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PubMedDate not supplied

The serotonin 5-HT4 receptor and the amyloid precursor protein processing.

A large body of evidence supports a major role for the serotonin 5-HT(4) receptor in learning and memory and it is suggested that 5-HT(4) agonists may be beneficial for memory disorders such as Alzheimer's disease (AD). The 5-HT(4) receptors are members of the G protein-coupled receptor superfamily and are positively coupled to adenylyl cyclase. In this communication we show that a neuronal isoform of the human 5-HT(4) receptor, h5-HT(4(g)) regulates the metabolism of the amyloid precursor protein (APP695). This process is observed in Chinese hamster ovary (CHO) cells stably coexpressing the neuronal h5-HT(4(g)) receptor isoform as well as the human APP695. The 5-HT(4) agonists strongly stimulate the release of the non-amyloidogenic soluble amyloid precursor protein sAPPalpha as detected by immunoblot. Prucalopride was more potent than serotonin (5-HT) with regard to enhanced of sAPPalpha secretion. This process was blocked by a selective 5-HT(4) antagonist, GR113808. Furthermore, 5-HT(4) ligands enhance sAPPalpha secretion via cAMP-dependent and PKA-independent signalling pathways indicating there are alternative pathways by which the h5-HT(4) receptor via cAMP regulates APP metabolism. Because the alpha-cleavage event may preclude the formation of amyloidogenic peptides, and secreted sAPPalpha has putative neuroprotective and enhancing-memory properties, our present data suggest the 5-HT(4) receptor as a novel target for the treatment of AD.

Aged↗
PubMed2006

[French adaptation of the Hopkins Verbal Learning Test].

INTRODUCTION: A number of tests are currently used in clinical and research settings for the assessment of patients with memory deficits. Among them, the Hopkins Verbal Learning Test (HVLT) is particularly appropriate for the longitudinal follow-up of patients with memory disorders because it exists in six parallel forms, and therefore avoids the risk of learning effect at retest. Since a test with these characteristics is not available in French, we decided to adapt a French version of the HVLT. METHODS: 180 normal subjects participated in the study. Their mean age was 41 years (SD=11), and they had had on average 12 years of schooling (SD=3). The subjects were randomly divided into 6 groups of 30 subjects. One of the six forms of the French version of the HVLT was administered orally to each group of subjects. Each form consisted of a list of 12 words belonging to 3 different semantic categories. For the construction of the French version of the HVLT, we adopted the same procedure as used in the original version of the test taking into account the French lexical and semantic characteristics of the items. In the first part of the test, the list was administered three times to the subjects. Following each administration, subjects were asked for an immediate free recall. Twenty minutes later, used for intercurrent tasks, subjects were asked for a delayed free recall, which was immediately followed by a recognition memory task. In this task, subjects listened to a list of 24 words, 12 belonging to the studied list and 12 were distractors; the subjects were asked to recognize the 12 studied words. RESULTS: The subjects' performance was equivalent in the six forms of the test, except for the immediate recall of Form 3 (which was excluded from the test). No significant difference emerged in free recall, delayed free recall, and recognition across the five remaining forms of the test. CONCLUSION: Our study provides a useful tool for the longitudinal evaluation of patients with memory impairment and may become the test of reference in European longitudinal clinical trials. The French adaptation of the HVLT represents only a first step, because it needs to be standardized, in order to provide norms, and validated, in order to provide values of sensitivity and specificity.

Adult↗
PubMed2005

Antidepressant and memory affecting influence of estrogen and venlafaxine in ovariectomized rats.

The experiments presented in this paper aimed to investigate whether estrogen level changes in oviariectomized rats (OVX) may lead to depression and memory disorders, and whether the effects of such changes may be reversible following administration of a new antidepressant, venlafaxine (CAS 9930-78-4, VEN, Efectin). The Porsolt forced swimming test and Morris water maze test were carried out on female Wistar rats after ovariectomy and in sham-ovariectomized rats. VEN 20 mg/kg was administered orally 30 min before the tests for the period of 14 days. Estradiol (17beta-estradiol benzoate, CAS 50-28-2, E2) administration (5 microg E2/0.2 ml sesame oil s.c.) was started 24 h after ovariectomy and was continued for 14 days--each dose was administered 180 min before the test. In the immobility test, which reflects antidepressant drug activity, it was found that VEN shortened immobility time (IT) after the 1st, 7th and 14th administration (days 1, 7, 14, respectively) in ovariectomized rats, whereas in the control group (sham-ovariectomized rats) VEN exerted antidepressant action only after single administration (day 1) and after 7 days of administration. E2 significantly reduced immobility behaviour both after single and chronic treatment in ovariectomized rats. After joint administration of VEN and E2 potentiation of the antidepressant activity of VEN could be observed in both groups except for concurrent administration of VEN and E2 after 14 days in sham-ovariectomized rats. VEN improved the spatial memory in the Morris water maze test, whereas E2 did not affect the memory of the tested animals. Joint administration of VEN and E2 maintained the memory improving effect induced by VEN. The regulatory role of the steroid hormone and the new antidepressant drug (VEN) in antidepressant activity and memory function could be related to the interactions between noradrenergic and serotoninergic systems.

Animals↗
PubMed1998

Neuromagnetic sequelae of herpes simplex encephalitis.

Spontaneous cortical activity and auditory evoked responses were recorded with a whole-scalp 122-channel neuromagnetometer from 4 patients after left-hemisphere dominant herpes simplex encephalitis and associated memory disorders. Spontaneous activity of one patient contained periodic sharp waves over the left hemisphere; the background activity was attenuated. The sources of periodic sharp waves clustered close to the sources of auditory evoked fields in the temporal lobe. In controls, dominant rhythmic activity over the parieto-occipital region had spectral maximum at 10.6 +/- 0.6 Hz; in patients the dominant rhythmic activity peaked at 8.6 +/- 1.8 Hz. The suppression of the parieto-occipital activity in eyes-open versus eyes-closed condition was smaller in patients than in controls. The patients' peak spectral frequency was correlated with neuropsychological tests reflecting deficient attentional capacity. The observed changes probably reflect decreased subcortical control of the cortical electric activity.

Adult↗
PubMed1985

Effects of bifemelane hydrochloride (MCI-2016) on experimental amnesia (passive avoidance failure) in rodents.

To further predict the possible activity on memory disorders, the effect of MCI-2016 (bifemelane hydrochloride) was examined using the passive avoidance (PAR) failure technique as an experimental model of amnesia. The amnesia was produced either by post training treatments of electroconvulsive shock (ECS), scopolamine (mice) and cycloheximide or by pre-test injection of scopolamine (rats). In ECS-PAR failure model, the retention test was carried out 3 hr (3 hr experiment) or 24 hr (24 hr experiment) after ECS. MCI-2016 showed a significant improvement when administered just after ECS (3 hr experiment, 30 mg/kg, i.p.) or 0.5 hr before the retention test (24 hr experiment, 10-30 mg/kg, i.p.). Cahopantenate was only active in the 3 hr experiment (500 mg/kg, i.p.), and piracetam was rather active in the 24 hr experiment (60 mg/kg, i.p.). MCI-2016 (30 mg/kg, i.p.) prevented the scopolamine-induced PAR-failure. In this model, physostigmine (0.3 mg/kg, i.p.) exhibited a tendency to improve the failure. In another scopolamine-induced PAR failure model in mice, all of the test drugs showed a significant improvement at different dose levels. The effect of MCI-2016 (25-100 mg/kg, p.o.) was superior to those of piracetam, aniracetam and choline chloride. Higher doses of MCI-2016 were required to improve the cycloheximide-induced PAR failure. Considering the experimental conditions and results, it may be suggested that MCI-2016 ameliorates the amnesia possibly through its influence on memory consolidation and retrieval processes.

Animals↗
PubMed1989

The spectrum of structural brain changes in schizophrenia: age of onset as a predictor of cognitive and clinical impairments and their cerebral correlates.

A range of cerebral structures was assessed in a series of 172 CT scans of groups of psychiatric patients (including 101 in-patients with chronic schizophrenia) and related to assessments of clinical state and psychological function. Ventricular indices were increased in patients with schizophrenia by comparison with patients with other psychiatric disorders: brain area, which is modestly positively correlated with ventricular indices, was significantly (P less than 0.01) reduced in patients with schizophrenia. Among in-patients with chronic schizophrenia, measures of increased ventricular size were significantly associated with impaired social behaviour and with movement disorder. Memory for famous names in the distant past (a test of remote memory) was the only psychological test which showed significant associations with indices of ventricular size; this suggests that ventricular enlargement and its psychological sequelae occur relatively early in the disease process. Dichotomization of the sample of schizophrenic patients around the mean age of onset revealed that a range of clinical and psychological functions are significantly more abnormal in those with an early age of onset than in those in whom the onset was later. Early onset cases also perform less well academically and occupationally before illness onset. Within the early onset group some significant correlations between cognitive function and brain area were seen. The findings suggest that: (i) some at least of the structural changes in schizophrenia arise at a time when the brain is still developing; and (ii) age of onset is an important determinant of social and intellectual impairment and is relevant to the relationship between brain structure and cognitive deficits.

Bipolar Disorder↗
PubMed2002

The long-term effects of nefiracetam on learning in older rabbits.

Classical conditioning of the nictitating membrane (NM)/eyeblink response has proven utility in the study of age-related memory disorders. The 750 ms delay eyeblink conditioning procedure was used to investigate the magnitude and duration of the nootropic drug nefiracetam's effect on retention and relearning. After administering daily injections of 0 (vehicle), 5, 10, or 15 mg/kg nefiracetam to 34 retired breeder rabbits during 15 days of acquisition, we tested retention and relearning 1, 5, and 12 weeks post-training. Rabbits received no drug after the initial 15 daily injections. Significant relearning was observed in the 10 mg/kg nefiracetam group 1 and 5 weeks after initial acquisition. Differences in tone-alone retention did not achieve statistical significance, although responses were numerically greater in the 10 mg/kg nefiracetam group. The effect of nefiracetam upon the ability of older rabbits to relearn a previously learned task is apparent up to 5 weeks after drug administration. Under normal conditions, a drug is administered continuously. In this experiment, nefiracetam had a significant effect long after drug administration had ceased. Prolonged administration of nefiracetam may have ameliorating effects greater than those observed in only 15 days of drug administration.

Aging↗
PubMedDate not supplied

[P300 and Parkinson disease. The role of cognitive changes].

Cognitive disturbances are frequently encountered in advancing Parkinson's disease (PD). Typically there are visuo-spatial disorders, memory impairment and bradyphrenia, defined as 'subcortical dementia' to distinguish it from the dementia that occurs in Alzheimer's disease, where the most prominent dysfunctions are agnosia, apraxia and aphasia. An electrophysiological test to study cognitive processing is the P300 (or P3) of the Event Related Potentials; in particular the latency of the P3 seems to correlate with cognitive decline. Thirty patients affected with idiopathic PD were investigated using a classic auditory "oddball" paradigm (rare tone--"target"--3000 Hz, frequent tone--"non target"--1000 Hz; the patients were instructed to recognize and keep a mental count of the number of rare tones). Electrophysiological findings were compared with those obtained in twenty normal subjects, age and sex matched with the patient's group. The parameters of P300 were correlated with patient's age, duration of the disease, motor and cognitive impairment levels and L-Dopa therapy. The P300 was loss in 16.6% (5 p.) and delayed in 33.3% (10 p.). Significative correlations were found only with age and cognitive impairment scores, but not with other variables analyzed. These results suggest that P300 could be a useful test to identify demented patients among those with PD, despite different motor disabilities.

Aged↗
PubMed1993

[Learning processing in an epileptic with amnesia after memory task repetition].

We reported that some learning accomplished by an epileptic patient (YS) with organic amnesia after memory task repetition. YS's learning appeared inflexible; That was depending memory task procedural. The purpose of this paper is to investigate procedural learning processing in YS with memory disorder. We examined procedural learning in picture naming task repetition in YS and normal controls, using semantic priming paradigm. After start key press, a prime picture was displayed on the CRT display, thereafter, a target picture appeared. The subjects' task was to name the target picture aloud as rapidly and accurately as possible. In the examination, we manipulated a time interval between start key press and the prime on. Two interval conditions were used. One was the constant interval, 1010ms and another was varied interval, varied between 400ms and 1010ms. After conditioning session with constant interval, the test session with constant and varied interval was carried out. We analyzed reaction time (RT) in naming the picture targets in the test session in relation to the conditions. YS's RT in the test session with constant was shorter than in the test session with varied interval. No interval effects were found in the controls. The results indicated that previous experiment in conditioning session had larger effect on the YS's performance than the controls'. This suggests hypotheses that the learning in the patient with amnesia is tied to the specific conditions in the learning experience. The results can be explained in terms of procedural learning in YS, which is automatic processing.

Adult↗
PubMed1983

Effect of 4-(o-benzylphenoxy)-N-methylbutylamine hydrochloride (MCI-2016) on the scopolamine-induced deficit of spontaneous alternation behavior in rats.

To predict the possible activity on memory disorders, the effect of MCI-2016 was compared with those of physostigmine, choline chloride, methamphetamine, apomorphine, imipramine and calcium hopantenate by applying scopolamine-induced deficit of spontaneous alternation behavior (scopolamine-SA) as a proposed animal model for senile dementia. MCI-2016 was shown to improve the scopolamine-SA at doses of 25 to 100 mg/kg p.o. without producing any remarkable behavioral abnormalities. As for the effect of reference drugs, two types of cholinomimetic drugs (physostigmine and choline chloride) and methamphetamine were shown to be active. In the cases of physostigmine and methamphetamine, however, behavioral abnormalities were observed at those dose levels effective on scopolamine-SA. MIC-2016 potentiated the effect of physostigmine on scopolamine SA at non active doses of 10 to 20 mg/kg p.o. In comparison with the deleterious effect of scopolamine on spontaneous alternation (SA) behavior itself, none of the test drugs except for imipramine were shown to disrupt the SA. Considering the disruptive or improving actions of various agents on SA or scopolamine-SA, it may be suggested that the present model is relatively sensitive to those drugs which affect the cholinergic mechanism either directly or indirectly. Mechanisms of the actions of MCI-2016 and methamphetamine were also discussed with reference to possible involvement of cholinergic mechanisms.

Animals↗
PubMed2002

Memories are made of this (perhaps): a review of serotonin 5-HT(6) receptor ligands and their biological functions.

The possible role of 5-HT(6) receptor antagonists in the treatment of learning and memory disorders has stimulated significant recent work in this area. The first selective antagonists of this receptor were identified by Roche (Ro 04-6790 and Ro 63-0563) and SmithKline Beecham (SB-271046), although they only had poor to modest brain penetration, respectively. Recently, several structurally different series of selective antagonists have been reported. Glennon s group and Merck Sharp & Dohme have discovered N,N-dimethyl-1-benzenesulfonyl-5-methoxytrypt amine as a reasonably selective, high affinity antagonist, while Allelix have gone on to find that a 6-bicyclopiperazinyl-1-naphthylsulfonylindole had improved affinity and selectivity. Roche have reported subsequently on more lipophilic analogs of Ro 04-6790 that appear to penetrate the brain better. Reversing the sulfonamide linkage of SB-271046 led to a new series of compounds, producing SB-357134, which also had increased CNS penetration. A series of selective partial agonists containing a 4-piperazinylquinoline system has also been described. Recent studies in the Morris water maze with both Ro 04-6790 and SB-271046 have concluded that 5-HT(6) receptor antagonists improved retention performance, although these results are open to interpretation. Other behavioural studies have also implicated a role for 5-HT(6) in cognition enhancement and this has been supported by in vivo microdialysis studies that showed SB-271046 produced an increase in extracellular glutamate levels in the frontal cortex. However, we have been unable to replicate these effects with either SB-271046 or Ro 04-6790, and clearly further work is required before we can be certain of the functional role of this receptor.

Animals↗
PubMed2006

Visual-spatial learning and memory in schizotypal personality disorder: continued evidence for the importance of working memory in the schizophrenia spectrum.

Verbal episodic memory deficits, a well-established feature of the schizophrenia spectrum, have also been found in individuals with schizotypal personality disorder (SPD), although visual-spatial episodic memory has proven harder to examine. To address this, we administered the Visual Object Learning Test (VOLT), a measure of visual-spatial learning and memory, as well as the California Verbal Learning Test (CVLT) and a verbal working memory test, to 50 individuals with SPD, 19 with other personality disorders (OPD), and 17 healthy volunteers. Compared to both other groups, individuals with SPD learned verbal and visual-spatial information at a reduced rate and recalled fewer words and objects after a long delay. Verbal working memory performance eliminated diagnostic differences in these episodic memory domains. These findings suggest that it is possible to detect both auditory and visual processing episodic memory abnormalities in the spectrum and that these deficits are uniformly a function of verbal working memory impairments.

Adult↗
PubMed1982

Visual hypoemotionality as a symptom of visual-limbic disconnection in man.

In a patient with bilateral occipitotemporal hematomas secondary to head trauma, profound prosopagnosia, topographical memory disturbance, and a modality-specific inability to become emotionally aroused by visual cues developed. Data from neurological, neuropsychological, and psychophysiological assessment of the patient's deficits were interpreted as indicating a visual-limbic disconnection syndrome. The patient's symptoms were related to findings of emotional changes and visual impairment in macaques with bitemporal ablations and/or complete visual-temporal disconnection.

Acoustic Stimulation↗
PubMed1984

Differential perceptual-spatial impairment in Huntington's and Alzheimer's dementias.

Because the severity of memory disorders exhibited by neuropsychiatric patients overshadows other cognitive deficiencies, we explored the visuoperceptual and constructive abilities of patients with Alzheimer's (AD) or Huntington's (HD) disease. The tasks assessed directional sense with reference to egocentric space, as well as visuodiscriminative and constructive skills of patients and matched controls. A double dissociation was found: the performance of patients with AD was found to be significantly impaired on tasks involving extrapersonal perception and construction but not on the test of egocentric space. In contrast, visuoconstructive performance by patients with HD was not significantly impaired, while salient deficits were apparent when manipulation of personal space was required. These differential patterns of defects may have been aligned with neuropathologic changes in different cortical and subcortical structures, respectively, in patients with AD and HD.

Adult↗
PubMed1984

Memory disturbance in chronic progressive multiple sclerosis.

Forty-four patients with chronic progressive multiple sclerosis (MS) were compared with age- and education-matched control groups on a battery of clinical and experimental memory measures. Patients with MS performed substantially below the control groups on both immediate learning and delayed recall tasks, particularly in the retrieval of spatial information. The MS sample was subdivided into three groups using a cluster analytic procedure. One group (N = 9) performed well below expectations on memory tasks, exhibited signs of global cognitive disturbance, and had an atypical personality adjustment, characterized by irritability, social withdrawal, and apathy. A second group (N = 19) showed mild memory disturbance, associated with a greater use of psychotropic medications and a higher incidence of reactive depression. A third group (N = 16) performed normally on memory measures. The three groups of patients with MS did not differ in length or overall severity of illness.

Adult↗
PubMed1985

Amnesia following basal forebrain lesions.

Of five patients with damage to the basal forebrain, four had lesions secondary to rupture of anterior cerebral or anterior communicating artery aneurysms, and one to the resection of an arteriovenous malformation. Computed tomographic scans and intraoperative reports confirmed damage to basal forebrain regions, which include septal nuclei, nucleus accumbens, substantia innominata, and related pathways. Behavioral disturbances featured a prominent amnesic syndrome and personality changes. The amnesia was distinguishable from that reported in patients HM and DRB and shared features with that seen in patients with Korsakoff's syndrome. We propose that the memory disorder can be explained by malfunctioning in the hippocampal system, secondary to damage in the basal forebrain structures with which it is strongly interconnected. The dysfunction might, in part, be caused by reduction of specific neurotransmitter innervation because the lesions are likely to damage cholinergic neurons and nearby catecholamine pathways within the basal forebrain.

Adult↗