Antiepileptic effects of allopurinol on EL mice are associated with changes in SOD isoenzyme activities

We have investigated the potential antiepileptic action of superoxide dismutase (SOD) activities in the brain of the epileptic mutant EL mouse. EL mice which experienced frequent seizures (EL[s]) had abnormally low levels of SOD isoenzyme activity in the hippocampal area. Once epileptogenicity was established in these animals, activity of cyanide-sensitive Cu,Zn-SOD was maintained at significantly lower levels than in control mice. However, cyanide-insensitive Mn-SOD activity was not different from non-epileptic controls. In EL mice which had not experienced seizure provoking stimulations and exhibited no seizures (EL[ns]) there was moderately lower levels of SOD isoenzyme activities compared to controls. In spite of the low level of Cu,Zn-SOD activity in EL[s] mice, the Cu,Zn-SOD protein content was high in the hippocampus of these animals, suggesting that inactive Cu,Zn-SOD might be induced during development. After allopurinol (ALP) was given orally to EL[s] mice, Cu,Zn-SOD activities increased dramatically in the hippocampus and seizure activity was decreased. Even after 48 h, when antiepileptic action of ALP was lost, the SOD activity was maintained at the high level associated with initial ALP administration. EL[s] mice also showed DNA fragmentation in the hippocampal CA1 region and the parietal cortex, detected with in situ terminal transferase-mediated dUTP nick labeling with the aid of alkaliphosphatase or peroxidase. The degree of DNA fragmentation was less severe in EL[ns] mice. We propose that abnormalities in region specific Cu,Zn-SOD isoenzyme activity might produce free radicals, leading to DNA fragmentations and cell loss. This might contribute to hippocampal epileptogenesis in EL mice.     

The structure of individual differences in batteries of rapid acquisition tasks in mice.

Two experiments examined the structure of individual differences in mice by means of tasks that produced significant acquisition within 1 session. In Experiment 1, 5 cognitive tasks-detour, winshift, olfactory discrimination, fear conditioning, and operant acquisition-were used in conjunction with two control procedures: an open field and a light- dark test. In Experiment 2, some modifications were made to the tasks used in the 1st experiment, and 3 new tasks were used in conjunction with the same control procedures. The battery consisted of 5 learning tasks: detour, Hebb-Williams, radial maze, olfactory foraging, and fear conditioning. Results of both experiments indicate that when cognitive tasks and control procedures were included in principal-components analyses most of the variance attached principally to individual tasks rather than to a general component as is found typically in human cognitive batteries. When control procedures were eliminated, there was better evidence for the presence of a general cognitive factor, particularly in Experiment 2. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Consequences of serial cortical, hippocampal, and thalamic lesions and of different lengths of overtraining on the acquisition and retention of learning tasks.

The ability of the rat brain to acquire or to retain specific learning tasks was tested under conditions of multiple lesions and widely varying amounts of practice in 53 male young adult rats. Ss were randomly assigned to 1 of 4 groups in which lesions were made in 2 of 3 structural complexes (the medial prefrontal and cingulate cortex, the anterior and mediodorsal thalamus, and the dorsal and ventral hippocampus) or in all 3 before acquisition of the 2 learning tasks (Groups 1–4), or they were assigned to 1 of 3 groups in which lesions of all 3 structural complexes were made following the acquisition of the 2 learning tasks (Groups 5–7). Results question the assumption that serial lesions with intermittent training between lesions have beneficial effects and emphasize the importance of task practice (i.e., behavioral experience). It is argued that prolonged training will lead to a widely distributed storage of information within the brain. The process of wide diffusion of information will, however, be disturbed (or at least retarded) by lesions made shortly after task acquisition or task reacquisition (as was the case for Ss of Group 5). (159 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of neurotoxic hippocampal lesions on two effects of context after fear extinction.

Three conditioned suppression experiments with rats examined the role of the hippocampus in 2 effects of context after extinction. Reinstatement is the context-specific recovery of fear to an extinguished conditioned stimulus (CS) that occurs following independent presentations of the unconditioned stimulus (UCS), after extinction. Renewal is the recovery of fear when the CS is presented in the context in which it was conditioned, after extinction in a different context. Results indicated that neurotoxic lesions of the hippocampus, performed before conditioning, abolished reinstatement, which depends on context–UCS associations, but not renewal, which does not. This dissociation is not the result of differences in the recentness of context learning that ordinarily governs the 2 effects. The results suggest that the hippocampus is necessary for some, but not all, types of contextual learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mutations uncover a role for two magnesium ions in the catalytic mechanism of adenylyl cyclase

The recent determination of the crystal structure of adenylyl cyclase has elucidated many structural features that determine the regulatory properties of the enzyme. In addition, the characterization of adenylyl cyclase by mutagenic techniques and the identification of the binding site for P-site inhibitors have led to modeling studies that describe the ATP-binding site. Despite these advances, the catalytic mechanism of adenylyl cyclase remains uncertain, especially with respect to the role that magnesium ions may play in this process. We have identified four mutant mammalian adenylyl cyclases defective in their metal dependence, allowing us to further characterize the function of metal ions in the catalytic mechanism of this enzyme. The wild-type adenylyl cyclase shows a biphasic Mg2+ dose-response curve in which the high-affinity component displays cooperativity (Hill coefficient of 1.4). Two mutations (C441R and Y442H) reduce the affinity of the adenylyl cyclase for Mg2+ dramatically without affecting the binding of MgATP, suggesting that there is a metal requirement in addition to the ATP-bound Mg2+. The results of this study thus demonstrate multiple metal requirements of adenylyl cyclase and support the existence of a Mg2+ ion essential for catalysis and distinct from the ATP-bound ion. We propose that adenylyl cyclase employs a catalytic mechanism analogous to that of DNA polymerase, in which two key magnesium ions facilitate the nucleophilic attack of the 3'-hydroxyl group and the subsequent elimination of pyrophosphate.     

Successful performance by monkeys with lesions of the hippocampal formation on AB? and object retrieval, two tasks that mark developmental changes in human infants.

In this study, (a) what determines success or failure in the AB? and object retrieval tasks and (b) the relation between brain maturation and cognitive development as indexed by these tasks were examined. Intact cynomolgus monkeys and those with bilateral lesions of the hippocampal formation (H+) were tested. Although H+ monkeys exhibited impaired memory by performing poorly on the delayed nonmatching to sample task, they performed well on AB? at delays of 2–25 s. Performance declined as delays increased to 30 s, but H+ monkeys never showed the AB? error pattern. On object retrieval, H+ monkeys succeeded quickly and efficiently, even when required to detour to the box opening. This research demonstrates that memory impairment alone cannot account for deficits on AB? or on object retrieval and strengthens the conclusion (A. Diamond, 1988) that improved performance on AB? and object retrieval during infancy reflects maturation of dorsolateral prefrontal cortex. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of cysteamine on the upper gastrointestinal tract of children with cystinosis

The purpose of this study was to evaluate the effects of cysteamine on gastric acid output and serum gastrin levels in children with nephropathic cystinosis. We studied four children with nephropathic cystinosis receiving a dose of free base cysteamine of 14.35 mg/kg four times a day (range 12.30-18.80 mg/kg). Gastric acid was measured for the hour before and after administration of the medication. Serum gastrin levels were obtained at 0, 30, 60, and 90 min following the medication. Gastrointestinal anatomy was evaluated by endoscopy and biopsy. Following administration of the medication, all subjects showed an increase in gastric acid output. Mean acid output increased from 0.79 to 2.22 mEq/h. Mean gastric acid output adjusted for body weight increased from 0.03 to 0.09 mEq/kg per hour. Following administration of the medication, all subjects showed an increase in serum gastrin. The mean increase above the base value was 38.3 pg/dl. Two of the four subjects demonstrated visual and histological evidence of inflammation. Cysteamine has a marked effect on gastric acid production and serum gastrin, even at the dose used in children with nephropathic cystinosis. The clinical effect of this acid production is unknown but may be significant.     

Regulation of adenylyl cyclase activity in human peripheral blood mononuclear cells: effects of protein kinase inhibitors and of a calcium ionophore

In a previous paper we presented evidence for a negative regulation of adenylyl cyclase activity by tyrosine protein kinase(s) in the human leukemic T cell line Jurkat. In order to examine this point in non malignant cells, we conducted the present study in human peripheral blood mononuclear cells (PBMC). In these cells, staurosporine, a broad spectrum protein kinase inhibitor, enhanced not only the receptor-mediated, induced by prostaglandin E2 (PGE2), but also the direct (forskolin-induced) stimulation of adenylyl cyclase activity. Herbimycin A, a specific protein tyrosine kinase inhibitor, reproduced only in part the effect of staurosporine, whereas bisindolylmaleimide, the most specific protein kinase C (PKC) inhibitor known at present time, was ineffective. All these observations were made both in the absence and presence of isobutylmethylxanthine, a phosphodiesterase inhibitor, indicating that the effects of staurosporine and herbimycin A on cAMP accumulation were not due to phosphodiesterase inhibition. The calcium ionophore A 23187 also enhanced the PGE2-induced cAMP accumulation, and this effect was not additive to that of staurosporine, but additive to that of herbimycin A. These results confirm and extend those obtained in Jurkat cells. Taken together, they indicate that in human PBMC the adenylyl cyclase activity is negatively regulated by tyrosine kinase(s) and not by PKC, and positively regulated by Ca2+. They also suggest that the major enhancement by staurosporine of the PGE2-induced cAMP accumulation, although chiefly mediated by protein tyrosine kinase inhibition, also depends on another, presently undetermined, effect of the drug simulating that of Ca2+.     

The effects of immediate stimulus repetition on reaction time and event-related potentials in tasks of different complexity.

Examined the effect of immediate stimulus repetition in lexical decision, face recognition, letter search, face/nonface discrimination, and word/number discrimination tasks using reaction time (RT), accuracy, and event-related brain potential (ERP) measures. Repetition facilitated performance in all tasks and for all stimulus types. However, ERPs were strongly affected by repetition only in lexical decision, face recognition, and letter search, when relatively long stimulus analysis and decision making processes were required. The ERP repetition effect consisted of a significant increase in P300 amplitude and a shortening of its latency. Repetition also resulted in the attenuation of a negative component that was tentatively identified as N400. These results suggest that immediate repetition facilitates stimulus identification and eliminates the need for stimulus analysis processes including access to semantic memory while making categorical decisions. While both factors affected RT, ERPs were modulated primarily by the elimination of the need to access to semantic memory and by the consequent speeding of categorical decision processes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Stimulation and antagonism of opioid !d-receptors produce opposite effects on active avoidance conditioning in mice.

The effects of opioid δ-receptor activation on conditioning in a one-way active avoidance paradigm were investigated in mice. Peripheral administration of 30 and 100 μg/kg of [Leu–5] enkephalin (LE) and 11.6 μg/kg of [D-Pen–2,D-Pen–5]enkephalin ({dpdpe}), a synthetic enkephalin analog with high δ-selectivity, impaired acquisition of avoidance responding. The dose response functions for both peptides were U-shaped. Deficits in responding were also present 24 hours after training, which suggests that the impaired performance observed during training was not an impairment in the ability of the mice to perform. Also, neither LE nor {dpdpe} decreased footshock sensitivity or open-field activity, which rules out analgesia and decreased activity levels as likely explanations for the deficits in conditioning. Finally, antagonizing endogenous ligands with the δ-selective antagonist ICI 154,129 enhanced acquisition, an effect opposite that produced by LE and {dpdpe}. The results suggest that activation of δ-receptors is normally involved in the modulation of active avoidance learning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

"The effects of neurotoxic hippocampal lesions on two effects of context after fear extinction": Errata.

Reports an error in the original article by R. J. Frohardt et al (Behavioral Neuroscience, 2000 [Apr], Vol 114[2], 227-240). On page 229, there is an error in the Method section. The second full sentence on that page should read: Neurotoxic lesions of hippocampus were produced by injections of a mixture of 5.0 μg ibotenic acid and 5.0 μg NMDA per 0.5 ml of normal saline. (The following abstract of this article originally appeared in record 2000-15286-001): Three conditioned suppression experiments with rats examined the role of the hippocampus in 2 effects of context after extinction. Reinstatement is the context-specific recovery of fear to an extinguished conditioned stimulus (CS) that occurs following independent presentations of the unconditioned stimulus (UCS), after extinction. Renewal is the recovery of fear when the CS is presented in the context in which it was conditioned, after extinction in a different context. Results indicated that neurotoxic lesions of the hippocampus, performed before conditioning, abolished reinstatement, which depends on context-UCS associations, but not renewal, which does not. This dissociation is not the result of differences in the recentness of context learning that ordinarily governs the two effects… (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of nucleus basalis magnocellularis lesions in Long-Evans hooded rats on two learning set formation tasks, delayed matching-to-sample learning, and open-field activity.

Rats with quisqualic acid lesions of the nucleus basalis magnocellularis (nBM) and control rats were compared in discrimination reversal learning set (DRLS) and olfactory discrimination learning set (ODLS) tasks, a delayed matching-to-sample task (DMTS), and open-field activity. Evidence of learning set formation was seen to control rats but not in nBM-lesioned rats in the DRLS and ODLS tasks. Better-than-chance performances were seen for both groups in open-field activity. These findings suggest that the nBM is important for higher cognitive processing such as "learning to learn" and thus is important for a complex form of reference memory. In addition, perseverational, working memory, and attentional deficits could not explain learning set impariment after nBM lesions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Conditioned effects of kindling three different sites in the hippocampal complex of the rat.

Rats received kindling stimulations to the perirhinal cortex (PRh), ventral hippocampus (VH), or dorsal hippocampus (DH) in 1 environment and an equivalent number of sham stimulations in a 2nd environment. The PRh-kindled rats displayed rapid kindling and a swift emergence of conditioned interictal defensiveness. In contrast, the VH- and DH-kindled rats displayed much slower kindling and slow or no conditioning, respectively. No effects of conditioning on the convulsions, comparable with those associated with amygdala kindling, were observed. These results establish the generality of some of the previously reported kindling-related conditioned effects, confirm the site specificity of some of these effects, and suggest that the convulsions, rather than the stimulations, function as the unconditioned stimuli for the conditioning of interictal behavior. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Step-tracking movements of the wrist. IV. Muscle activity associated with movements in different directions

We examined the patterns of muscle activity associated with multiple directions of step-tracking movements of the wrist in humans and monkeys. Human subjects made wrist movements to 12 different targets that required varying amounts of flexion-extension and radial-ulnar deviation. Wrist muscles displayed two patterns of electromyographic (EMG) modulation as movement direction changed: amplitude graded and temporally shifted. The amplitude-graded pattern was characterized by modulation of the quantity of muscle activity that occurred during two distinct time periods, an agonist burst interval that began before movement onset and an antagonist burst interval that began just after movement onset. The timing of muscle activity over the two intervals showed little variation with changes in movement direction. For some directions of movement, EMG activity was present over both time intervals, resulting in "double bursts." Modulation of activity during the agonist burst interval was particularly systematic and was well fit by a cosine function. In contrast, the temporally shifted pattern was characterized by a gradual change in the timing of a single burst of muscle activity. The burst occurred at a time intermediate between the agonist and antagonist burst intervals. The temporally shifted pattern was seen less frequently than the amplitude-graded pattern and was present only in selected wrist muscles for specific directions of movement. Monkeys made wrist movements to 8-16 different targets that required varying amounts of flexion-extension and radial-ulnar deviation. These movements were performed more slowly than those of human subjects. The wrist muscles of the monkeys we examined displayed the amplitude-graded pattern of activity but not the temporally shifted pattern. Stimulation of individual wrist muscles in monkeys resulted in wrist movements that were markedly curved, particularly for the wrist extensors. These results indicate that step-tracking movements of the wrist are generated mainly by using the amplitude-graded pattern to modulate muscle activity. We propose that this pattern reflects a central process that decomposes an intended movement into an agonist, "propulsive" component and an antagonist, "braking" component. Separate bursts of muscle activity then are generated to control each component. On the other hand, we argue that the temporally shifted pattern may function to reduce the amount of movement curvature associated with the activation of wrist muscles.     

The effects of tasks on integrating information from multiple documents.

The authors examine 2 issues: (a) how students integrate information from multiple scientific documents to describe and explain a physical phenomenon that represents a subset of the information in the documents; and (b) the role of 2 sorts of tasks to achieve this type of integration, either writing an essay on a question requiring integration across texts or answering shorter intratext questions that require students to integrate information within a single text, while superficial and deep comprehension measurements are obtained. Undergraduate students answered 1 of the 2 types of questions, and their reading times were recorded. Half of the sample thought aloud. Results showed that the integration question increased integration and decreased the processing of isolated units of information, which enhanced deep learning, whereas no differences between the 2 sorts of tasks on memory recall were apparent. This research also provides evidence for the discrepancy between training and posttraining effects (R. A. Schmidt & R. A. Bjork, 1992). (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Developmental changes in the awareness of memory benefits associated with different types of picture organization.

First-, 3rd, and 5th-grade children judged the relative ease of recalling a list that was organized semantically, physically, or randomly. Results suggest that awareness that semantic organization yields higher recall than physical organization appears at a later age than the simpler understanding that semantic organization yields higher recall than no organization. (2 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Pretraining effects on performance of rats with hippocampal lesions.

Investigated the role of pretraining factors in the overresponding observed on differential-reinforcement-of-low-rate (DRL) schedules following hippocampal lesions. 24 Long-Evans hooded rats divided into unoperated Ss and Ss with large or small hippocampal lesions were given 10 or 20 days of continuous reinforcement (CRF) pretraining before exposure to a DRL 20-sec schedule. Either large lesions or extended CRF pretraining resulted in only a transient elevation in response rates, while the unique combination of a large lesion and extended pretraining was required for persistent overresponding on DRL. It is concluded that the overresponding produced by hippocampal damage is not solely a function of loss of hippocampal tissue but depends upon unique training conditions for its appearance. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The effects of adenine dinucleotides on epileptiform activity in the CA3 region of rat hippocampal slices

Alpha, omega-adenine dinucleotides (Ap(n)A) consist of two adenosine molecules linked at the 5' position by phosphate groups, the number of which is denoted by n and can range from 2 to 6. The aim of this study was to investigate the effect of Ap4A and Ap5A on the rate of epileptiform activity. Hippocampal slices (450 microm), when perfused with a medium containing no added magnesium and 4-aminopyridine (50 microM), generate epileptiform activity of an interictal nature. Ap4A and Ap5A at 1 microM depressed the discharge rate to a significant extent. At this concentration adenosine (1 microM) did not produce any effect. However at 10 microM adenosine, Ap4A and Ap5A all decreased the burst frequency. Adenosine deaminase (0.2 U/ml) totally annulled the inhibition of epileptiform activity produced by 10 microM adenosine or 1 microM Ap4A and Ap5A. Adenosine deaminase did not significantly change the maximum depression of activity produced by 10 microM Ap4A and Ap5A. 8-cyclopentyl-1,3-dimethylxanthine, an A1, receptor antagonist, increased the basal rate of epileptiform activity and prevented the depression of burst discharges by Ap4A. 5'-adenylic acid deaminase converts AMP into IMP which is inactive. 5'-adenylic acid deaminase did not prevent the inhibitory effects of Ap4A. The results suggests that in the CA3 region of the hippocampus, Ap4A and Ap5A act partly by stimulating xanthine-sensitive receptors directly and partly through the formation of the metabolite, adenosine.     

The effects of reserpine on the acquisition of the conditioned avoidance response.

"Six Macacus cynomolgus monkeys were trained in a shock-avoidance situation while under the influence of reserpine. Three sessions of 60 trials were given a week apart. Subsequent acquisition of the habit was retarded." (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of transplantation of fetal hippocampal or hindbrain tissue into the brains of adult rats with hippocampal lesions on water maze acquisition.

Rats were given bilateral aspiration lesions of the hippocampus. Some of these rats then received bilateral transplants of fetal hippocampal or dorsal ventricular ridge tissue that was dissected from embryonic rat brains at 16 or 17 days of gestation. The remaining rats with hippocampal lesions did not receive fetal brain transplants. Rats with neocortical aspiration lesions, but without transplants, and rats without brain damage were also included in the study. All of the rats were trained to find a submerged platform in a Morris water maze. Rats with the fetal brain transplants were more impaired in some measures of maze learning than were rats with hippocampal lesions only. The results indicate that transplants of fetal brain tissue are not always associated with recovery of behavioral function after brain damage and may even increase a lesion-induced behavioral impairment in tasks that require complex cognitive functioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)