. Neurotoxicology 2007;28:541-7]. On the other hand, other behavioural effects of CPF are time-dependent [López-Crespo G, Carvajal F, Flores P, Sánchez-Santed F, Sánchez-Amate MC. Time-course of biochemical and behavioural effects of a single high dose of chlorpyrifos. Neurotoxicology 2007;28:541-7], raising the question that the effects of CPF could be task and post-administration time dependent. To test this hypothesis, three groups of rats were treated with a single high dose of CPF (250 mg/kg); one of the groups was tested on day 5 on the elevated plus-maze, to complete our previous study on day 2 [Sánchez-Amate MC, Flores P, Sánchez-Santed F. Effects of chlorpyrifos in the plus-maze model of anxiety. Behav Pharmacol 2001;12:285-92]. The remaining groups were tested on the elevated T-maze on days 2 and 5. CPF produced an increased open arm activity on the elevated plus-maze on day 5, an increased escape latency on the elevated T-maze on day 2 and an impaired inhibitory avoidance on day 5. Data are discussed taking together all studies carried out in our laboratory, confirming that CPF effects on emotional behaviour are dependent on both task contingencies and post-administration time.

Time course of biochemical and behavioural effects of a single high dose of chlorpyrifos.

The purpose the present study was to determine if tolerance is developed to all behavioural effects produced by a single high dose of chlorpyrifos (CPF). For this, the study was divided in two phases; in the first phase, we studied the time course of the effects produced by treatment with a high dose of CPF (250 mg/kg s.c.) on rat locomotor activity and anxiety behaviours recorded on an open-field, as well as on AChE inhibition. Results showed that CPF produced a maximum inhibition of AChE (72% of inhibition) 2 days after its administration, exhibiting a partial recovery of its activity by day 30 (55% of inhibition). On locomotor activity CPF produced a biphasic effect; a reduction only on day 2, and an increase on day 30. An anxiolytic-like effect was only observed within 2 and 5 days after CPF treatment. These results indicate that the tolerance has been developed to the behavioural effects produced by s.c. administration of CPF, but with a different time course. In the second phase, since disturbances in cholinergic system might trigger dopaminergic dysfunctions, we tested the locomotor activity following challenge with amphetamine (1mg/kg i.p.) at 11 and 30 days after CPF treatment. Data obtained showed that amphetamine produced an increase in total distances and rearing in vehicle and CPF groups on days 11 and 30. However, CPF group exhibited lower increase relative to vehicle group in both days. This effect is independent of the percentage of AChE inhibition and therefore, of change in the cholinergic system. Data are discussed under the light of the adaptative mechanisms underlying the recovery of the cholinergic overstimulation after s.c. exposure to high doses of CPF.

Vulnerability of long-term neurotoxicity of chlorpyrifos: effect on schedule-induced polydipsia and a delay discounting task.

INTRODUCTION: Chlorpyrifos (CPF) is a common organophosphate (OP) insecticide that has been widely used in extensive agriculture as a pesticide. The primary mechanism of acute toxic action of OPs is inhibition of acetylcholinesterase (AChE). However, targets other than AChE have been proposed to contribute to the acute lethal action and side effects of short- or long-term exposure to these compounds. Bekkedal et al. (Sci Total Environ 274:119-123;2001) showed that chronic administration of the OP trimethylolpropane phosphate (TMPP) reduces the number of schedule-induced polydipsia (SIP) sessions necessary to induce asymptotic drinking level. MATERIALS AND METHODS: In the present work, rats were injected with 250 mg/kg CPF and 6 months later, its effect on schedule-induced polydipsia was evaluated. In addition, after stable levels of SIP, a pharmacological study was carried out to determine the implication of other systems in the long-term effects of OPs. Finally, these animals were evaluated in a delay discounting task, as a measure of impulsivity. RESULTS: Results indicate that the CPF group gives more licks to obtain the same amount of water than control rats (VHC). Moreover, the administration of diazepam produces an increased water intake in the CPF without any observable effect in VHC rats. Data of the delay discounting task show that CPF rats prefer an immediate reward and show a major impulsive choice. DISCUSSION: Taken together, our data confirm and extend the long-term behavioral effects of subcutaneous administration of CPF and point to a role for other systems that, besides AChE inhibition, contribute to the long-term neurotoxicity of CPF.

Differences in corticosterone level due to inter-food interval length: implications for schedule-induced polydipsia.

The purpose of this study was to determine the effects of different food-reinforcement schedules on plasma corticosterone (CORT), and its possible involvement in the acquisition and maintenance of schedule-induced polydipsia (SIP). In Experiment 1, three groups of rats were submitted to two different fixed-interval (FI) schedules with inter-food intervals of 30 and 120 s, and to a massed-feeding presentation for 40 days until SIP was well stabilized. In Experiment 2, six groups of rats were exposed to the same schedules, FI 30s and FI 120s, and to the massed-feeding condition, but no water bottles were presented. CORT levels were determined on Days 3 and 40. Results of Experiment 1 indicated that FI 30s schedule, but not FI 120s or the massed-feeding condition, induces excessive drinking from Day 3. Results in Experiment 2 indicated that CORT levels were similar for all the groups on Day 3. However, only animals on the FI 30s schedule did increase their CORT levels on Day 40, with no variation in the hormone in the other two conditions, FI 120s and massed-feeding presentations. The data are discussed in terms of the implications of these results for hypotheses of SIP as anxiolitic behavior.

Neuroanatomical targets of the organophosphate chlorpyrifos by c-fos immunolabeling.

Chlorpyrifos (CPF) is an organophosphate widely used as an insecticide in agriculture which elicits short- and long-term neurobehavioral deficits after acute administration. Because little is known about the specific brain areas targeted by CPF, investigating for the location of its neuroanatomical targets could help to describe the brain systems involved in the neurobehavioral toxicity developed in CPF-exposed organisms. To meet this objective, in the present study we evaluated CPF-induced c-fos expression. In addition, locomotor behavior and cerebral cholinesterase level were evaluated. We found two main sets of results. First, no significant c-fos expression was found in cholinoceptive regions in CPF-treated rats 2 h or 24 h post-administration, despite the fact that 41% and 62% acetylcholinesterase inhibition, respectively, were present in brain homogenates. These results are consistent with previous reports showing CPF-induced activation of adaptive neural mechanisms re-establishing cholinergic tone. Second, 24 h post-intoxication CPF elicited c-fos expression in cytokine-related areas. Cytokines have been involved in anxiety-like responses and psychiatric stress syndromes. Taking into account that CPF triggers the synthesis of peripheral cytokines, the present data stress the need to further clarify functional relations between organophosphate-triggered peripheral cytokines and emotional disturbances reported in intoxicated organisms.

[Neuropsychological sequelae of acute poisoning by pesticides containing cholinesterase inhibitors]. / Departamento de Neurociencia y Ciencias de la Salud, Universidad de Almería, Amlería, Espana. mdroldan@ual.es

In recent years a number of studies have drawn attention to the possible neuropsychological sequelae stemming from acute poisoning by certain substances, namely cholinesterase inhibitors. These chemicals, carbamates and organophosphorates (OP), have been used in industry, for washing cattle, as insecticides and even as chemical agents in terrorist attacks and in wars. Nowadays, they are widely used as a pesticide and this is particularly so in regions such as the west of Almeria. The intensive farming in greenhouses carried out in this area, together with the conditions in which these products are used and handled, leads to a relatively high number of cases of poisoning. Yet this is not an isolated fact; the first clinical study to describe cases of poisoning by these substances in workers was published back in 1955. Some of the neurotoxic sequelae deriving from such intoxications are well defined: acute cholinergic syndrome, intermediate syndrome and delayed polyneuropathy provoked by OP (OPIDN). Several studies have been carried out over the past few decades to measure the long term neuropsychological disorders produced by acute poisoning by these substances, and findings suggest that both cholinesterase inhibition and other biochemical phenomena can have permanent neurotoxic consequences. This communication aims to bring some order to the data offered by the different studies by analysing and verifying the evaluation protocols followed, the results of the neurophysiological and neurocognitive biochemical measurements, the type of poisoning and the time elapsed since they occurred, so that they can be summarised and taken as guidelines for possible work to be carried out in the future.

Secuelas neuropsicológicas de las intoxicaciones agudas por plaguicidas inhibidores de las colinesterasas / Neuropsychological sequelae of acute poisoning by pesticides containing cholinesterase inhibitors

En los últimos años, algunos estudios han señalado las posibles secuelas neuropsicológicas derivadas de la intoxicación aguda por ciertas sustancias: los inhibidores de las colinesterasas. Estos productos, carbamatos y organofosforados, se han utilizado en la industria, el lavado de ganado, como insecticidas e incluso como armas químicas en atentados terroristas y guerras. Actualmente está muy difundido su uso como plaguicida, de especial relevancia en zonas como el poniente almeriense, donde la agricultura intensiva de invernaderos, junto con las condiciones de uso y manipulación de estos productos, hace que se registre un buen número de intoxicaciones. Pero este hecho no es aislado: ya en 1955 se publicó el primer estudio clínico que describía intoxicaciones por estas sustancias en trabajadores. Algunas de las secuelas neurotóxicas que se derivan de dichas intoxicaciones están bien definidas: síndrome colinérgico agudo, síndrome intermedio y polineuropatía retardada inducida por organo fosforados. En las últimas décadas se han realizado varios estudios que miden las alteraciones neuropsicológicas a largo plazo producidas por la intoxicación aguda con estas sustancias, y apuntan a que tanto la inhibición de las colinesterasas como otros fenómenos bioquímicos pueden tener consecuencias neurotóxicas permanentes. La presente comunicación pretende poner orden en el conjunto de datos que aportan los diversos estudios, analizando y contrastando los protocolos de evaluación realizados, los resultados de las medidas bioquímicas neurofisiológicas y neurocognitivas, el tipo de intoxicaciones y el tiempo transcurrido tras éstas, de forma que puedan servir de resumen y guía para posibles trabajos futuros (AU)

In recent years a number of studies have drawn attention to the possible neuropsychological sequelae stemming from acute poisoning by certain substances, namely cholinesterase inhibitors. These chemicals, carbamates and organophosphorates, have been used in industry, for washing cattle, as insecticides and even as chemical agents in terrorist attacks and in wars. Nowadays, they are widely used as a pesticide and this is particularly so in regions such as the west of Almeria. The intensive farming in greenhouses carried out in this area, together with the conditions in which these products are used and handled, leads to a relatively high number of cases of poisoning. Yet this is not an isolated fact; the first clinical study to describe cases of poisoning by these substances in workers was published back in 1955. Some of the neurotoxic sequelae deriving from such intoxications are well defined: acute cholinergic syndrome, intermediate syndrome and delayed polyneuropathy provoked by organophosphorates. Several studies have been carried out over the past few decades to measure the longterm neuropsychological disorders produced by acute poisoning by these substances, and findings suggest that both cholinesterase inhibition and other biochemical phenomena can have permanent neurotoxic consequences. This communication aims to bring some order to the data offered by the different studies by analysing and verifying the evaluation protocols followed, the results of the neurophysiological and neurocognitive biochemical measurements, the type of poisoning and the time elapsed since they occurred, so that they can be summarised and taken as guidelines for possible work to be carried out in the future (AU)

Chlorpyrifos shares stimulus properties with pentylenetetrazol as evaluated by an operant drug discrimination task.

Based on previous data from elevated plus-maze tests suggesting a possible anxiogenic effect of the insecticide chlorpyrifos (CPF), the experiment reported here was designed to determine whether this organophosphate (OP) caused an interoceptive discriminative stimulus (IDS) in rats similar to that produced by the anxiogenic drug pentylenetetrazol (PTZ). Rats were trained to discriminate PTZ (20 mg/kg) from saline, using a drug discrimination procedure. When appropriate lever selection was achieved, generalization tests were performed. Tests of various doses of PTZ showed that the drug exerts dose-dependent discriminative control over response. Two more generalization tests were conducted with 250 mg/kg of CPF and 76.8 mg/kg of LiCl for up to 9 days. Results revealed that CPF (250 mg/kg s.c.) produced a PTZ-like IDS that fully substituted for PTZ 24 h after injection and that subjective effects remain for at least 6 days. However, administration of LiCl did not produce any generalization to PTZ on any of the days tested. These results suggest that CPF shares a site of action, and perhaps functional properties, with PTZ that last for several days, are not due to general malaise and should be taken into account in the use of cholinesterase inhibitors in the treatment of different types of dementia.

Effects of chlorpyrifos in the plus-maze model of anxiety.

The purpose of the present study was to determine the effect of two different doses of the organophosphate insecticide O,O'-diethyl-O-3,5,6-trichloro-2-pyridylphosphorothionate [chlorpyrifos (CPF)], a cholinesterase (ChE) inhibitor, in the plus-maze test of anxiety in the rat, as well as on acetylcholinesterase (AChE) activity in the brain. In a first experiment, the behavioural methodology was validated by showing the anxiolytic and anxiogenic effects of diazepam and pentylenetetrazole (PTZ), respectively. Acute exposure to CPF (166 mg/kg and 250 mg/kg, s.c.) produced significant dose-dependent inhibition (54% and 71%, respectively) of whole-brain AChE 48 hours after treatment. Neither dose produced signs of acute cholinergic toxicity at any time following treatment, as was verified by a functional observational battery. Both doses of CPF were injected 48 h before testing in the plus-maze and were shown to have anxiogenic effects as demonstrated by the significant decrease in the percentage of time spent and percentage of entries into open arms. This report thus shows clear behavioural alteration as an acute effect of an organophosphate in the absence of any classic sign of cholinergic toxicity. Our results are relevant to the understanding of both the pharmacology of anxiety and the behavioural toxicology of cholinesterase inhibitors.

Spatial delayed alternation of rats in a T-maze: effects of neurotoxic lesions of the medial prefrontal cortex and of T-maze rotations.

The medial prefrontal cortex (mPFC) is usually considered to be a brain area important for working memory processes. In rats this statement is evidenced by their diminished performance in delay-type tasks following mPFC damage, notably in spatial delayed alternation (SDA) in a T-maze. This study has addressed two questions. First, to examine whether the functional deficiency in SDA, observed in rats with (usually large) mPFC damage, can be ascribed to an anatomically defined subarea of mPFC, the dorsal anterior cingulate area (ACd). Small, bilateral, NMDA-induced lesions were made, restricted to the dorsal part of mPFC. The performance of such animals in a T-maze paradigm, using delays of 0 and 15 s, was compared with sham-operated animals. Although these small lesions resulted in an increased number of perseverative errors, this effect was not delay-dependent, and, moreover, by the end of the training group differences had disappeared. The second aim was to study whether or not spatial (extra-maze) cues are important for the performance of this task. This was achieved by subjecting the well-trained sham-operated animals to a series of systematic trial-to-trial variations in the position of the maze in the experimental room. These spatial manipulations severely impaired the performance of the SDA task, indicating that extra-maze information is required to solve this task. In animals with ACd lesions, subjected to the same manipulations, the deficiency was comparable to that of the sham-operated animals.