Previously we reported delayed cell death, defined by clear-cut cell loss 60 days after a nitrite-induced hypoxic episode. The loss of cells was not apparent two weeks after the treatment, although some changes in cellular appearance were observed at that time. A similar delayed loss of neurons in the hippocampus after hypoxia induced by blood vessel occlusion has also been found. In addition, we reported that the amount of methemoglobinemia induced by the sodium nitrite can be reduced by the stress produced by handling and the injection of saline 2 or 24 h before the nitrite administration. The degree of methemoglobin formed is directly related to cell death in certain areas of the brain, including regions within the hippocampus. Considering the many effects that can be produced by chronic and acute stress of several kinds and the length of time during which these effects manifest themselves, we undertook to determine the histologic effects of the stresses of transport on the neuroanatomic effects of sodium nitrite administration 60 days post administration. Comparisons were made of the effects of two methods of transport from the laboratory in which the animals (male CD-1 mice) were injected with the sodium nitrite or saline (Tufts Medical School) to the laboratory in which the histologic evaluations were made (Binghamton University). The animals began their travel several hours after the injections. One transport method was by commuter airline and the other was by automobile. All animals had the same transport from the supplier to the Boston location (truck). Thus, the stress of experimental interest occurred after the nitrite administration. Upon arrival at Binghamton University, the animals were housed at the University in their own colony room for 60 days before sacrifice. After sacrifice, sections from their brains were subjected to a number of histologic staining procedures, including PTAH, the Bielschowsky silver method, GFAP, and the standard Nissl procedure. Although special attention was paid to hippocampal areas, changes in cells in the habenulae and the linings of ventricular areas were also prominent. Surprisingly, the nitrite treatment before transport to Binghamton offered partial protection against the very substantial and lasting effects of the injections, transport, and handling found in the control animals. Differential effects caused by the two methods of transport were also noted.

OLTON, D. S. AND R. L. ISAACSON. Hippocampal lesions and actwe avo:dance. PHYSIOL. BEHAV. 3 (5) 719-724, 1968.Rats with lesions of the hlppocampus were impaired relative to normal rats in the acquisition and retention of a one-way active avoidance task, but were superior to normal and partially neodecorticate rats in the acquisition of a two-way active avoidance task. The deficit of rats with hippocampal damage in the one-way task was accentuated when "no shock trials" (CS only) preceded acquisition or reacqulsition training. Neocortically lesioned animals showed a shght deficit on both response and latency measures of performance. It is suggested that hippocampectomized rats are deficient in the ability to associate noxious events with cues indicating spatial location.

The continuing explosion of scientific interest in the hippocampus began in the 1950s, initiated in large part by the recognition of the importance of the observations of hippocampectomized monkeys made by Klüver and Bucy and the remarkable memory loss of patient H. M. following temporal lobe surgery. Subsequent to these studies, research and theories about the hippocampus grew exponentially in number and diversity. As yet, no theory of hippocampal function explains all of the phenomena discovered in the clinic or laboratory. In this article, experimental results that have been forgotten or ignored in most theories are presented. Adequate theories of hippocampal function must account for known, reliable postsurgical behavioral observations and consider the conditions under which anomalies are noted. Comprehensive theories will require new approaches in which the interactions of the hippocampus with the central nervous system are understood.

The results of the study reported in Brain Research in 1995 by Isaacson et al. [Isaacson, R.L., Varner, J.A., Baars, J.-M., de Wied, D., 1995. The effects of pregnenolone sulfate and ethylestrenol on retention of a passive avoidance task. Brain Res. 689, 79-84] have been re-examined with special emphasis placed on the distributions of latencies found in the passive avoidance task using rats. This study used two retention tests, one 24 h after training the other at 48 h after training. In the first experiment in that study a range of doses of two anabolic steroids, pregnenolone sulfate and ethylestrenol, were given s.c. just after the footshock training trial. In experiment 2 a similar range of doses of both steroids was given to the rats 1 h before the first retention test. Placing emphasis on the distributions rather than measures of central tendencies revealed that, in contrast to the vehicle treated animals, the anabolic steroid treated animals exhibited bimodal distributions of response latencies. These differences between control and hormone treated animals were observed in both experiments. The new information was interpreted in terms of non-linear dynamics including some aspects of Chaos theory.

The brain depends on other organ systems of the body for oxygen, nutrients, and the elimination of metabolic byproducts. The primary route for such transfer of these essentials is the cerebrovasculature. The cerebrovasculature also participates in metabolizing or excluding xenobiotics, segregating components of the immune response, regulating pH and osmolarity of the cerebrospinal fluid, selectively distributing hormones, and impeding pathogenic invasion. Various aspects of these diverse functions are attributed to the complex structural and molecular properties of cerebral endothelial cells collectively referred to as the blood-brain barrier (1-7). The hallmark structural specialization of the blood-brain barrier is the tight junction between the endothelial cells, which prevents diffusion of plasma proteins and molecules of a similar size or larger (8-12). Other structural specializations include close apposition of astrocytic endfeet, sparsely distributed pericytes, and extensive association with microglia. Molecular specializations include endothelial expression of transporters and enzymes, such as those involved in xenobiotic metabolism (12-27).

This study describes alterations in the nervous system resulting from chronic administration of the fluoroaluminum complex (AlF3) or equivalent levels of fluoride (F) in the form of sodium–fluoride (NaF). Twenty seven adult male Long–Evans rats were administered one of three treatments for 52 weeks: the control group was administered double distilled deionized drinking water (ddw). The aluminum-treated group received ddw with 0.5 ppm AlF3 and the NaF group received ddw with 2.1 ppm NaF containing the equivalent amount of F as in the AlF3 ddw. Tissue aluminum (Al) levels of brain, liver and kidney were assessed with the Direct Current Plasma (DCP) technique and its distribution assessed with Morin histochemistry. Histological sections of brain were stained with hematoxylin & eosin (H&E), Cresyl violet, Bielschowsky silver stain, or immunohistochemically for β-amyloid, amyloid A, and IgM. No differences were found between the body weights of rats in the different treatment groups although more rats died in the AlF3 group than in the control group. The Al levels in samples of brain and kidney were higher in both the AlF3 and NaF groups relative to controls. The effects of the two treatments on cerebrovascular and neuronal integrity were qualitatively and quantitatively different. These alterations were greater in animals in the AlF3 group than in the NaF group and greater in the NaF group than in controls.

Until our knowledge of the etiology of Alzheimer's dementia, as well as related conditions involving mental impairments, is greatly extended, no line of investigation should be ignored. We believed that the possible contributions of aluminum exposure to neural impairments deserved further study. In coming to this opinion we were mindful of the work of Roberts on the neurotoxic effects of inhaled aluminum silicate' as well as the neuropathologic results reported by Per1 and his associates indicating an association of aluminum with disease-affected neurons in Alzheimer's patients.*.' The possibility that certain metals including aluminum, either alone or in combination, play a role in dementia remains a viable hypothesisP While the possibility of transport of A1 to the brain via the olfactory system, especially under conditions of a partially compromised immune system, remains a likely route of entry into the nervous system, it is not the only entry route for aluminum. A1 and other elements with toxic potential enter the nervous system through many pathways, including our food and water. Initially, we investigated the effects of low doses of aluminum given to rats through their drinking water. The entry of A1 into the circulation and the brain depends on the particular species of A1 available as well as the conditions in the stomach and the digestive tract. The bioavailability of A1 may be enhanced by its complexing with fluorine (F) to form various monomeric fluoaluminum species. Of these, AIF3 was of special interest due to its lipid solubility and ability to pass

Two experiments using male rats evaluated the effects of a range of doses of the neurosteroid, pregnenolone sulfate (PS), or of the synthetic neurosteroid, ethylestrenol (E), on the retention of a passive avoidance task. The steroids either were given immediately after the training trial or 1 h before the first retention test. Retention tests were given both 24 h and 48 h after acquisition. In both experiments, separate groups of animals were trained under low or moderate footshock conditions. At all doses tested both PS and E improved retention under the low footshock conditions. In groups trained with the higher footshock, the steroid-treated groups performed no better than the vehicle controls. Indeed, there were suggestions that some doses impaired retention. These results seem best understood as an induction of bimodality or 'turbulence' in behavior as used in Chaos theory rather than a shift in an inverted U-shaped retention function. In the second experiment in which the steroids were given before retention testing, they were generally without effect.

Ethylestrenol, a synthetic anabolic steroid, was administered to adult male Long-Evans rats to investigate its role in acquisition and retention of a spatial food-search task. The animals were injected i.p. every other day either with 100 µg of ethylestrenol or with the vehicle alone. Injections began 1 week prior to testing and continued throughout the study. A modified hole-board task was used. After modest food deprivation, the animals were required to find a food reward placed in a given hole. Acquisition of the task was measured by the time required to reach the food hole. Eight trials were given per day. Following a 10-day period without deprivation (but with 2 injections on separate days), eight retention trials were given. Following this, the rats were trained to find the reward at a new location for 2 subsequent days. There were small differences between the groups in performance during acquisition in the original 5-day period but not in the final 2-day “new-hole” training period. During the retention test, however, the ethylestrenol-treated rats reached the food reward significantly faster than did the vehicle-treated rats. These results indicate that retention was substantially enhanced by the synthetic hormone-like agent under conditions in which there was only limited enhancement of acquisition.

Male CD-1 mice (6-8 week old) were tested for open field locomotion after the administration of various doses (10-150 mg/kg) of pregnenolone sulfate (PS). An initial high level of activity lasting for 10 minutes appeared in the control animals followed by a sustained level of activity that remained stable over the last 20 minutes of the session. Pregnenolone sulfate at doses of greater than or equal to 50 mg/kg decreased activity in the first 10 minutes of testing and reduced the overall activity of the mice in the entire test period. The lowest dose of 10 mg/kg PS significantly increased distance traveled in the first 10 minute interval. Flumazenil, a GABAA antagonist, and CPP, an NMDA antagonist, had no effect on the distance traveled by the 50 mg/kg PS group in the first 10 minute period. Nimodipine, an L-type VSCC antagonist, increased distance traveled in the initial 10 minute period. PS administered with nimodipine inhibited the increase in activity seen with the calcium antagonist in the first 10 minutes. These data indicate that PS produces a dose-dependent biphasic effect on exploratory behavior in animals placed in a novel environment and that this effect may involve alterations in intracellular calcium.

Annals of the New York Academy of SciencesVolume 765, Issue 1 p. 134-142 Potential Interactions between Nimodipine and Adrenal Hormones ROBERT L. ISAACSON, ROBERT L. ISAACSON Department of Psychology Binghamton University Binghamton, New York 13902–6000Search for more papers by this authorJULIE A. VARNER, JULIE A. VARNER Department of Psychology Binghamton University Binghamton, New York 13902–6000Search for more papers by this author ROBERT L. ISAACSON, ROBERT L. ISAACSON Department of Psychology Binghamton University Binghamton, New York 13902–6000Search for more papers by this authorJULIE A. VARNER, JULIE A. VARNER Department of Psychology Binghamton University Binghamton, New York 13902–6000Search for more papers by this author First published: September 1995 https://doi.org/10.1111/j.1749-6632.1995.tb16569.xAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Volume765, Issue1Neuroprotective Agents: Clinical and Experimental AspectsSeptember 1995Pages 134-142 RelatedInformation

This study examined the behavioral effects of chronic ingestion of various monofluoroaluminum complexes (AlF3) in drinking water. Forty young adult male Long-Evans rats were divided into four groups of 10 rats each. The groups received different concentrations of AlF3 in the drinking water from three sample solutions having a total Al concentration of 0.5, 5.0, and 50 ppm, respectively, or double-distilled deionized water on an ad lib. basis for 45 weeks. General decline of bodily appearance was observed in the lowest concentration AlF3 group, and animals in this group succumbed in greater numbers during the course of the study than those in any other group. Examinations of performance in an open field, an analysis of walking patterns, and a balance beam test did not find any difficulties indicative of motor disorder. Indeed, on the initial trial on the balance beam, the AlF3-treated animals exhibited superior performance. No group differences were found in behavior assessed by spontaneous alternation or by a modified Morris water maze test. When retested in the Morris maze after a low dose of scopolamine (0.4 mg/kg), the control animals took longer to reach the platform while the AlF3-treated rats were not affected. In an olfactory preference test, the AlF3-treated animals failed to show preferences exhibited by the controls, indicating a possible olfactory impairment. The level of Al in the brains of the AlF3-exposed rats, as determined by direct current plasma analysis, was almost double that of the control animals. There was a similar trend for the Al content found in the kidneys. (C) 1994 Academic Press, Inc.

Two experiments were undertaken in which the effects of semichronic administration of the precursor steroid, pregnenolone, were examined in a food search task. In both experiments male rats were required to find a food reward in a designated hole in an arena with 16 equally spaced holes. Hormone administration began 8 days before the onset of training. Training was given on an every-other-day schedule for five sessions. Animals were deprived of food for 18 h before training or testing. Retention testing occurred 10 days after acquisition and this was followed by 2 days of training using a different hole for the reward. The two experiments differed only in the method of hormone administration. In one experiment the rats received an implanted (sc) slow release pellet containing pregnenolone before training. In the second experiment the animals received ip injections of pregnenolone sulfate before and during initial training and then had the slow release pellet implanted between acquisition and retention. Significant enhancement of retention was found during the middle trials of the retention test when the treated and control groups from the two experiments were combined. No differences were found during acquisition training in either experiment. On the first day of training the animals to find the reward in a new location, the group injected with pregnenolone sulfate and later implanted with pregnenolone slow-release pellets exhibited performance superior to that of their matched control group.

This study examined the behavioral effects of chronic ingestion of various monofluoroaluminum complexes (AlF3) in drinking water. Forty young adult male Long-Evans rats were divided into four groups of 10 rats each. The groups received different concentrations of AlF3 in the drinking water from three sample solutions having a total Al concentration of 0.5, 5.0, and 50 ppm, respectively, or double-distilled deionized water on an ad lib. basis for 45 weeks. General decline of bodily appearance was observed in the lowest concentration AlF3 group, and animals in this group succumbed in greater numbers during the course of the study than those in any other group. Examinations of performance in an open field, an analysis of walking patterns, and a balance beam test did not find any difficulties indicative of motor disorder. Indeed, on the initial trial on the balance beam, the AlF3-treated animals exhibited superior performance. No group differences were found in behavior assessed by spontaneous alternation or by a modified Morris water maze test. When retested in the Morris maze after a low dose of scopolamine (0.4 mg/kg), the control animals took longer to reach the platform while the AlF3-treated rats were not affected. In an olfactory preference test, the AlF3-treated animals failed to show preferences exhibited by the controls, indicating a possible olfactory impairment. The level of Al in the brains of the AlF3-exposed rats, as determined by direct current plasma analysis, was almost double that of the control animals. There was a similar trend for the Al content found in the kidneys.

The monoethylcholine aziridinium ion, AF64A, (3 nmol in 1 μl) or artificial CSF (1 μl) was infused unilaterally into the right dorsal lateral ventricle of male adult rats. Treatment with the L-type calcium channel antagonist, nimodipine (70 μg/kg b.wt.) or its vehicle was administered beginning before and for seven days following surgery. The infusion of AF64A reduced spontaneous alternation rates in the T-maze when compared to CSF and sham infused animals. F64A-treated animals also took longer to reach the goal area in a complex maze task on specific trials relative to CSF and sham-infused animals. Locomotion and habituation to the open field did not differ between surgery groups. Unilateral AF64A significantly depleted acetylcholinesterase (AChE) positive terminals in the ipsilateral hippocampus and cell bodies in the ipsilateral medial septal area (MSA). Receptors for nerve growth factor (NGF-R), often colocalized with cholinergic cell bodies and terminals, also were depleted in the ipsilateral MSA of AF64A infused animals. Treatment with nimodipine did not have a neuroprotective effect on AF64A animals in either behavioral or histological results. However, some degree of protection was found in the vehicle-treated rats. This effect was likely a consequence of the stress of the injection procedure rather than the content of the vehicle, largely polyethylene glycol 400. Nimodipine-treated animals, regardless of surgery group, exhibited fewer emotional responses and had lower spontaneous alternation rates than untreated animals. The behavioral alterations found in the nimodipine groups are most easily explained in terms of altered emotionality. Overall our findings indicate that AF64A is a potent cholinotoxin that can selectively eliminate the ipsilateral septohippocampal cholinergic system when unilaterally infused into the lateral ventricle. It is possible that the mechanism of action of AF64A, like other nitrogen mustard analogues, involves disruption of basic processes involved in protein synthesis and DNA activities. Because of this, the toxic effects of the aziridinium mustard are independent of extracellular calcium and thus may not be susceptible to protection by calcium channel antagonists.

This paper attempts to merge two quite diverse major themes: the application of Paul MacLean's ideas on the evolution of the brain and certain of the principles and ideas arising from the relatively recent developments in ''fuzzy set theory.'' MacLean proposes three major divisions of mammalian brains that have been elaborated over the course of evolution: an R-Complex (reptile-like), a limbic system. and a Neomammalian (Neocortical) system. Neural elements in all of these systems at various times, contribute to goal oriented behaviors and to the analysis of the environment. All of these major categories of brain organization have mechanisms of plasticity that allow alterations in behavior to be made on the basis of environmental contingencies.However, these major components of the nervous system in the MacLean model cannot be firmly defined in traditional anatomical terms, In fact, given the complexity and variability of the mammalian nervous system, firm definitions may be impossible, In a real sense the brain areas involved and the interconnections among brain regions are uncertain and, therefore, ''fuzzy.'' The significance of conceptualizing the nervous system in Fuzzy Set terms and the implications to come from doing so are discussed.

Male Long-Evans rats were divided into four groups based on the concentrations of the AlF3 in the drinking water: 0.5 ppm, 5.0 ppm, 50 ppm, or a control solution of double-distilled, de-ionized water. Water was available ad libitum for 45 weeks. Following the behavioral studies, histological, immunohistochemical, and overall brain aluminum (Al) evaluations were made on portions of the brains from these animals. Selected coronal sections were stained by the Bielschowsky silver stain method, the Morin Al-fluorescence procedure, several standard neurohistological methods for cellular proteins, and through the use of several immunohistochemical methods, including ones that reveal neurofilaments and reactive astrocytes (GFAP). This report presents descriptions of the responses of the brains to the toxin exposure in regard to cell loss and other changes in the neocortex and hippocampus. The brain sections were immunohistochemically studied using antibodies both to neurofilament and phosphorylated neurofilament proteins. The three AlF3 groups did not differ from each other in overall brain Al content, but all treated groups had about twice the Al levels as did the control group. There were significant reductions in the number of neurons in the hippocampal CA1 and CA3 areas of the AlF3 treated groups. In addition the cells of the hippocampal formation appeared disorganized and many cells in all subdivisions stained excessively for Nissl-like proteins and that may reflect cellular dysfunction. Cells in the outer layers of the neocortex of the AlF3 groups exhibited darker Nissl staining and were more argentophilic than cells in similar areas from brains of the controls. These intracellular accumulations were not associated with increases in either phosphorylated or non-phosphorylated protein. Reduced numbers of cells evidencing neurofilament reaction product were found selectively in neocortical layer 4. There were large numbers of GFAP-positive cells in the brains of rats from all groups but the number of reactive cells was not greater in the treated animals than in the controls.