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Previous studies show that prenatal exposure to alcohol results in sleep deficits in rats, including reductions in paradoxical sleep. Little is known, however, about the extent or duration of sleep impairments beyond the neonatal period. The present experiment examined effects of prenatal exposure on sleep in young adulthood. Three-hour, daytime sleep EEGs were obtained in 6-month-old female rats prenatally exposed to alcohol. Compared to isocaloric pair-fed and ad libitum control groups, the alcohol-exposed group showed reduced paradoxical sleep. Non-paradoxical sleep did not differ between groups. Concurrent deficits were obtained in radial arm maze, but not inhibitory (passive) avoidance, performance. One year later, at the age of 18 months, alcohol-exposed rats showed deficits in spontaneous alternation behavior which were reversed by administration of glucose (100 mg/kg). Deficits in paradoxical sleep at 6 months of age were highly correlated with deficits in spontaneous alternation behavior at 18 months of age, in individual, alcohol-exposed animals. These results provide the first evidence that prenatal exposure to alcohol results in selective and persistent deficits in sleep. They also show that measures of paradoxical sleep can predict impaired memory over a large portion of the life span, and suggest that glucose can attenuate memory deficits in this population.

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1. Female MR ("anxious") and MNRA ("non-anxious") Maudsley rats were tested in the CSD behavioral conflict paradigm (anxiety-like measure) and also in the FST paradigm (depression-like measure). 2. As expected, MNRA rats accepted significantly more shocks in the CSD paradigm than did MR rats (i.e., MNRA rats were less "anxious"), MNRA rats also exhibited significantly less immobility in the FST procedure (i.e., MNRA rats were less easily made "depressed"). 3. When the data were pooled across the two strains, there was a significant correlation between CSD and FST behavioral scores; however, there was no significant correlation between these measures when the data from the two strains were evaluated separately. Multiple regression (independent variables of rat strain and CSD score, dependent variable of FST score) revealed a significant effect of rat strain, but not CSD score, on FST behavior. 4. The relationship of these findings to the apparent relationship between anxiety and depression in humans is discussed.

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Extracellular single-unit recording techniques were used to evaluate the physiological and pharmacological characteristics of noradrenergic locus coeruleus (LC) neurons in urethane-anesthetized Maudsley reactive (MR) and non-reactive (MNRA) rat strains, a presumed genetic model for differences in 'anxiety'. LC neurons from MNRA rats were found to have a significantly higher basal discharge rate than LC neurons from either the MR or Sprague-Dawley (SD) rats. The discharge pattern of MNRA LC neurons also differed significantly from that of LC neurons from SD and MR rats, with LC neurons from MNRA rats exhibiting a burst-like pattern of discharge. Finally, MNRA LC neurons were significantly less sensitive to the inhibitory effects of i.v. clonidine on spontaneous activity.

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Recent reports have suggested that plasma concentrations of inorganic sulfate may be lower in patients with Alzheimer's disease (AD). We measured sulfate concentrations in 10 patients with AD and found an average concentration of 0.28 mM, which was not significantly different from the mean concentration in age-matched controls (0.32 mM) or young healthy controls (0.27 mM). These results indicate that plasma sulfate concentrations are not altered in AD and that previous reports suggesting altered metabolism of sulfur-containing xenobiotics in neurodegenerative diseases should be reevaluated.

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The present studies were designed to examine the effects of treatment with the noradrenergic neurotoxin N-(2-chloroethyl)-n-ethyl-2-bromobenzylamine HCl (DSP4; 65 mg/kg, IP) on conflict behavior in the Maudsley reactive (MR) and nonreactive (MNRA) rat strains. In daily 10-min sessions, water-restricted rats were trained to drink water from a tube that was occasionally electrified; electrification was signaled by the presence of a tone (7-s duration; ISI = 30 s). Consistent with previous reports, the number of shocks accepted by rats of the MR and MNRA strains did not differ initially, but MNRA rats exhibited a dramatic increase in punished responding relative to their MR counterparts over the course of several weeks of conflict testing. This MR vs. MNRA strain difference in punished responding did not exhibit extinction following discontinuation of CSD conflict behavior testing for a period of 6 weeks. Whether it was administered after conflict training or before, DSP4 treatment did not reduce the MR vs. MNRA strain difference in conflict behavior; rather, DSP4 treatment tended to increase the magnitude of the MR vs. MNRA difference in conflict behavior. The effects of DSP4 on norepinephrine (NE) and 5-hydroxytrypamine (5-HT) concentrations in the pons medulla region were determined in one group of conflict-experienced MR and MNRA rats (35 weeks after administration) and in a second group of naive MR and MNRA rats (3 weeks after administration). There were no MR vs. MNRA strain differences in NE or 5-HT concentrations in vehicle-treated rats. DSP4 treatment significantly reduced NE, but not 5-HT, concentrations when compared to control values; rats that were sacrificed 3 weeks following DSP4 administration exhibited a greater NE depletion than did rats sacrificed 35 weeks after DSP4 administration. Finally, there were no significant correlations between pons medulla region NE concentrations and conflict behavior in either strain alone or when the data from the two strains were combined. The present results are not consistent with the hypothesis that the MR vs. MNRA strain difference in conflict behavior is the result of strain differences in brain NE function.

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Maudsley reactive (MR) and nonreactive (MNRA) and Sprague-Dawley (SD) male rats were tested for their immobility response in the forced swim test when the water was fresh or soiled by a rat of the same or other strain. For all strains, rats tested in soiled water were less immobile than rats in fresh water. The three strains did not differ as producers of soiling substance, but did differ in their response to it. The MR strain was least responsive, whereas the MNRA and SD did not differ from one another. These results support a previous study suggesting that MR rats are more immobile than MNRA rats in the forced swim test. The interpretation of these findings regarding the use of the Maudsley rat strains as an animal model for studying anxiety and/or depression is discussed.

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We recently reported that post-training administration of serotonergic receptor antagonists attenuated the inhibitory-avoidance memory deficits normally exhibited by aged rats. In the present study, we determined whether a subeffective dose of the serotonergic type-2 receptor antagonist, ketanserin, would augment the facilitative effects produced by the acetylcholinesterase inhibitor, physostigmine, on memory in aged rats using the same task. The drugs were injected intraperitoneally alone, or in combination, immediately following training. Retention testing occurred 24 hours following training. A dose-dependent enhancement of memory was demonstrated as a result of the two treatment conditions (physostigmine 0.01-10.0 micrograms/kg, ketanserin 1.0 mg/kg + physostigmine 0.001-0.01 micrograms/kg). The facilitation of memory produced by the combined treatment was observed at doses well below those required to produce a similar effect when each drug was administered alone. The results provide additional evidence for an interaction between the cholinergic and serotonergic neurotransmitter systems in learning and memory, and may have important implications in the treatment of age-related memory impairments.

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The present studies were designed to characterize the behavior of Maudsley reactive (MR/Har) and nonreactive (MNRA/Har) rats in a modification of the Geller-Seifter operant conflict paradigm. Food-restricted (85% of free-feeding weights) female MR/Har and MNRA/Har rats were trained to lever press for food reinforcement in a multiple-schedule operant conflict paradigm. In the absence of a tone, a fixed ratio-30 (FR-30) schedule for reinforcement only was in effect (i.e., every 30th lever press resulted in the delivery of a 45-mg food pellet). During the presence of a tone, a fixed ratio-1 (FR-1) schedule of both reinforcement (food) and punishment (0.20 mA footshock applied for 500 ms) was in effect (i.e., each lever press resulted in both food and shock delivery). The tone periods were 27 s in duration and were presented on a variable interval (VI)-120-s schedule (approximately 20 tones/40-min session). Behavioral testing was conducted 5 days/week for 35 weeks. Initially, punished responding between the MR/Har and MNRA/Har rat strains did not differ dramatically. However, over the course of many weeks of conflict testing, rats of the MNRA/Har strain came to accept significantly more shocks than did subjects of the MR/Har strain. A direct examination of footshock sensitivity in these rats revealed that this difference in conflict behavior over time was not due to strain differences in shock sensitivity. The mechanism for this time-dependent difference in conflict behavior between the MR/Har and MNRA/Har rats remains undetermined.

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The effects of lesions of the central nucleus of the amygdala on anxiety-like behaviors in the rat were determined using two animal models, the conditioned suppression of drinking (CSD) and defensive burying paradigms. For CSD conflict testing, water-restricted rats were trained to drink water from a tube that was occasionally electrified (0.25 mA); electrification was signaled by a tone. CSD test sessions were 10 min in duration and were conducted 4 days per week. After at least 3 weeks of conflict testing, both punished (30-40 shocks per session) and unpunished (10-12 ml water per session) responding had stabilized. Subjects then received bilateral electrolytic lesions of the central nucleus of the amygdala or sham lesions. After a 1-week recovery period, CSD conflict testing was reinstated and continued for 20 weeks. Amygdaloid-lesioned subjects accepted significantly more shocks than did sham controls. In addition, acute challenges with the benzodiazepine chlordiazepoxide (2.5-10 mg/kg, IP, 30-min pretreatment), the barbiturate phenobarbital (20 mg/kg, IP, 10-min pretreatment), and carbamazepine (10 mg/kg, IP, 10-min pretreatment) produced an increase in punished responding in both amygdaloid-lesioned and sham-treated subjects. Analysis of covariance (ANCOVA)-based adjusted means for the change in shocks received were not significantly different between the two groups. Following completion of the CSD studies, subjects were tested in the defensive burying paradigm. Although there was no significant difference between lesioned and sham-treated subjects on the percent of animals that exhibited burying, subjects with lesions of the central nucleus of the amygdala exhibited a significantly greater latency to initiate defensive burying.(ABSTRACT TRUNCATED AT 250 WORDS)

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Regional cerebrovascular permeability-capillary surface area products (rPS) and brain vascular space (BVS) were measured in aging, conscious, unrestrained Sprague-Dawley rats. Three groups of animals were examined: young-mature (6 months), middle-aged (12-14 months), and old (24-26 months) rats. Complex maze learning had been previously characterized in these same animals. Maze learning declined with age. Brain vascular space did not differ significantly with age in any brain region. However, small, but significant age-dependent decreases in rPS (25-33%) were observed. These decreases occurred mainly in the old animals in the basal ganglia and parietal cortex, and in the middle-aged and old rats in the olfactory bulbs. Significant and unexpected positive average correlations between brain permeability-capillary surface area products (PS) and learning errors occurred primarily in young rats and were attributable mainly to changes in 5 of 14 brain regions; hypothalamus, hippocampus, parietal cortex, septal area and superior colliculus. The higher correlations between maze learning errors and PS in young animals may indicate dynamic regulation of this cerebrovascular parameter which is lessened with aging. Average correlations between PS and cerebral blood flow also were determined and found to be generally small and not significant for most brain regions and age groups.

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The purpose of the present experiment was to determine the effects of lesions of cholinergic neurons originating from the nucleus basalis magnocellularis (NBM), alone or in combination with central serotonin depletion, on learning and memory in rats trained in the Stone 14-unit T-maze--a complex, positively-reinforced spatial discrimination task. Lesion of cholinergic neurons within the NBM was accomplished by bilateral infusion of ibotenic acid. Serotonin depletion was accomplished by the systemic administration of p-chloroamphetamine (PCA). The results show that PCA-induced serotonin depletion enhanced learning. This effect was completely prevented by NBM lesions, despite the fact that NBM lesions alone did not affect the performance of rats in this task. The results of this study support the view that the cholinergic and serotonergic systems may functionally interact in learning and memory processes. The significance of this interaction in the etiology and treatment of dementia should be further investigated.

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Learning in rats trained in the Stone 14-unit T-maze, a complex, positively reinforced spatial discrimination task was assessed following cytotoxic (5,7-dihydroxytryptamine; 5,7-DHT) deafferentation of the serotonergic inputs to the hippocampus. Serotonergic deafferentation was accomplished by infusing the cytotoxin in to the fornix-fimbria/cingulum bundle. Lesioned rats reached criterion (i.e. learned) in significantly fewer trials and made significantly fewer errors throughout training than either vehicle-injected or sham-operated controls. This represents the first time that the effects of selective chronic destruction of serotonergic inputs to the hippocampus have been investigated. The present results provide, therefore, evidence in support of a neuromodulatory role for serotonin (5-HT) within the rat hippocampus in the mediation of the processes underlying learning and memory for this task. Other studies are, therefore, warranted in order to determine whether hippocampal 5-HT also plays a role in the mediation of the processes underlying learning and memory in other types of tasks.

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The Maudsley Reactive (MR/Har) and Non-Reactive (MNRA/Har) rat strains, bred originally by Broadhurst for differences in Open Field Defecation, also differ in their control (i.e., non-drug) behavior in the Conditioned Suppression of Drinking (CSD) conflict procedure, a second "model" behavior for the study of anxiety and/or emotionality in rats. The present studies compared the effects of diazepam and alprazolam on CSD behavior in these two strains of rats. In daily 10-min sessions, water-deprived rats were trained to drink from a tube that was occasionally electrified (0.2-0.5 mA), electrification being signaled by a tone. Both diazepam and alprazolam increased punished responding in a dose-related manner. The per cent increase in punished responding (for diazepam only) was comparable in the two strains; however, both statistical and empirical approaches indicated that the magnitude of the anti-conflict effect of benzodiazepines in MNRA/Har versus MR/Har rats was not related to differences in baseline (i.e., non-drug) punished responding. Based on the absolute change in shocks received, rats of the MNRA/Har strain exhibited a significantly greater anti-conflict effect following diazepam or alprazolam treatment than did rats of the MR/Har strain. These findings further the hypothesis that the behavioral differences exhibited by Maudsley MR/Har and MNRA/Har rat strains may constitute a genetically-based "animal model" for the study of emotionality and/or anxiety.

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The present study examined the effects of the anxiolytics diazepam and phenobarbital, the A-1 adenosine agonist N6-R-phenylisopropyladenosine (l-PIA), and the A-2 adenosine agonist 5'-N-ethylcarboxamidoadenosine (NECA) on conflict behavior. Water-restricted rats were trained to drink from a tube that was electrified (0.5 mA intensity) on a FI-29s schedule, electrification being signaled by a tone. After 3 weeks of daily 10-min sessions, the animals accepted a stable number of shocks (punished responding) and consumed a consistent volume of water (unpunished responding) per session. Different doses of l-PIA and NECA were then tested separately at weekly intervals. In addition, the effects of diazepam and phenobarbital were determined in animals pretreated with saline, l-PIA, or NECA. Neither l-PIA (15-250 nmole/kg) nor NECA (2.5-20 nmole/kg) produced a significant anti-conflict effect when administered alone. Diazepam (1.25-10 mg/kg) or phenobarbital (10-40 mg/kg) administration to saline-pretreated rats resulted in a dose-dependent increase in punished responding (shocks received) with minimal effects on unpunished responding (water intake). Neither l-PIA nor NECA pretreatment reliably altered the effects of diazepam on conflict behavior. Pretreatment with l-PIA, but not NECA, significantly reduced the anti-conflict effects of phenobarbital on conflict behavior. These data suggest that phenobarbital, but not diazepam, anti-conflict responses may involve interactions with A-1 adenosine receptors.

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Learning in male Sprague-Dawley rats was assessed in two types of positively reinforced complex spatial discrimination tasks (Stone 14-unit T-maze and eight-arm radial-arm maze) following cytotoxic lesions of central serotonergic terminal projection fields with p-chloroamphetamine (PCA). Learning, as expressed as mean number of errors per day and mean number of trails required to reach criterion, was significantly enhanced in the PCA-lesioned animals trained in the Stone maze. On the other hand, the performance of the PCA-lesioned animals trained in the eight-arm radial-arm maze was not found to differ significantly from that of saline-injected animals. The improved acquisition of the PCA-lesioned rats trained in the Stone maze was completely abolished following pretreatment with the selective serotonergic reuptake inhibitor norzimeldine. Neurochemical analyses of the brains of representative animals revealed that the levels of serotonin and its major metabolite, 5-hydroxy-3-indoleacetic acid, were both significantly reduced by PCA in all regions examined. While it is clear from these and other studies that the serotonergic nervous system plays an important role in the processes underlying learning and memory, these results further underscore the selective role of this neurotransmitter system in the way information is processed by the brain.

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Relations between sleep and memory were examined as a function of aging in rats. Sleep (24 hr), passive avoidance retention, and choline acetyltransferase (CAT) activity were assessed in 3 age-groups (6, 15, and 24 months old). Age-related alterations were evident in sleep, memory, and cortical and striatal CAT activity. Retention deficits in old rats were significantly correlated with several measures of paradoxical sleep. Similar analyses in 6- and 15-month-old rats with ibotenic acid-induced lesions of the nucleus basalis magnocellularis (NBM) showed several alterations in sleep, memory, and cortical CAT activity comparable to those seen in the old rats. One measure of paradoxical sleep, bout duration, correlated significantly with retention scores in rats with lesions. Thus, fragmented paradoxical sleep accompanies memory impairments in old rats and in young rats with NBM lesions.

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The Maudsley Reactive (MR/Har) and Non-Reactive (MNRA/Har) rat strains, selectively bred for differences in open field defecation, have also been shown to differ in their baseline behavior in the Conditioned Suppression of Drinking (CSD) procedure, a second "model" behavior for the study of anxiety and/or emotionality in rats. The present studies were designed to compare the responsiveness of these two strains to the typical antianxiety agent chlordiazepoxide in the CSD paradigm. In daily 10-minute sessions, water-deprived rats were trained to drink from a tube that was occasionally electrified (0.5 mA), electrification being signaled by a tone. Consistent with previous reports, after several weeks of CSD testing, MNRA/Har rats accepted significantly more shocks than did MR/Har rats during control (nondrug) sessions. In both strains, the number of shocks accepted was inversely related to the intensity of the shock used (0.25-1.0 mA), with MNRA/Har rats accepting significantly more shocks than MR/Har rats at all intensities examined. The effects of various doses (1.25-28.4 mg/kg, IP) of chlordiazepoxide were determined in subjects of the MNRA/Har strain at the original training intensity (0.5 mA), while a lower intensity (0.25 mA) was utilized in MR/Har rats. Although punished responding in control (i.e., nondrug) CSD sessions did not differ under these conditions, MNRA/Har rats were found to be more responsive to the anticonflict effects of chlordiazepoxide than rats of the MR/Har strain. This strain difference in anticonflict efficacy of chlordiazepoxide was quite dramatic, with MNRA/Har rats accepting twice as many shocks as MR/Har rats following maximally effective doses of chlordiazepoxide. Low doses of chlordiazepoxide increased water intake slightly, while higher doses decreased water intake. Surprisingly, the chlordiazepoxide-induced depression of water intake was greater in rats of the MR/Har strain. Thus, these Maudsley Reactive and Non-Reactive rat strains, bred originally for their differences in open field behavior, also differ markedly in their responsiveness to chlordiazepoxide in the CSD paradigm. These findings further support the hypothesis that the MR/Har and MNRAHar rat strains may represent a genetically-based "animal model" for the study of emotionality and/or anxiety.

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Based upon differences in open field and conflict behaviors, the MR/Har and MNRA/Har rat strains have been proposed as a genetically-based "animal model" for the study of emotionality and/or anxiety. The present study compared the MR/Har and MNRA/Har rat strains in the Defensive Burying paradigm. Prior to testing, female MR/Har and MNRA/Har rats were placed in a 40 X 30 X 40 cm Plexiglas chamber containing clay bedding material (5 cm deep) for 30 minute periods on each of four consecutive days. On the fifth day, a wire wrapped prod was placed at one end of the chamber. Rats were placed in the chamber singly and a 3 mA shock was delivered upon contact with the prod. Defensive Burying behavior (i.e., the moving of bedding material toward or over the prod) was recorded for each animal for 15 minutes postshock. There was no MR/Har versus MNRA/Har difference in the percent of animals exhibiting Defensive Burying, nor was there a MR/Har versus MNRA/Har difference in the latency to initiation or the duration of this behavior. Thus, these genetically-defined Maudsley rat strains do not appear to differ in all "animal models" for the study of anxiety or fear.

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Stimulation of muscarinic cholinergic receptors with the highly potent and selective receptor agonist oxotremorine produced hypothermia in rats. Alaproclate, a purported selective serotonergic reuptake inhibitor, potentiated this response. Destruction of central presynaptic serotonergic terminals with the potent cytotoxin p-chloroamphetamine (PCA) failed to attenuate the hypothermic response to oxotremorine in alaproclate-pretreated animals. These results could be taken to suggest that alaproclate may act, at least in part, via a non-serotonergic mechanism to potentiate the oxotremorine-induced hypothermic response.

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