Biomedical subjects

S E File

Publications and source records attributed to S E File.

At least 55 records · Page 3Linked to original sources

PubMed1999

Chronic fluoxetine in tests of anxiety in rat lines selectively bred for differential 5-HT1A receptor function.

Selective breeding for high and low sensitivity to the hypothermic response induced by the 5-HT1A receptor agonist 8- OH-DPAT has established two lines of rat (HDS and LDS, respectively) whose behavior differs in a model of depression and in the social interaction test of anxiety. The HDS line has a higher level of anxiety and, furthermore, does not display the usual anxiogenic response to intrahippocampal administration of 8-OH-DPAT. It was therefore hypothesized that this line of rat might be a useful model of high trait anxiety with a susceptibility to depression. We thus investigated whether chronic treatment with fluoxetine would result in an anxiolytic effect in the social interaction test in the LDS and HDS lines of rat. In both lines, acute fluoxetine (10 mg/kg) produced an anxiogenic effect in the social interaction test; when rats were tested 24 h after 14 days of fluoxetine treatment there were no anxiolytic effects in either line. In the social interaction test, chronic fluoxetine treatment did not change either the anxiogenic effect of 8-OH-DPAT (100 ng) injected bilaterally into the dorsal hippocampus in the LDS line or the lack of response in the HDS line. In the elevated plus-maze, chronic fluoxetine treatment resulted in a significant anxiogenic effect in the HDS line, but was without effect in the LDS line. Intrahippocampal 8-OH-DPAT was without effect in the plus-maze in either line. These results suggest that chronic treatment with fluoxetine did not modify the hippocampal 5-HT1A receptor in either line. The anxiogenic effects observed in the plus-maze in the HDS line after chronic fluoxetine might relate to line differences in 5-HT1A receptors in other brain regions.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1999

Factor analysis shows that female rat behaviour is characterized primarily by activity, male rats are driven by sex and anxiety.

This experiment explored sex differences in behaviour using factor analysis to describe the relationship between different behavioral variables. A principal component solution with an orthogonal rotation of the factor matrix was used, ensuring that the extracted factors are independent of one another, and thus reflect separate processes. In the elevated plus-maze test of anxiety, in male rats factor 1 accounted for 75% of the variance and reflected anxiety, factor 2 represented activity, and accounted for 24% of the variance. This contrasted with the finding in female rats in which factor 1 was activity, accounting for 57% of the variance, with the anxiety factor accounting for only 34% of the variance. When behaviour in both the plus-maze and holeboard were analysed, a similar sex difference was found with anxiety emerging as factor 1 in males and holeboard activity as factor 1 in females. Locomotor activity in the inner portion of the holeboard loaded on the anxiety factor for males, but on activity for females. When behaviours in the plus-maze and sexual orientation tests were analysed, anxiety emerged as factor 1 in males, sexual preferences factor 2, and activity factor 3. In females, activity was factor 1, sexual preference factor 2, anxiety factor 3, and social interest factor 4. These results suggest caution should be exercised in interpreting the results from female rats in tests validated on males because the primary controlling factor may be different.

Animals↗

PubMed1999

Role of the dorsomedial hypothalamus in mediating the response to benzodiazepines on trial 2 in the elevated plus-maze test of anxiety.

Trial 2 in the elevated plus-maze provides an animal model of specific phobia (fear of heights). On this trial, rats no longer respond to benzodiazepines. The present experiment examined the role of the dorsomedial hypothalamus in mediating insensitivity to chlordiazepoxide on trial 2. Rats received a 5 min exposure to the maze, undrugged. Forty-eight hours later, rats injected with control infusions into the dorsomedial hypothalamus showed the usual lack of response to chlordiazepoxide (5 mg/kg, i.p.). However, those receiving lidocaine injections (40 micrograms/microliter in a volume of 0.2 microliter) in the dorsomedial hypothalamus (producing functional inactivation), immediately before trial 2, responded with an anxiolytic response to chlordiazepoxide, characterised by an increased percentage of time on the open arms and by an increased number of entries into, and time spent on, the distal portions of the open arms. Since the lidocaine injections were without anxiolytic effects, our results suggest that this region of the hypothalamus regulates the functional state of benzodiazepine receptors in other brain regions.

Animals↗

PubMed1999

Stimulation of nicotinic receptors in the lateral septal nucleus increases anxiety.

The present study investigated the role of nicotinic receptors in the lateral septum in the modulation of anxiety. The effects of direct injections of nicotine into the lateral septum were first investigated in two tests of anxiety, social interaction and elevated plus-maze tests. Intra-septal injection of nicotine (1 and 4 microgram) induced consistent anxiogenic effects in both tests. The reversal of nicotinic effects with mecamylamine was then studied in the social interaction test. Intra-septal injection of mecamylamine at a low dose (15 ng) induced an anxiolytic effect, suggesting the presence of intrinsic cholinergic tone increasing anxiety. At higher doses (30-50 ng), mecamylamine was without effect in the social interaction test, but blocked the anxiogenic effects of nicotine (4 microgram). These findings provide further evidence for the role of the lateral septum in the modulation of anxiety and suggest that cholinergic projections to this brain area facilitate anxiety through nicotinic receptors.

Animals↗

PubMed1999

Conditions under which lorazepam can facilitate retrieval.

Memory is composed of three stages: acquisition, consolidation, and retrieval. By impairing acquisition processes, benzodiazepines cause anterograde amnesia while leaving intact information learned before the drug was taken. In some circumstances, retrieval of this information is even improved by benzodiazepines. It has been hypothesized that this phenomenon is not a true facilitation of retrieval processes, but is the result of reduced interference from items presented after drug administration and is thus a secondary consequence of drug-induced amnesia. Experiment 1 investigated the effect of 0.5, 1, and 2.5 mg of lorazepam on explicit episodic memory in healthy young volunteers. The 1-mg dose was found to significantly improve recall of items presented before drug administration without causing amnesia for items presented after drug administration, thus excluding an interference explanation. Experiment 2 investigated the conditions necessary to obtain facilitated retrieval with 1 mg of lorazepam. The results showed that facilitation was found only when two lists of semantically related material were presented, but that both of the lists could be presented before drug administration, thus excluding an effect of lorazepam on consolidation. Facilitation could be demonstrated in both direct (free recall) and indirect (backwards reading) retrieval tasks and when all of the material was presented after lorazepam administration. This improved retrieval could therefore be of clinical relevance, but any benefits would be reduced at higher doses that at the same time impair acquisition of new information. However, because 1 mg of lorazepam is an effective anxiolytic dose, these results suggest that it is possible to combine effective anxiety reduction with some benefits to memory.

Adolescent↗

PubMed1999

Beneficial effects of glycine (bioglycin) on memory and attention in young and middle-aged adults.

The N-methyl D-aspartate receptor complex is involved in the mechanism of long-term potentiation, which is thought to be the biological basis of learning and memory. This complex can be manipulated in a number of ways, one of which is through the strychnine-insensitive glycine receptor coagonist site. The effects of Bioglycin(Konapharma, Pratteln, Switzerland), a biologically active form of the amino acid glycine, were therefore studied in healthy students (mean age, 20.7 years) and middle-aged men (mean age, 58.9 years) with tests that measured attention, memory and mood, using a double-blind, randomized, crossover design. Compared with the young group, the middle-aged group had significantly poorer verbal episodic memory, focused, divided, and sustained attention; they also differed in their subjective responses at the end of testing. Bioglycin significantly improved retrieval from episodic memory in both the young and the middle-aged groups, but it did not affect focused or divided attention. However, the middle-aged men significantly benefited from Bioglycin in the sustained-attention task. The effects of Bioglycin differed from those of other cognitive enhancers in that it was without stimulant properties or significant effects on mood, and it primarily improved memory rather than attention. It is likely to be of benefit in young or older people in situations where high retrieval of information is needed or when performance is impaired by jet lag, shift work, or disrupted sleep. It may also benefit the impaired retrieval shown in patients with schizophrenia, Parkinson's disease, and Huntington's disease.

Adolescent↗

PubMed1999

Time-course of changes in the social interaction test of anxiety following acute and chronic administration of nicotine.

The purpose of these experiments was to explore the hypothesis that the effects of nicotine on anxiety depend on the time since administration and the duration of treatment. In the social interaction test of anxiety, acute nicotine administration (0.1 mg/kg, subcutaneously) decreased social interaction when rats were tested 5 min after injection, but increased it when they were tested 30 min after injection. Social interaction was also decreased 1 h post-injection, but levels returned to baseline between 3 and 30 h. As these changes were independent of any changes in locomotor activity, nicotine seemed to be having both anxiogenic and anxiolytic effects at different times after injection. An anxiolytic effect was also observed 30 min after the second nicotine injection, and the anxiogenic effect observed 5 min after injection remained after 4 days of nicotine administration. However, after 7 days of nicotine treatment, tolerance was observed to both these effects. When rats were tested 72 h after the last of 7 or 14 days of nicotine treatment, an anxiogenic withdrawal response was observed. Thus, an oppositional mechanism may underlie tolerance to the anxiolytic effects, whereas there is as yet no evidence for this type of mechanism mediating tolerance to the anxiogenic effects.

Animals↗

PubMed1998

Striking changes in anxiety in Huntington's disease transgenic mice.

Huntington's disease transgenic mice were tested in the elevated plus-maze test of anxiety at 6, 8, 10 and 12 weeks of age. At all ages, they showed significant and striking increases in the percentages of open arm entries and time spent on the open arms, compared with their normal littermates, indicating reduced anxiety. These increases were not secondary to a non-specific stimulant effect, since the transgenic mice made fewer closed arm entries, significantly so from 10 weeks of age. The mice were also tested in the holeboard, which provides measures of locomotor activity and directed exploration. From 8 weeks of age, the Huntington's mice were significantly less active than their normal littermates and made fewer exploratory head-dips. The increased open arm activity in the elevated plus-maze cannot therefore be secondary to increased exploration in the transgenic mice. In order to determine whether the reduced anxiety was due to differences in benzodiazepine receptor function, the mice were challenged with the benzodiazepine receptor antagonist, flumazenil. The results indicated that some of the reduced anxiety could be attributed to the presence of an endogenous anxiolytic ligand.

Animals↗

PubMed1998

The influence of alcoholism and cirrhosis on benzodiazepine receptor function.

In a previous study we reported that the affinity of the platelet benzodiazepine receptor was greater in alcoholic cirrhotic patients compared with normal controls and that there were detectable ligands for the neuronal benzodiazepine receptor in plasma from both alcoholic and nonalcoholic cirrhotic patients. The aim of the present study was to assess the separate contributions of alcoholism and cirrhosis to the presence of ligands in plasma for the neuronal and peripheral benzodiazepine receptors and to changes in peripheral benzodiazepine receptor binding in platelets. These parameters were measured in 10 alcoholic cirrhotics, 9 nonalcoholic cirrhotics, 7 alcoholics with a normal liver function, and 15 nonalcoholic subjects and normal liver function. Both groups of alcoholics had been abstinent for several months and the nonalcoholic groups had abstained for 24 h before the study. The concentration of ligands for the peripheral benzodiazepine receptor were significantly higher in both cirrhotic groups compared with the other two groups, suggesting that cirrhosis was responsible for this accumulation. Furthermore, the cirrhotic patients with detectable concentrations of these ligands had significantly poorer episodic memory than those without ligands. However, the presence of ligands for the peripheral benzodiazepine receptor did not correlate with the change in receptor affinity, which was increased in the alcoholic cirrhotic group compared with all other groups. Neither cirrhosis nor alcoholism altered the peripheral benzodiazepine receptor number. The cirrhotic patients with detectable ligands for the neuronal benzodiazepine receptor showed psychomotor slowing and executive dysfunction. The results suggest that the ligands for the peripheral benzodiazepine receptor may contribute to some of the cognitive deficits seen in hepatic encephalopathy, but are not responsible for the receptor affinity change seen in the alcoholic cirrhotics. This affinity change is not solely due to the effects of alcohol and could possibly serve as a marker for those at risk for developing alcoholic cirrhosis.

Adult↗

PubMed1998

Does the sedation resulting from sleep deprivation and lorazepam cause similar cognitive deficits?

It is notoriously difficult to assess the contribution of the sedative effects of benzodiazepines to the cognitive impairments that they produce. The purpose of the present experiment was to determine whether a similar pattern of cognitive impairment would be seen in conditions when subjects felt equally sleepy as the result of sleep deprivation. The effects of a sedative dose of lorazepam (2.5 mg) in healthy volunteers was therefore compared with the effects of acute sleep deprivation (a night on-call) in a group of junior doctors and the effects of chronically disturbed sleep due to snoring. Lorazepam, acute sleep deprivation, and chronic sleep disturbance all significantly increased subjective sedation. In addition, lorazepam significantly impaired performance in two tests of psychomotor speed and caused significant anterograde amnesia. Semantic and short-term memory were not impaired by lorazepam, nor was there any impairment in executive function. The only deficit found following acute sleep deprivation was in a test of semantic memory, generating examples from a difficult category. The only significant deficit in the group suffering from chronically disturbed sleep, compared with age-matched controls, was in executive function, and there was a nearly significant impairment in sustained attention. These results suggest that, despite the common factor of increased subjective sedation, the profile of cognitive impairment in the two sleep deprivation groups are neither similar to each other nor to that seen following an acute dose of lorazepam.

Adult↗

PubMed1998

Selectively bred lines of rats differ in social interaction and hippocampal 5-HT1A receptor function: a link between anxiety and depression?

Selective breeding for high and low sensitivity to the hypothermic response of the 5-HT1A receptor agonist 8-OH-DPAT has established two lines (HDS and LDS, respectively) whose behavior differs in a model of depression, but not in the elevated plus-maze test of anxiety. The lines also differed in postsynaptic, but not presynaptic, 5-HT1A receptors. Based on previous evidence that postsynaptic 5-HT1A receptors mediate anxiogenic effects in the social interaction test of anxiety, but not the elevated plus-maze, we investigated possible differences between the lines in these two tests. The HDS line had a consistently lower level of social interaction compared with the LDS line, but no differences were found on any of the measures of the anxiety on trials 1 or 2 in the elevated plus-maze. To determine whether the line differences in anxiety were mediated by different hippocampal 5-HT1A receptor function, 8-OH-DPAT (50 and 100 ng) was applied bilaterally to the dorsal hippocampus. This elicited anxiogenic effects in the LDS line, as has been previously reported in other rat strains, but there was no response in the HDS line, thus demonstrating an abnormal 5-HT1A receptor function in the hippocampus. The 5-HT1A receptor antagonist WAY100635 (200 ng) was administered to the dorsal hippocampus to test for possible differences between the lines in 5-HT tone. There were no significant changes in social interaction in either the HDS or LDS rats, indicating that the different level of anxiety between lines is not due to differences in hippocampal 5-HT tone. It is proposed that the HDS line may prove a useful model of a type of high trait anxiety linked to a susceptibility to depression.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed1998

Role of the basolateral nucleus of the amygdala in the formation of a phobia.

Specific phobia is an anxiety disorder that does not respond to benzodiazepines. The elevated plus-maze test of anxiety is sensitive to benzodiazepines on trial 1, but during the first 5-min trial the nature of the anxiety generated changes to a specific fear of heights, and, as a result, on trial 2 the rats no longer respond to benzodiazepines. However, rats that received reversible bilateral lesions of the basolateral amygdala (by lidocaine injection) immediately after trial 1 responded with an anxiolytic response to chlordiazepoxide when tested 48 h later on trial 2. Those that received vehicle injections after trial 1 showed the usual lack of response to chlordiazepoxide on trial 2. Thus, the basolateral amygdala plays a crucial role in the consolidation of information that leads to the formation of a specific phobia and subsequent insensitivity to benzodiazepines.

Amygdala↗

PubMed1998

Endogenous acetylcholine in the dorsal hippocampus reduces anxiety through actions on nicotinic and muscarinic1 receptors.

Dorsal hippocampal cholinergic modulation of behavior in different tests of anxiety was investigated by direct injection of the muscarinic M1 and M2 receptor antagonists, pirenzepine and gallamine, and the nicotinic receptor antagonist mecamylamine. In the social interaction test, the anxiogenic effect of pirenzepine (30-100 ng) provided evidence for a tonic cholinergic anxiolytic action mediated by postsynaptic M1 receptors. The anxiogenic action of mecamylamine (30 and 100 ng) was most likely mediated by its action of presynaptic nicotinic receptors to reduce acetylcholine release. Gallamine (10-1,000 ng) was without effect, suggesting that M2 receptors in this brain region do not play a significant role in this behavioral test. On Trial 1 in the elevated plus-maze, the receptor antagonists were without any effect, but in those with a previous 5-min experience of the plus-maze pirenzepine and mecamylamine had anxiogenic effects in the dose range of 30-300 ng; gallamine (100 and 300 ng) was without significant effect.

Acetylcholine↗

PubMed1998

Bimodal modulation by nicotine of anxiety in the social interaction test: role of the dorsal hippocampus.

In conditions generating moderate levels of anxiety in the social interaction test (low light, unfamiliar arena or high light, familiar arena), parenteral administration of nicotine had bimodal actions, low doses (0.01 and 0.1 mg/kg i.p.) had anxiolytic effects and high doses (0.5 and 1.0 mg/kg i.p.) had anxiogenic effects. In test conditions where anxiety was lowest (low light, familiar arena) and highest (high light, unfamiliar arena), nicotine was without effect after intraperitoneal or hippocampal administration. Thus, nicotine plays a modulatory role in which the activity of other neurotransmitters is crucial to its expression. After bilateral administration to the dorsal hippocampus, nicotine (0.1-8.0 microg) had anxiogenic effects in conditions of moderate anxiety; mecamylamine (30 ng) was silent in these conditions, indicating no intrinsic tone. Our results show that the dorsal hippocampus is one area that can mediate anxiogenic effects in the social interaction test, but the brain region mediating anxiolytic effects remains to be identified.

Animals↗

PubMed1998

Stimulation of benzodiazepine receptors in the dorsal hippocampus and median raphé reveals differential GABAergic control in two animal tests of anxiety.

The effects of pharmacological challenges to the benzodiazepine receptors in the dorsal hippocampus and median raphé nucleus were investigated in the social interaction and the elevated plus-maze tests of anxiety in rats. In the social interaction test, bilateral administration of midazolam (1 and 2 micrograms), into the dorsal hippocampus had anxiolytic effects; flumazenil (500 ng) was silent, but was able to antagonize the anxiolytic effects of midazolam (2 micrograms). In the social interaction test, midazolam was also anxiolytic when infused into the median raphé nucleus; flumazenil (100 and 500 ng) increased locomotor activity, but did not change anxiety measures. As an anatomical control, midazolam (1 and 2 micrograms) was infused into the adjacent pontine reticular nucleus, and was without effect. In contrast to the social interaction test, local infusion of midazolam (1 and 2 micrograms) and flumazenil (100 and 500 ng) into either the dorsal hippocampus or the median raphé nucleus failed to change anxiety measures in the elevated plus-maze (trials 1 and 2). These results show that stimulation of the benzodiazepine receptors in the hippocampus or the median raphé nucleus leads to anxiolytic effects in the social interaction test, but not in the elevated plus-maze. It would therefore appear that the two tests detect different types of anxiety that are differentially modulated by GABAA-benzodiazepine receptors in the dorsal hippocampus and the median raphé nucleus.

Animals↗

PubMed1998

Effects of moderate alcohol consumption on the central nervous system.

The concept of moderate consumption of ethanol (beverage alcohol) has evolved over time from considering this level of intake to be nonintoxicating and noninjurious, to encompassing levels defined as "statistically" normal in particular populations, and the public health-driven concepts that define moderate drinking as the level corresponding to the lowest overall rate of morbidity or mortality in a population. The various approaches to defining moderate consumption of ethanol provide for a range of intakes that can result in blood ethanol concentrations ranging from 5 to 6 mg/dl, to levels of over 90 mg/dl (i.e., approximately 20 mM). This review summarizes available information regarding the effects of moderate consumption of ethanol on the adult and the developing nervous systems. The metabolism of ethanol in the human is reviewed to allow for proper appreciation of the important variables that interact to influence the level of exposure of the brain to ethanol once ethanol is orally consumed. At the neurochemical level, the moderate consumption of ethanol selectively affects the function of GABA, glutamatergic, serotonergic, dopaminergic, cholinergic, and opioid neuronal systems. Ethanol can affect these systems directly, and/or the interactions between and among these systems become important in the expression of ethanol's actions. The behavioral consequences of ethanol's actions on brain neurochemistry, and the neurochemical effects themselves, are very much dose- and time-related, and the collage of ethanol's actions can change significantly even on the rising and falling phases of the blood ethanol curve. The behavioral effects of moderate ethanol intake can encompass events that the human or other animal can perceive as reinforcing through either positive (e.g., pleasurable, activating) or negative (e.g., anxiolysis, stress reduction) reinforcement mechanisms. Genetic factors and gender play an important role in the metabolism and behavioral actions of ethanol, and doses of ethanol producing pleasurable feelings, activation, and reduction of anxiety in some humans/animals can have aversive, sedative, or no effect in others. Research on the cognitive effects of acute and chronic moderate intake of ethanol is reviewed, and although a number of studies have noted a measurable diminution in neuropsychologic parameters in habitual consumers of moderate amounts of ethanol, others have not found such changes. Recent studies have also noted some positive effects of moderate ethanol consumption on cognitive performance in the aging human. The moderate consumption of ethanol by pregnant women can have significant consequences on the developing nervous system of the fetus. Consumption of ethanol during pregnancy at levels considered to be in the moderate range can generate fetal alcohol effects (behavioral, cognitive anomalies) in the offspring. A number of factors--including gestational period, the periodicity of the mother's drinking, genetic factors, etc.--play important roles in determining the effect of ethanol on the developing central nervous system. A series of recommendations for future research endeavors, at all levels, is included with this review as part of the assessment of the effects of moderate ethanol consumption on the central nervous system.

Adult↗

PubMed1998

A rat model of spontaneous myopathy and malignant hyperthermia.

Malignant hyperthermia is a main cause of death during general anesthesia, particularly in children. However, research has been hampered by the lack of a convenient animal model, the only one available being a special strain of pig. In this study, we describe spontaneous myopathy and a fatal syndrome of generalized muscle rigidity triggered by halothane in an outbred strain of rat. Histological examination of skeletal muscle reveals severe abnormalities indicating chronic underlying myopathy. The association of histological abnormalities with an acute, fatal syndrome clinically resembling malignant hyperthermia provides a strong basis for a new and extremely useful animal model to study this fatal disorder.

Animals↗

PubMed1997

A five minute experience in the elevated plus-maze alters the state of the benzodiazepine receptor in the dorsal raphe nucleus.

A single 5 min exposure to the elevated plus-maze test of anxiety renders animals insensitive to the anxiolytic effects of the benzodiazepines in this test. The purpose of the present experiments was to explore whether this phenomenon resulted from a change in the functional state of benzodiazepine receptors in the dorsal raphe nucleus. The benzodiazepine receptor agonist midazolam (0.5, 1, and 2 microg) and antagonist flumazenil (100 and 500 ng) were directly administered to the dorsal raphe nucleus in rats either naive to, or with one previous 5 min exposure of, the elevated plus-maze. In naive rats, midazolam produced significant anxiolytic effects at all doses, and flumazenil was silent. In plus-maze-experienced rats, midazolam no longer had anxiolytic effects in the plus-maze, but flumazenil did, indicating that the previous experience of the maze had changed the state of the benzodiazepine receptor. This changed receptor function generalized to the social interaction test. Thus, in naive animals tested in high light, midazolam (0.5, 1, and 2 microg) had significant anxiolytic effects and flumazenil (100 and 500 ng) was silent, whereas in plus-maze-experienced rats both midazolam (1 microg) and flumazenil (500 ng) had significant anxiolytic effects. Extensive analysis of locomotor activity in both tests showed that the changed responsivity to midazolam could not be explained by habituation, because on none of the measures used was there any difference in motor activity scores between plus-maze-naive and experienced rats.

Animals↗