Flash visual evoked potentials in mice can be modulated by transcranial direct current stimulation.

Transcranial direct current stimulation (tDCS) in humans has been shown to affect the size of visual evoked potentials (VEPs) in a polarity-dependent way. VEPs have been widely employed in mice to study the visual system in physiological and pathological conditions and are extensively used as animal models of neurological and visual disorders. The present study was performed to evaluate whether mice VEPs could be modulated by tDCS in the same manner as in humans. We describe here the effects of 10 min tDCS (anodal, cathodal or no stimulation) on flash-VEPs in C57BL/6 mice under sevoflurane anesthesia. VEP amplitudes of the first major peak (P1) were analyzed before, at 0, 5 and 10 min after tDCS. Compared with no stimulation condition, anodal tDCS increased P1 amplitude slightly more than 25%, while cathodal stimulation had opposite effects, with a decrease of P1 amplitude by about 30%. After-effects tended to reverse toward basal levels within 10 min after tDCS. These results, suggesting polarity-dependent modulation similar to what described in humans of tDCS effects on VEPs, encourage the use of mice models to study tDCS mechanisms of action and explore therapeutic applications on neurological models of disease.

Expresión del receptor del factor de crecimiento epidérmico en biopsias renales de pacientes con nefronoptisis del adolescente / Expression of epidermal growth factor receptor in renal biopsy from patients with adolescent nephronophthisis

Introducción: En Venezuela se ha descrito una nueva variedad de nefronoptisis, denominada nefronoptisis del adolescente, la cual expresa características clínicas e histológicas similares a las otras variedades ya descritas. Sin embargo, la patogenia de esta enfermedad aún no es bien conocida. El objetivo de este trabajo fue determinarla expresión del receptor del factor de crecimiento epidérmico (EGFR) humano en las células epiteliales tubulares de pacientes con nefronoptisis del adolescente. Métodos: Se estudiaron las biopsias renales de 8 pacientes con nefronoptisis del adolescente, mediante la técnica de inmunohistoquímica, para determinar la expresión renal del EGFR. Resultados: En todas las muestras la expresión del receptor del factor de crecimiento epidérmico fue negativa. Conclusión: Estos hallazgos indican una deficiencia del receptor del factor de crecimiento en los epitelios indiferenciados, lo cual podría ser uno de los factores desencadenantes del desarrollo de los quistes en la nefronoptisis (AU)

Introduction: In Venezuela has been described a new form of nephronophthisis, called adolescent nephronophthisis, with clinical and histological findings very similar to others varieties described. However, pathogenesis in not wellknown. The aim of this study was to determine the expression of human epidermal growth factor receptor (EGFR) in tubular epithelial cells of patients with adolescent nephronophthisis. Methods: Renal biopsies of 8 patients with adolescent nephronophthisis were studied by immunohistochemistry to determine renal expression of EGFR. Results: In all patients, there was no expression of epidermal growth factor receptor. Conclusion: These findings indicate a deficiency of growth factor receptor in undifferentiated epithelialcells, which could be one factor in the development of cysts in nephronophthisis (AU)

A brain microdialysis study on 5-HT release in freely moving rat lines selectively bred for differential 5-HT1A receptor function.

Breeding for high and low hypothermic responses to systemic administration of a serotonin1A (5-HT1A) receptor agonist (8-hydroxy-2-(di-n-propylamino)tetralin, 8-OH-DPAT) has resulted in high DPAT-sensitive (HDS) and low DPAT-sensitive (LDS) lines of rats, respectively. These lines also differ in several behavioral measures associated with stress. In the present microdialysis study we observed that basal 5-HT concentrations in the prefrontal cortex and dorsal hippocampus did not differ significantly between HDS and LDS rats. Thus, behavioral differences between the HDS and LDS lines might not be attributed to differences in basal 5-HT release. However, both lines had lower basal levels of 5-HT release than their randomly bred control group (random DPAT-sensitive, RDS) in the prefrontal cortex (mean +/- SEM, pg/20 microl, was 3.0 +/- 0.4 for LDS, 3.8 +/- 0.3 for HDS and 6.4 +/- 0.6 for RDS; F(2,59) = 5.8, P<0.005). The administration of (+/-)-fenfluramine (10 mg/kg) induced a greater increase in hippocampal 5-HT levels in HDS rats (500%) as compared with LDS (248%) or RDS (243%) rats (P<0.0001). There were no significant differences in the prefrontal cortex among lines, with a fenfluramine-induced 5-HT increase of about 900% in the three groups. This differential response to fenfluramine may be due to functional alterations of hippocampal 5-HT reuptake sites in the HDS line.

A brain microdialysis study on 5-HT release in freely moving rat lines selectively bred for differential 5-HT1A receptor function

Breeding for high and low hypothermic responses to systemic administration of a serotonin1A (5-HT1A) receptor agonist (8-hydroxy-2-(di-n-propylamino)tetralin, 8-OH-DPAT) has resulted in high DPAT-sensitive (HDS) and low DPAT-sensitive (LDS) lines of rats, respectively. These lines also differ in several behavioral measures associated with stress. In the present microdialysis study we observed that basal 5-HT concentrations in the prefrontal cortex and dorsal hippocampus did not differ significantly between HDS and LDS rats. Thus, behavioral differences between the HDS and LDS lines might not be attributed to differences in basal 5-HT release. However, both lines had lower basal levels of 5-HT release than their randomly bred control group (random DPAT-sensitive, RDS) in the prefrontal cortex (mean ± SEM, pg/20 æl, was 3.0 ± 0.4 for LDS, 3.8 ± 0.3 for HDS and 6.4 ± 0.6 for RDS; F(2,59) = 5.8, P<0.005). The administration of (±)-fenfluramine (10 mg/kg) induced a greater increase in hippocampal 5-HT levels in HDS rats (500 percent) as compared with LDS (248 percent) or RDS (243 percent) rats (P<0.0001). There were no significant differences in the prefrontal cortex among lines, with a fenfluramine-induced 5-HT increase of about 900 percent in the three groups. This differential response to fenfluramine may be due to functional alterations of hippocampal 5-HT reuptake sites in the HDS line

Cholinergic modulation of the sleep state-dependent P13 midlatency auditory evoked potential in the rat.

Injections into the pedunculopontine nucleus (PPN) of the cholinergic receptor agonist, carbachol (CAR), were found to reduce the amplitude of the vertex-recorded, sleep state-dependent P13 midlatency evoked potential in a dose- and time-dependent manner. This effect was blocked or reduced by pretreatment with the muscarinic receptor antagonist, scopolamine, injected into the PPN.

Microdialisis cerebral en humanos: experiencia en la enfermedad de parkinson / Brain microdialysis in human: experienci in the Parkinson disease

Se ha efectuado el procedimiento de microdiálisis cerebral durante talamotomía estereotáxica N.V.L en 3 pacientes de enfermedad de parkinson, para corregirles el síndrome del temblor. Se realizó correlación entre la concentración intersticial del GABA y los cambios de intensidad del tremor. La microdiálisis es un método seguro, reproductible y fácil de practicar durante operaciones neuroquirúrgicas estereotáxicas. Se expone los resultados preliminares. Debido a la muestra de 3 pacientes, no se puede establecer conclusiones definitivas. Esta investigación está actualmente en progreso

Monitoring gamma-aminobutyric acid in human brain and plasma microdialysates using micellar electrokinetic chromatography and laser-induced fluorescence detection.

Due to its low electrophoretic mobility, few studies have been able to measure gamma aminobutyric acid (GABA) in biological samples by means of capillary zone electrophoresis. Nevertheless, in micellar electrokinetic chromatography (MEKC) by adding a surfactant to the mobile phase separation can be carried out on the basis of the partition coefficient of the molecules rather than their electrophoretic mobility. In the present study microdialysis coupled to MEKC with laser induced fluorescence detection was used to successfully monitor GABA from cerebrospinal fluid and plasma dialysates. Moreover, we monitored changes in extracellular GABA from a human brain. Microdialysis samples were collected from a Parkinson's disease patient undergoing a thallamotomy as part of her treatment. Significant decreases in extracellular GABA were detected during high frequency electrical stimulation and following a thermolesion of the thalamus. These results demonstrate the feasibility of MEKC coupled to laser-induced fluorescence detection in resolving neutral amino acids, specifically GABA, from different human body fluids.

In vivo monitoring of gabapentin in rats: a microdialysis study coupled to capillary electrophoresis and laser-induced fluorescence detection.

Gabapentin (GP) is a new anticonvulsant used in refractory epilepsy. Few studies have monitored the drug in vivo. We report the combination of capillary electrophoresis and laser-induced fluorescence detection (CZE-LIFD) with brain microdialysis and plasma ultrafiltration in an attempt to measure GP and offer an alternative technique for pharmacokinetic studies. We found that CZE-LIFD is capable of linearly measuring 10(-7)-10(-9) M GP in a 1 nL volume. It was also demonstrated that it is possible to monitor GP in prefrontal cortex dialysates and plasma in rats. It is concluded that the method permits in vivo monitoring of the drug in pharmacological as well as in clinical studies.

Mechanism of the neuroleptic-induced obesity in female rats.

1. Obesity is an undesirable side effect of neuroleptics which affects 50% approximately of patients under a program of chronic administration. 2. An animal model of neuroleptic-induced obesity and hyperphagia has been developed in female rats treated chronically with sulpiride (20 mg/Kg/ip. for 21 days). However, it is unknown whether or not the hyperphagia is essential for the development of this type of obesity. 3. Sulpiride or vehicle was administered in two experimental conditions: in the first one, food was available in an amount which was three times the previous individual daily food intake; in the second one, the daily food provision was maintained at the individual daily average before starting the treatments. This way hyperphagia was prevented in half of the groups. Besides the body weight gain measurement in all the groups, the serum levels of estradiol, prolactin, glucose and lipids were assessed in the groups with unrestricted food intake. 4. Food restriction prevented the sulpiride-induced weight gain, even though the rats displayed a permanent diestrus which suggests an hyperprolactinemia-induced impairment in the balance of the reproductive hormones that may promote weight gain. However, the basal levels of estradiol were not affected by sulpiride. 5. The high density cholesterol was significantly increased by sulpiride, and the serum glucose levels were significantly decreased, however these changes were only detected during the first week of treatment. 6. The decrease in the serum glucose levels may be an early consequence of hyperinsulinemia. 7. Neuroleptic-induced obesity in rats appears to mimic energy intake, endocrine status and carbohydrate metabolism in humans under chronic neuroleptic administration. However, these rodents did not display the typical changes in blood lipids observed in human obesity.

Amantadine in the treatment of neuroleptic-induced obesity in rats: behavioral, endocrine and neurochemical correlates.

The efficacy of the antiviral agent Amantadine (AM, 5-100 mg/kg/sc, ip or intrahypothalamically, 12.5-100 micrograms bilaterally) in influencing body weight and food intake in drug-free rats, and in preventing neuroleptic-induced weight gain, was assessed in adult female rats. In drug-free rats, acute administration of systemic AM or directly injected in the lateral hypothalamus (LH) displayed a significant dose-dependent anorectic effect (p < 0.001). This effect could be mediated by the brain monoaminergic system, because systemic or local injections of AM increased dopamine and serotonin overflow in the nucleus accumbens and in the LH. Chronic administration of AM significantly decreased body weight gain in drug-free rats only at the dose of 100 mg/kg/sc. Similarly, obesity induced by the neuroleptic drug sulpiride (SUL, 20 mg/kg/ip for 21 days) was prevented by AM only at the dose of 100 mg/kg. AM did not prevent SUL-induced hyperprolactinemia, disruption of the vaginal cycle and a decrement in the weight of the uterus and ovaries at any dosage. This lack of efficacy of AM contrasts with that of bromocriptine, which completely prevented SUL-induced weight gain and hyperprolactinemia. The results show that despite a potent acute anorectic effect, AM displays a weak antagonistic action on SUL-induced obesity in rats, in contrast to the preliminary results obtained in humans. As AM metabolism differs in humans and rats, additional research is needed before its systematic testing in counteracting neuroleptic-induced obesity in patients with mental disorders.

Systemic and local cocaine increase extracellular serotonin in the nucleus accumbens.

The effect of systemic or intra-accumbens injections of cocaine on serotonin (5-HT) overflow was studied by nucleus accumbens microdialysis in freely moving rats. In Experiment 1, cocaine was injected intraperitoneally at 0, 10, 20, and 30 mg/kg. In Experiment 2, cocaine (3.6, 7.2, and 14.4 mM), lidocaine (7.2 mM), or saline was infused through the probe by reverse microdialysis. Extracellular serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were measured by high-pressure liquid chromatography and electrochemical detection. Systemic administration of cocaine induced a dose-related increase in 5-HT overflow and a decrease of 5-HIAA. Intra-accumbens cocaine infusion also caused a dose-related increase in 5-HT, but no effect on 5-HIAA. As a control for local anesthesia, equimolar lidocaine did not increase 5-HT. The difference between lidocaine and cocaine was not due to unequal diffusion out of the probe, because previous in vivo calibration of the probe showed that more lidocaine than cocaine diffused out of the probe when equimolar solutions were infused. These experiments suggest that systemic cocaine acts on the nucleus accumbens to increase synaptic 5-HT.

Diabetes decreases limbic extracellular dopamine in rats.

Mesolimbic dopamine (DA) was measured by ventral striatum (including nucleus accumbens) microdialysis in freely moving streptozotocin (STZ)-diabetic male rats. DA and dihydroxyphenylacetic acid (DOPAC) basal levels and amphetamine-induced DA increase were lower in diabetic than in normal rats. These results are discussed in terms of decreased DA neuron activity and DA receptor hypersensitivity in the mesolimbic system of STZ-diabetic rats.

Lithium and body weight gain.

Weight gain is an undesirable side-effect of long-term lithium administration which notably interferes with treatment compliance. The mechanisms of this weight gain remain unclear, making its management in patients difficult. In this paper, studies describing the features of this weight gain in patients and in rats treated with chronic lithium administration are reviewed. The effects of lithium on body weight differ between patients and rats in a number of ways, including the observation that excessive weight gain is observed in both male and female patients, but only in female rats. Nevertheless, an animal model of lithium-induced weight gain may be able to provide useful insights into some of the specific mechanisms involved, particularly those related to interactions with gonadal steroid function. We discuss the effects of lithium on the endocrine system, neurotransmitters, metabolism, electrolyte regulation, and feeding behavior, which might underlie lithium's effects on body weight. Finally, suggestions for the management of weight gain in the clinical setting are presented. These include, in the long term, dietary control and physical activity and, in the short term, choosing among several drugs that have been tested either in patients or in animal models of obesity. If weight gain still cannot be controlled and treatment compliance is at risk, the mood stabilizers carbamazepine or valproic acid might be substituted for lithium treatment.

Hyponatremia and neuroleptic-induced obesity in rats.

The weight gain and hyperphagia induced by chronic administration of sulpiride in female rats were not prevented by the concomitant administration of an extra source of sodium. In addition, serum sodium levels were not affected, but potassium levels were significantly reduced by sulpiride administered for 1 week. These results suggest that sulpiride-induced obesity in rats is not related to sodium imbalance. The mechanism for the decrease in serum potassium levels and its relation with sulpiride-induced weight gain warrant further investigation.

Enhancement of amphetamine anorexia after chronic administration of sulpiride in rats.

Long-term administration of sulpiride induces hyperphagia and obesity in female rats. After sulpiride withdrawal, a significant hypophagia has been observed. The hyperphagia could be related to the blockade and the hypophagia to supersensitivity of dopamine D2 receptors, in particular those D2 receptors located in the perifornical hypothalamus. If this were the case, an enhancement of anorexia induced by amphetamine and dopamine should be observed after interruption of long-term sulpiride treatment. Two doses of systemic sulpiride (20 or 200 mg/kg) and one dose of intrahypothalamic sulpiride (15 micrograms) were tested. Amphetamine was administered by systemic or intrahypothalamic infusion. Dopamine was administered in the hypothalamus. After withdrawal of systemic administration of sulpiride (200 mg/kg), an enhancement of anorexia induced by systemic amphetamine was observed. However, the anorexia induced by intrahypothalamic injections of amphetamine or dopamine was not affected by the interruption of the sulpiride treatment. These results suggest that the hypophagia following chronic sulpiride treatment is not due to supersensitivity of D2 dopamine receptors in the lateral hypothalamus. Moreover, the change in the response to amphetamine might be related to supersensitivity of extrahypothalamic D2 receptors.

Effects of long-term administration of clozapine on body weight and food intake in rats.

Previous reports have shown that long-term administration of typical and atypical neuroleptics induced obesity in female but not in male rats. It has been suggested that impaired ovarian steroidogenesis related to neuroleptic-induced hyperprolactinemia is necessary to observe the body weight changes. This hypothesis was tested with clozapine, an atypical neuroleptic that produces in rats a shorter increase in serum prolactin levels than do other neuroleptics. The effects of clozapine on body weight and food intake were assessed in female and male rats under treatment with any of the following doses: 0.5, 1, 2.5, 5, 10, and 20 mg/kg IP for 21 days. Vaginal cycle under clozapine treatment, as an indirect indicator of ovarian steroidogenesis, was also assessed. Obesity was not observed in any group. By contrast, clozapine at the doses of 10 and 20 mg/kg significantly decreased body weight and feeding in male rats. Clozapine at the doses of 5 and 10 mg/kg IP induced permanent diestrus. The failure of clozapine to induce obesity in female rats, despite impaired vaginal cycle, can be considered indirect evidence that drug-induced hyperprolactinemia is not sufficient to observe neuroleptic-induced obesity in rats.

Effects of acute and chronic lithium treatment on amphetamine-induced dopamine increase in the nucleus accumbens and prefrontal cortex in rats as studied by microdialysis.

The effects of acute and chronic administration of lithium (Li) on the basal levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 5-hydroxy-indoleacetic acid (5-HIAA), and the amphetamine-induced DA increase were assessed in the Nucleus Accumbens (NAC) and Prefrontal Cortex (PFC) by brain dialysis in freely-moving rats. Acute Li (2 meq/L) was locally administered by reverse dialysis. Chronic Li (2 meq/kg) was intragastrically administered for 14 days. No effect was observed after acute Li administration. However, after chronic Li administration, the basal levels of DOPAC and the amphetamine-induced DA increase in the NAC were significantly higher in the Li-treated rats than in the saline-treated controls. In the PFC, while the amphetamine-induced DA increase was not affected by chronic Li, the basal levels of DA and DOPAC were significantly decreased after Li administration. The effects of chronic Li in the NAC could be due to increased synthesis and/or decreased release of DA, whereas in the PFC the effects could be due to a decreased synthesis of DA. The absence of effects of acute Li administration is in agreement with the therapeutic inefficacy of the acute use of the cation. The changes observed after chronic treatment in the NAC and the PFC could be related to the effects of Li on mood disorders and cognitive functions, respectively.