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Biomedical subjects

A K Mohammed

Publications and source records attributed to A K Mohammed.

At least 19 recordsLinked to original sources

Influence of place learning on somatostatin levels in the rat brain following environmental deprivation.

We have previously reported increased somatostatin levels in the cerebral cortex of rats housed in impoverished environment and subsequently subjected to a behavioural testing procedure, consisting of open-field exposure and spatial learning. The aim of the present study was to evaluate the degree of neurochemical specificity of the activation of somatostatin neurotransmission and to examine whether the altered levels were due to learning stimulation. Adult rats, previously housed individually for 30 days, were exposed to repeated sessions of a spatial learning task (2 days or 14 days) or repeated sessions of free swimming (14 days). The training sessions of the 14 day group consisted in recurrently changed position of the platform in a learning-set paradigm. Our data showed increased somatostatin immunoreactivity, and unchanged substance P immunoreactivity in the posterior part of the cerebral cortex. However, somatostatin levels increased to a similar extent following 14 days of repeated spatial learning sessions as free swimming sessions. We conclude that the activity of the cortical somatostatin system appears to be sensitive to environmentally induced sensorimotor stimulation in general, rather than learning per se. Thus, external stimulation of early clinical dementia patients with preserved sensorimotor receptivity, in an attempt to restore cognitive function, might be associated with altered somatostatin levels.

Analysis of Variance↗

Transcription factor AP-2 gene expression in adult rat hippocampal regions: effects of environmental manipulations.

Environmental enrichment increases glucocorticoid receptor expression in hippocampal pyramidal neurons, but the molecular mechanisms are unknown. Several transcription factors are expressed in hippocampal neurons where they respond to environmental stimuli. In this study 12 adult male rats (n = 6 in each group) were exposed to enriched or isolated environment for 30 days. The expression of AP-2 mRNA, studied by in situ hybridization, was attenuated by environmental enrichment in the CA2 and CA3 subfields of the hippocampus. AP-2 may be involved in the environmental effect of glucocorticoid receptor gene expression in these neurons.

Animals↗

Environmental influence on somatostatin levels and gene expression in the rat brain.

In the present study we have quantified preprosomatostatin-mRNA and somatostatin levels in rat brain following environmental stimulation. Animals were housed for 30 days in an enriched or impoverished environment prior to analysis. After 30 days of housing half of the rats from each environment were behaviourally tested for 3 days. Housing in enriched environment improved performance in a spatial learning situation. The open-field behaviour of these animals was characterized by initially higher rearing scores and a more rapid habituation to novel environment as measured by spontaneous locomotor activity. We found significantly elevated somatostatin levels in the cortex following enriched environment, compared with impoverished environment. Exposure to behavioural testing of impoverished animals led to increased cortical somatostatin levels. Hypothalamic somatostatin levels increased significantly after housing in enriched environment, while the testing procedure had no influence. Our data shows that the somatostatin system in the rat brain was activated in association with cognitive changes, that were induced by housing in an enriched environment.

Animals↗

Increased expression of brain-derived neurotrophic factor mRNA in rat hippocampus is associated with improved spatial memory and enriched environment.

Enriched environment has been shown to enhance learning and memory and to induce morphological changes in the hippocampus. We report that rats housed in an enriched environment showed improved performance in the Morris water maze and decreased spontaneous motor activity. Exposure to behavioural tests increased expression of the mRNA that encodes brain-derived neurotrophic factor in the hippocampus. This was not seen when rats subjected to impoverished housing were tested suggesting that environmental history of the animal is of importance to induce expression of brain-derived neurotrophic factor in the hippocampus that may promote neuronal changes related to learning and memory.

Analysis of Variance↗

Environmental influence on behaviour and nerve growth factor in the brain.

The influence of the environment on the endogenous levels of nerve growth factor (NGF) in the cortex, hippocampus and septum was examined in adult (82 days old) and juvenile (51 days old) rats. Animals were reared/housed for 30 days in an enriched, standard or isolated environment prior to analysis. In addition, another group of rats were given behavioural tests (4 days) after differential rearing/housing before measurements of NGF. We found complex variations in the level of NGF both in juvenile and adult hippocampus after differential environmental rearing/housing. Rearing/housing in an enriched environment improved performance in the Morris maze and decreased spontaneous motor activity. Exposure to behavioural tests caused alterations in adult hippocampus and septum NGF levels. The results show that testing in a novel environment causes small but significant changes in the hippocampal and septal NGF levels depending upon the environmental history of the animal. In view of the purported involvement of the septohippocampal pathway and NGF in the pathophysiology of Alzheimer's disease, our finding suggests that lack of adequate environmental stimulation might be of importance in age-related behavioural and neurochemical deficits.

Analysis of Variance↗

Learning deficits in aged rats pretreated chronically with barbital and tested late in abstinence: alleviation by tetrahydroaminoacridine.

Physostigmine and tetrahydroaminoacridine (THA) have been reported to improve cognitive function in patients with Alzheimer's disease. Two experiments were conducted to examine the effects of these anticholinesterase agents on learning in aged rats pretreated chronically with barbital. In the first experiment animals received barbital in their drinking water for 46 weeks. Controls were given only water. On days 100-104 of abstinence, when the animals were 20 months old, acquisition of the Morris maze task was initiated after treatment with physostigmine. It was found that physostigmine improved learning of the maze task in control but not barbital treated rats. In the second experiment animals received barbital solution or water as in experiment one. On days 100-103 of abstinence they were injected with THA before being tested in the Morris water maze. It was found that THA improved learning in both barbital treated and control rats. These results corroborate clinical findings of improved cognitive function following treatment with THA, and suggest that the therapeutic effects of THA may be mediated by mechanisms distinct from cholinesterase inhibition. Furthermore chronic barbital treatment could be used as a model to study cognitive disturbances in experimental animals.

Age Factors↗

Multiple effects of tetrahydroaminoacridine on the cholinergic system: biochemical and behavioural aspects.

9-Amino-1,2,3,4-tetrahydroaminoacridine (THA) in combination with lecithin has been reported to improve the memory of Alzheimer's disease patients. We have examined some properties of THA in vitro and in vivo so as to define some of the mechanism(s) by which THA might produce its therapeutic effects. In vitro, THA was more potent at inhibiting human plasma cholinesterase (IC50 = 0.03 microM) than human erythrocyte acetylcholinesterase (IC50 = 0.3 microM) and rat brain acetylcholinesterase (IC50 = 0.32 microM). Radioligand binding studies indicated that THA binds reversibly and competitively to primary M1 and M2 human cortical muscarinic receptors with similar affinities. Moreover, THA showed similar affinity for temporal cortices muscarinic receptors from Alzheimer and non-Alzheimer (control) brains. In vivo, subcutaneous administration of THA (1-8 mg/kg body weight) to adult rats (6 months old) produced a dose dependent decrease in general activity compared to saline-treated rats. However, at a concentration of 0.5 mg/kg body weight, the general activity of the rats was increased compared to saline-treated rats. The cognitive function of the THA-treated adult rats (subcutaneously 2 mg/kg body weight) was not significantly improved compared to saline-treated rats. It is concluded that the mechanisms of action of THA on the cholinergic system involve reversible inhibition of cholinesterases and reversible and competitive interaction with muscarinic acetylcholine receptors. These effects might be of therapeutic value in the treatment of Alzheimer's disease.

Aged↗

Behavioural deficits and serotonin depletion in adult rats after transient infant nasal viral infection.

Dysfunction of subcortical serotoninergic neurons has been implicated in some behaviour disturbances. The serotoninergic neurons in the dorsal and median raphe project widely in the brain. They innervate the olfactory bulbs and can be targets for exogenous agents attacking the olfactory epithelium and bulbs. We report here an injury to the serotoninergic neurons after intranasal infection in 12-day-old rats with a temperature-sensitive mutant of vesicular stomatitis virus. The brain infection was focal and transient. Viral antigens could no longer be detected 13-15 days after infection. In spite of this the animals, as adults, had a severe serotonin depletion in the cerebral cortex and hippocampus, and showed abnormal locomotor and explorative behaviour as well as learning deficits. The neocortex was histologically intact and parameters related to other neurotransmitters such as dopamine, noradrenaline, GABA and acetylcholine showed no marked changes. A relatively selective damage to serotoninergic nuclei as a result of virus neuroinvasion through a natural portal of entry, may constitute a new pathogenetic mechanism for cortical dysfunction and behavioural deficits.

3,4-Dihydroxyphenylacetic Acid↗

Effects of THA on ionic currents in myelinated axons of Xenopus laevis.

In voltage-clamp experiments with the myelinated nerve fibre of Xenopus laevis, 9-amino-1,2,3,4-tetrahydroacridine (THA) decreased both Na+ and K+ currents and shifted the steady state inactivation potential curve in a negative direction. The effects may be described as (a) a decrease of the permeability constant PNa, (b) a modified potential dependence of the inactivating system and (c) a decrease of PK. The Na+ system was affected more than the K+ system.

Aminoacridines↗

Effects of the noradrenaline neurotoxin N-2-chloroethyl-N-ethyl-2-bromo-benzylamine hydrochloride (DSP4) on the blood-brain barrier. An experimental study in the mouse using protein tracer and density determination techniques.

Cerebral microvessels receive a noradrenergic innervation originating from the locus coeruleus. Previously, many studies have tried to elucidate the role of the central noradrenergic innervation on the blood-brain barrier (BBB). Many of them are based on chemical destruction of the innervation by local injection of 6-hydroxydopamine (6-OHDA) or physical injury to the locus coeruleus. Such methods are not selective and the results reported are contradictory. We have treated mice with a single i.p. injection of the compound, N-2-chloroethyl-N-ethyl-2-bromo-benzylamine hydrochloride (DSP4). This substance induces a selective noradrenaline depletion and, unlike 6-OHDA, it can pass into the brain after an i.p. injection. The animals were allowed to survive for 6 h to 60 days and the BBB was investigated with i.v.-injected horseradish peroxidase (HRP). Brain density values were also determined to find out of edema developed. The light microscopic distribution of HRP in the brain of DSP4-treated animals did not differ from that in control mice, i.e., there were no signs of increased BBB permeability to this protein tracer caused by DSP4. Density determinations revealed statistically significant reduced values in cerebrum (P less than 0.005) and rhombencephalon (cerebellum) (P less than 0.0005) of animals given 100 mg/kg body wt. of DSP4 indicating development of edema. A minor drop in density of the rhombencephalon (cerebellum) (P less than 0.05 at 48 h) and of the cerebrum (statistically not significant) appeared when 50 mg/kg body wt. of DSP4 was injected.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Adaptive changes in alpha-2 adrenoceptor mediated responses: analgesia, hypothermia and hypoactivity.

The acute effects of the alpha-2 adrenoceptor agonists, clonidine and guanfacine, upon antinociception, hypothermia and motor activity were compared under conditions of receptor antagonism, denervation, and chronic administration of a tricyclic antidepressant compound. The analgesic actions of clonidine and guanfacine were antagonised by idazoxan, an alpha-2 receptor antagonist, but potentiated by pretreatment with the noradrenaline neurotoxin DSP4, and attenuated by chronic treatment with desipramine (DMI). Clonidine- and guanfacine-induced hypothermia was antagonised by idazoxan, potentiated by prior treatment with DSP4 and attenuated by chronic administration with DMI. Both clonidine and guanfacine produced decreases in motor activity that were attenuated by idazoxan but unaffected by prior DSP-4 treatment. Chronic DMI administration also attenuated clonidine-induced hypoactivity but potentiated guanfacine-induced hypoactivity. These diverse results describe both similar and differential adaptive mechanisms modulating the functional effect of alpha-2 receptor systems in the central nervous system.

Adaptation, Physiological↗

Impaired performance of rats in the Morris swim-maize test late in abstinence following long-term sodium barbital treatment.

Rats were tested for place learning in the Morris swim maze on days 110-114 of abstinence following 48 weeks of treatment with sodium barbital. A retarded acquisition of the swim-maze task, that could not be ascribed to motor impairments, was found in the barbital-treated rats. There was a significant difference in brain weight, but there were no significant differences between the control and barbital-treated rats in the frontal cortical concentrations of noradrenaline (NA), dopamine (DA), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA), nor in the intra- and extrasynaptosomal activities of cerebral cortical monoamine oxidase towards NA and 5-HT. Postsynaptically, neither the cerebral cortical inositol phospholipid breakdown responses to carbachol and NA (mediated by muscarinic and alpha 1-adrenergic receptors, respectively), nor the striatal and cortical densities of muscarinic receptors labelled by [3H]quinuclidinyl benzilate [( 3H]QNB) were found significantly to be altered in the barbital-treated rats. A strong correlation between the density of striatal and cortical [3H]QNB binding sites was seen for the barbital-treated (r = 0.91) but not for the control (r = -0.05) rats. It is suggested that the deficit in performance of the barbital-treated rats in the Morris maze may be related to a cholinergic dysfunction.

Animals↗

Lack of effects of prenatal exposure to lidocaine on development of behavior in rats.

The objective of this investigation was to study the effects of lidocaine upon postnatal development of the rat. Lidocaine, 6 mg/kg (21 mumol/kg), was given to a group of 12 rats. Injections were administered intramuscularly, bilaterally in the masseter muscles, once a day on days 10 and 11 of pregnancy. Twelve control rats were given physiologic saline. Clinical signs, mortality, body weight, and food consumption were recorded during pregnancy and lactation. The duration of gestation was also recorded. The development of the offspring was monitored by tests of spontaneous activity, nociception, learning ability, and physical development. No clinical signs of adverse reactions were seen in any of the groups. In the majority of the learning ability tests, the control and lidocaine-treated groups showed similar results. However, in the schedule of differential reinforcement of low rates of responding (DRL 20), the lidocaine-exposed males received more reinforcements than the controls and made fewer responses. In the tests of nociception, a significant difference between sexes was recorded, in that the females were more sensitive than the males in the shock-titration test. Physical development, as monitored by swimming ability and spontaneous activity, showed no inter-group difference. The present results indicate that prenatal exposure to lidocaine fails to result in postnatal impairment of the development of behavioral performance of a wide range of tasks.

Animals↗

Selective lesioning of forebrain noradrenaline neurons at birth abolishes the improved maze learning performance induced by rearing in complex environment.

The effect of selective destruction of forebrain noradrenaline (NA) neurons induced by 6-hydroxydopamine (6-OHDA) at Day 1 after birth on Hebb-Williams maze performance was investigated in adult rats housed after weaning in a complex environment (EC) or an isolated (IC) environment for 35 days. Saline treated control rats raised in the EC made fewer errors than those raised in the IC. This effect of EC was completely abolished in 6-OHDA treated rats; for these animals no improved performance due to the housing condition was obtained. Protection of the NA neurons against 6-OHDA neurotoxicity by pretreatment with desipramine (DMI) resulted in an effect of EC identical to that seen in saline-treated controls. Postweaning housing in the IC led to an increased locomotion as compared to housing in EC, but this effect was not affected by neonatal 6-OHDA and/or DMI treatment. Neurochemical analysis confirmed cortical NA and metabolite depletion as well as a good protection by the DMI pretreatment. The present results indicate that central NA neurons are involved critically in mediating mainly the cognitive components of behavioral alterations induced by EC.

Animals↗

The effect of selective noradrenergic lesions upon the stimulation by noradrenaline of inositol phospholipid breakdown in rat hippocampal miniprisms.

The breakdown of inositol phospholipid (PI) stimulated by hippocampal noradrenaline in rat miniprisms in vitro was used as an index of alpha 1-adrenoceptor function after selective noradrenergic denervation. Selective denervation was produced by microinjections of 6-hydroxydopamine (6-OHDA) into either the dorsal noradrenergic bundle (DNAB) or the locus coeruleus (LC), or by systemic treatment with the noradrenergic neurotoxin DSP4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine). Fourteen days after these treatments, there was a large depletion of cortical noradrenaline but no change in the stimulation of hippocampal PI breakdown by noradrenaline. It is concluded that selective noradrenergic denervation under the conditions used here does not lead to hippocampal alpha 1-adrenoceptor supersensitivity as assessed by noradrenaline-stimulated PI breakdown.

Animals↗

Central noradrenaline depletion attenuates amphetamine-induced locomotor behavior.

Male rats were given 6-hydroxydopamine-induced lesions of the locus coeruleus (LC) or the dorsal noradrenergic bundle (DNAB), prior to the measurement of locomotor and rearing activity induced by D-amphetamine. The increased locomotor activity induced by D-amphetamine (1.8 mg/kg) was significantly attenuated by both the LC and the DNAB lesions. The stimulatory effect of the 7.2 mg/kg dose of amphetamine was attenuated by the LC lesion, whereas the DNAB lesion potentiated this effect. The LC lesion also attenuated rearing induced by the 7.2 mg/kg dose of amphetamine. These results suggest some involvement of central noradrenergic neurons in the activity induced by amphetamine in the rat.

Animals↗

Central noradrenaline depletion antagonizes aspects of d-amphetamine-induced hyperactivity in the rat.

The effects of noradrenaline (NA) depletion upon amphetamine-induced hyperactivity were examined in five experiments. Central NA depletion via either systemic DSP4 or neonatal 6-OHDA antagonised the amphetamine-induced (2 mg/kg SC) increase in rearing behaviour, whereas lesions of the dorsal noradrenergic bundle using 6-hydroxydopamine antagonised the increase in locomotor activity. Peripheral NA depletion following systemic 6-hydroxydopamine to adult rats did not cause any changes in motor activity after acute amphetamine administration. Desipramine, the selective NA uptake inhibitor, blocked the effects of DSP4 upon amphetamine-induced rearing. NA depletion antagonised hyperactivity produced by the 2 mg/kg dose of amphetamine, but not the hyperactivity (rearing or locomotion) effects of amphetamine at 1, 4 or 8 mg/kg.

Animals↗

5-HT agonist induced analgesia modulated by central but not peripheral noradrenaline depletion in rats.

The antinociceptive effect elicited by the 5-hydroxytryptamine (5-HT) agonist 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) was reversed or blocked in animals which had previously sustained severe spinal noradrenaline (NA) depletion via either systemic N-2-chlorethyl-N-ethyl-2-bromobenzylamine hydrochloride (DSP 4), neonatal 6-hydroxydopamine (neon. 6-OHDA), or intrathecal 6-OHDA treatment. Biochemical analysis of the lumbar spinal cord samples confirmed severe central NA depletions. Animals were tested with nondamaging heat pain (tail-flick test, hot-plate test) and electric footshock titration to determine the amount of antinociception or nociception. Peripheral NA depletion following intravenous (i.v.) 6-OHDA injection to adult rats had no effect on the antinociception induced by 5-MeODMT, but did cause severe NA depletions in the left heart atrium. These results suggest a modulatory effect of central and not peripheral noradrenergic system upon 5-HT agonist induced analgesia, and also give evidence that this effect is spinally mediated.

5,7-Dihydroxytryptamine↗