Biomedical subjects

P Riekkinen

Publications and source records attributed to P Riekkinen.

At least 19 recordsLinked to original sources

PubMed2001

alpha(2C)-Adrenoceptors modulate the effect of methylphenidate on response rate and discrimination accuracy in an operant test.

The present study investigated the role of alpha(2C)-adrenoceptors in the regulation of activity and discrimination accuracy in an operant chamber test. We trained food deprived control and alpha(2C)-adrenoceptor knockout mice to collect liquid food rewards in an operant chamber during the light (20 s) period. No food reward was delivered during the dark period (40 s). The alpha(2C)-adrenoceptor knockout mice tended to make fewer total responses and collect less rewards than their controls after saline treatment. However, only response accuracy of alpha(2C)-adrenoceptor knockout mice was significantly lower than that of the control mice. Methylphenidate, a drug blocking dopamine re-uptake and increasing dopamine release, dose-dependently decreased the number of total responses and collected food rewards in control mice but increased those measures in alpha(2C)-adrenoceptor knockout mice. In addition, the effect of methylphenidate on discrimination accuracy differed between knockout and control mice. Our results indicate that alpha(2C)-adrenoceptors may regulate dopamine-mediated functions.

Animals↗

PubMed2001

Spatial working memory improvement by an alpha2-adrenoceptor agonist dexmedetomidine is not mediated through alpha2C-adrenoceptor.

1. Aged alpha2C-adrenoceptor knockout and wild type mice were used to investigate whether alpha2C-adrenoceptors are involved in mediating the beneficial effects of alpha2-adrenoceptor agonist, dexmedetomidine, on spatial working memory. 2. A win-stay task in the radial arm maze was used to dissociate the effects of dexmedetomidine on working vs. reference memory. In addition, the animals were tested in simple response habit learning in the T-maze. 3. Knockout mice made more working memory errors after the change of the baited arm in radial arm maze, but after training reached again as accurate level of performance as wild type controls. Dexmedetomidine 5 and 10 microg/kg alleviated the increase in spatial working memory errors after the change of the baited arm in knockout mice. Knockout and wild type mice performed equally well in T-maze, and dexmedetomidine had no effect on this simple response learning. 4. The present results indicate that alpha2-adrenoceptor agonists have a selective effect on spatial working memory not only in monkeys but also in mice. Further, this study confirms our earlier finding that the presence of alpha2C-adrenoceptors is not necessary for the spatial working memory enhancing effect of alpha2-adrenoceptor agonists.

Adrenergic alpha-Agonists↗

PubMed2000

Pre-training blocks the improving effect of tetrahydroaminoacridine and D-cycloserine on spatial navigation performance in aged rats.

We investigated the effect of pre-training on the improvement of spatial navigation performance provided by a cholinesterase inhibitor, tetrahydroaminoacridine (3 mg/kg, i.p.), and a positive modulator of NMDA receptor, D-cycloserine (10 mg/kg, i.p.), or their combination in aged rats. Pre-training consisted of spatial or non-spatial conditions and took place in either the same or a separate room. We found that any kind of pre-training was able to eliminate the enhancing effect of tetrahydroaminoacridine and D-cycloserine on spatial navigation. However, none of these pre-training conditions was able to block the age-related deficit in spatial navigation. These results indicate that tetrahydroaminoacridine and D-cycloserine, separately or in combination, do not themselves alleviate the age-related spatial memory deficit, but may enhance procedural aspects of water maze learning in aged rats.

Aging↗

PubMed2000

Overexpression of alpha2C-adrenoceptors impairs water maze navigation.

We investigated the role of overexpression of alpha2C-adrenoceptors in water maze navigation in mice transgenically manipulated to have a threefold overexpression of the alpha2C-adrenoreceptors. Alpha2C-adrenoreceptors overexpressing mice swam more in the peripheral annulus of the pool and did not find the hidden escape platform as well as the wild type control mice. A subtype-nonselective alpha2-adrenoreceptor antagonist, atipamezole (ATI, 1000 microg/kg, s.c.), fully reversed the deficit in platform finding and search strategy in overexpressing mice. Noradrenaline depletion (-95%) induced by N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) did not impair platform finding of wild type or overexpressing mice. The DSP-4 lesion slightly increased swimming in the peripheral annulus in wild type mice, but not in overexpressing mice. The DSP-4 lesion produced a dissociable effect on the action of atipamezole to improve platform finding and search strategy in overexpressing mice: atipamezole did not alleviate the platform finding deficit in DSP-4 lesioned overexpressing mice, but normalized their abnormal search strategy. These results suggest that the abnormal search pattern and deficit in the accuracy of platform finding are mediated by constitutive activity of overexpressed alpha2C-adrenoreceptors.

Adrenergic alpha-Antagonists↗

PubMed2000

Impaired recovery of noradrenaline levels in apolipoprotein E-deficient mice after N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine lesion.

We investigated the effect of the noradrenergic neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) (1 or 3 x 50 mg/kg, intraperitoneally), on hippocampal, cortical and cerebellar noradrenaline levels after recovery of one, five and 11 months in control and apolipoprotein E-deficient mice. Apolipoprotein E-deficient mice had lower hippocampal noradrenaline levels than control mice. DSP-4-lesioned control mice had a more extensive recovery of hippocampal and cortical noradrenaline levels than DSP-4-lesioned apoE-deficient mice after five months' survival. Furthermore, the hippocampal noradrenaline levels after five and 11 months and cortical noradrenaline levels after five months of recovery had slightly recovered in control but not in apolipoprotein E-deficient mice treated with a single dose of DSP-4 compared with mice treated with three doses of DSP-4. These results show that apolipoprotein E-deficient mice have impaired recovery capacity in their locus coeruleus neurons.

Alzheimer Disease↗

PubMed2000

Apolipoprotein E-deficient mice are not more susceptible to the biochemical and memory deficits induced by nucleus basalis lesion.

We investigated whether the nucleus basalis lesion induced by quisqualic acid was associated with a more severe impairment of spatial navigation in a water maze, a greater reduction in frontal choline acetyltransferase activity and decrease in the number of choline acetyltransferase-positive neurons in the nucleus basalis in apolipoprotein E-deficient mice than in control mice. We also studied the effect of ageing on water maze spatial navigation and cortical choline acetyltransferase activity in 16-month-old control and apolipoprotein E-deficient mice. We found that the lesion decreased choline acetyltransferase-positive neurons in the nucleus basalis and frontal choline acetyltransferase activity equally in control and apolipoprotein E-deficient mice. The nucleus basalis lesion had no effect on the initial acquisition in the water maze in control and apolipoprotein E-deficient mice after 25 or 106 days of recovery. However, the nucleus basalis lesion impaired the reversal learning in the water maze similarly in both strains after 25 days of recovery, but had no effect after 106 days of recovery. Finally, water maze spatial navigation and cortical choline acetyltransferase activity were similar in old control and apolipoprotein E-deficient mice. These results suggest that young and old apolipoprotein E-deficient mice do not have impairments in cholinergic activity or spatial navigation. Furthermore, apolipoprotein E deficiency does not increase the sensitivity to cholinergic and spatial navigation deficits induced by lesioning of the nucleus basalis with an excitatory amino acid and does not slow down the behavioral recovery.

Acetylcholine↗

PubMed1999

Comparison of dopamine and noradrenaline release in mouse prefrontal cortex, striatum and hippocampus using microdialysis.

In vivo release of dopamine (DA) and noradrenaline (NA) in mouse medial prefrontal cortex, medial striatum and hippocampus was characterized using in vivo microdialysis. Basal release of NA was similar in these areas, but DA in striatum was 13-30 times higher than in other areas. Unconditioned stimuli (handling, novelty) induced strong increases, except for striatal DA. Striatal NA was more sensitive to handling than NA in other areas.

Animals↗

PubMed1999

Effects of apamin on memory processing of hippocampal-lesioned mice.

We investigated the effects of acute i.p. injections of the Ca(2+)-dependent K(+) channel blocker, apamin, on water maze spatial navigation and radial arm maze performance in mice with partial hippocampal-lesions. In the radial arm maze, apamin 0.06 and 0.2 mg/kg dose-dependently reversed the lesion-induced defect. In the water maze, apamin 0.2 mg/kg alleviated the defect, but a lower dose 0.06 mg/kg was ineffective. At a higher dose, 0.4 mg/kg, apamin impaired the water maze performance. These results suggest that Ca(2+)-dependent K(+) channel blockers can alleviate the spatial reference memory and working memory impairment induced by partial hippocampal lesions.

Animals↗

PubMed1999

Estrogen and NMDA receptor antagonism: effects upon reference and working memory.

Since both estrogen and NMDA receptor antagonists act on the hippocampus CA1 region and behaviorally affect hippocampal memory tasks, we examined how estrogen depletion (ovariectomy) and NMDA receptor antagonism interact upon spatial memory of the mouse. After ovariectomy or sham operation, mice were given a 2-week recovery before behavioral tests began under the influence of vehicle or (+/-)-3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP 2, 5 and 10 mg/kg) intraperitoneal injections. CPP is a competitive, full NMDA receptor antagonist. Spatial reference memory was tested by the water maze, spatial working memory was tested by the radial arm maze, while overall locomotive activity was monitored by the Y-maze. Results from the water maze and the Y-maze did not show any spatial reference memory or activity differences between sham-operated and ovariectomized mice. The radial arm maze, however, highlighted some working memory differences between intact and ovariectomized mice. CPP treatment impaired dose dependently--the performance of ovariectomy and sham-operated mice equally on both water maze and radial arm maze, while the drug had no effect on Y-maze performance. These results suggest that short term estrogen deprivation has no effect upon spatial-reference memory, while it impairs spatial working memory. This effect is probably not mediated by NMDA receptors.

Animals↗

PubMed1999

Vigabatrin, a gabaergic antiepileptic drug, causes concentric visual field defects.

OBJECTIVE: To determine whether there is a causal link between vigabatrin treatment and concentric visual field defects and to evaluate the prevalence of these visual field constrictions. BACKGROUND: While the GABAergic antiepileptic drug (AED) vigabatrin was being clinically developed, only rare cases (less than 1:1000) of symptomatic visual field constriction and retinal disorders were reported. During 1997 to 1998, concentric visual field constrictions were described in case reports of mostly drug-resistant epilepsy patients receiving vigabatrin concurrently with other AEDs. METHODS: Ophthalmologic tests including Goldmann perimetry were performed on 32 adult patients on long-term successful vigabatrin monotherapy (treatment duration 29 to 119 months) and on 18 patients on carbamazepine monotherapy (treatment duration 32 to 108 months). Eighteen healthy adults served as controls. RESULTS: None of the patients complained about vision problems when asked to participate into the study. Thirteen out of the 32 (40%) epilepsy patients treated with vigabatrin monotherapy had concentrically constricted visual fields (9% severely, 31% mildly constricted), whereas none of the carbamazepine monotherapy patients or normal controls presented with a visual field defect (chi-square test, p = 0.0001). The extents of the visual fields were significantly constricted in vigabatrin group as compared with the visual fields of the patients in carbamazepine group or healthy controls (analysis of variance, Scheffe F-test, significant at 99%). CONCLUSIONS: The use of vigabatrin seems to increase the risk of a unique and specific pattern of bilateral, mainly asymptomatic visual field constriction. This risk should be considered when using vigabatrin. Visual field testing should also be performed before treatment and during routine follow-up for patients on vigabatrin.

Adolescent↗

PubMed1999

Antiplatelet treatment does not reduce the severity of subsequent stroke. European Stroke Prevention Study 2 Working Group.

OBJECTIVE: To assess the the effect of antiplatelet therapy on the severity of subsequent stroke in patients with stroke and TIA. BACKGROUND: The Second European Stroke Prevention Study (ESPS2) recruited 6,602 patients in four treatment groups: placebo, 2 x 25 mg acetylsalicylic acid (ASA), 2 x 200 mg dipyridamole (DP), and the combination of 50 mg ASA and 400 mg DP per day. Seventy-six percent of the patients had had a stroke as the qualifying event, whereas 24% had a TIA. All patients were followed at 3-month intervals for 2 years. ESPS2 showed a benefit from antiplatelet treatment compared with placebo and an additional benefit using ASA and DP together compared with either of these antiplatelet agents alone. METHODS: In the ESPS2, the study protocol included assessment of severity of end point stroke with the modified Rankin scale once the stroke had clinically stabilized, and no further impairment was observed. There were 824 new stroke events during follow-up. In 701 of them, the initial Rankin scale was known, and this was also evaluated after each nonfatal recurrent stroke. The difference in Rankin scale between treatment groups was analyzed after recurrent stroke, and the progress in Rankin scale between entry and recurrent stroke was quantified by calculating the number of patients with a change of one or more degrees in the scale. RESULTS: There were no significant differences in these changes in Rankin scale between the treatment groups. The mean time to reach an end point of stroke was longest in patients who used ASA + DP (p = 0.057). However, there was no difference among the treatment groups in the time to death during follow-up. CONCLUSION: This study suggests that antiplatelet therapy does not influence the severity of recurrent stroke as evaluated with the Rankin scale. However, antiplatelet therapy seems to lengthen the time the patient remains free from a recurrent stroke.

Aged↗

PubMed1999

Characterization of learning and memory behaviors and the effects of metrifonate in the C57BL strain of mice.

In the near future, a number of transgenic mouse models with neuropathological characteristics of Alzheimer's disease are expected to become widely available. It will be important to characterize their behavior in models for learning and memory. As a first step, we have characterized normal, medial septal-lesioned and hippocampal-lesioned C57BL mice, in different behavioral tests, i.e., water maze spatial navigation, Y-maze and passive avoidance behavior. These experiments were complemented by an investigation of the effects of acute treatment with an acetylcholinesterase inhibitor, metrifonate, in these behavioral tests. Normal C75BL mice perform very well in the water maze and the Y-maze, but suboptimally in the passive avoidance task. Lesioning of the medial septum or the dorsal hippocampus clearly impaired the performance of the mice. In medial septal-lesioned mice, metrifonate stimulated spatial navigation and alleviated the loss of activity in the Y-maze and passive avoidance. In hippocampal-lesioned mice, metrifonate had no effect on spatial navigation. It is concluded that C75BL mice are useful for testing in classical models for learning and memory, and that septohippocampal pathology is very likely to induce cognitive deficits in some of these models.

Animals↗

PubMed1999

In mice tonic estrogen replacement therapy improves non-spatial and spatial memory in a water maze task.

We investigated the effects of estrogen replacement therapy on water maze non-spatial and spatial navigation in mice. Three groups of mice were ovariectomized and two of these groups being implanted with s.c. pellets that produce blood levels of estrogen close to those found in estrous (estrogen low, 75-100 pg/ml blood) or proestrous (estrogen high, 300-400 pg/ml). The behavioral assessment was initiated 7 days after pellet implantation. Non-spatial navigation to a clearly visible platform was stimulated by low and high levels of estrogen. However, spatial navigation to a hidden platform was improved by low estrogen levels. We found that estrogen improves two different types of memory processes that depend on striatal (non-spatial navigation) and hippocampal (spatial) memory systems.

Animals↗

PubMed1999

Blockade of NMDA receptors located at the dorsomedial prefrontal cortex impairs spatial working memory in rats.

We investigated the effects of NMDA and muscarinic acetylcholine receptor blockade in the rostral part of dorsomedial (dmPFC) and dorsolateral prefrontal cortex (dlPFC) on spatial working memory (SWM) (delayed non-matching to position task (DNMTP)). The NMDA antagonist, CPP (0.01, 0.03, 0.1 and 0.3 microg/hemisphere) and the muscarinic antagonist, scopolamine (10 microg/hemisphere) were locally infused into the brain of male Wistar rats. In the mPFC CPP 0.1 microg disrupted SWM delay-dependently and CPP 0.3 microg caused a delay-independent performance deficit. Scopolamine disrupted non-cognitive performance, but did not affect SWM accuracy. In the dlPFC, scopolamine or lower doses of CPP did not affect SWM accuracy, but CPP 0.3 microg disrupted non-cognitive performance. We concluded that the NMDA receptors in the dmPFC regulate SWM processes, whereas the muscarinic receptors in the dmPFC mediate non-cognitive performance in the DNMTP task.

Animals↗

PubMed1999

Tetrahydroaminoacridine and D-cycloserine fail to alleviate the water maze spatial navigation defect induced by hippocampal inactivation.

The present study examined the efficacy of single and combined treatment with an anticholinesterase, tetrahydroaminoacridine (i.p.), and a glycine-B site partial agonist, D-cycloserine (i.p.; a positive allosteric modulator of NMDA receptors), in alleviating the deficit in water maze spatial navigation induced by electrolytic lesion of the medial septum or lidocaine infusion into the dorsal hippocampi. In medial septum-lesioned rats, a combination of tetrahydroaminoacridine 3 mg kg(-1) and D-cycloserine 10 mg kg(-1) facilitated acquisition of the water maze test more effectively than either of the drugs alone. Single or combined treatment with tetrahydroaminoacridine 3 mg kg(-1) and D-cycloserine 10 mg kg(-1) had no effect on the water maze deficit induced by hippocampal lidocaine infusion. These results suggest that combined treatment with tetrahydroaminoacridine and D-cycloserine can effectively stimulate water maze spatial navigation, and that functioning of the hippocampus is a prerequisite for this effect.

Anesthetics, Local↗

PubMed1999

Moderate cortical EEG changes in apolipoprotein E-deficient mice during ageing and scopolamine treatment but not after nucleus basalis lesion.

RATIONALE: Recent studies suggest that apoE-deficient mice may have impaired central cholinergic function and neuronal recovery capacity. OBJECTIVE: We investigated whether apoE-deficient mice are more susceptible to the biochemical and EEG defects induced by ageing or nucleus basalis (NB) lesion. METHODS: ApoE-deficient and control mice were used. The baseline EEG activity and EEG response to a muscarinic acetylcholine receptor antagonist, scopolamine (0.05 and 0.2 mg/kg) and a benzodiazepine receptor agonist, diazepam (0.5 and 2.0 mg/kg), were studied during ageing. In addition, the cortical and hippocampal ChAT activities were measured in aged mice. The baseline EEG activity and EEG response to scopolamine (0.05 and 0.2 mg/kg), and cortical ChAT activity, were studied after quisqualic acid-induced unilateral NB lesion. RESULTS: The baseline EEG fast wave activity (relative alpha and beta) was higher in apoE-deficient mice. Ageing decreased relative alpha activity similarly in both strains. The scopolamine induced EEG slowing was less prominent in apoE-deficient than in control mice, and the difference between the strains became slightly clearer during ageing. The NB lesion failed to produce more severe changes in cortical EEG and ChAT activity in apoE-deficient mice. Cortical and hippocampal ChAT activity was equal in young and aged apoE-deficient and control mice. The EEG response to diazepam in young and aged mice was similar in both strains. CONCLUSIONS: The regulation of cortical EEG activity of apoE-deficient mice was somewhat altered during ageing and the response to scopolamine treatment was blunted. However, the cholinergic cells of the NB of apoE-deficient mice were not more sensitive to lesion or to ageing, suggesting that apoE does not have to be present to preserve the viability of cholinergic neurons.

Aging↗

PubMed1999

Reactive microglia in aging and dementia: an immunohistochemical study of postmortem human brain tissue.

Significantly increased up-regulation of HLA DR (major histocompatibility complex class II antigen) was seen using immunohistochemistry in postmortem brain tissue from demented patients with Alzheimer's disease (AD) (73 cases, 61 females/12 males, mean age 84 +/- 9 years) compared to controls (22 cases, 10 females/12 males, mean age 78 +/- 9 years). The counts of HLA DR-expressing activated microglia were significantly higher in female AD patients compared to males, significantly higher in AD patients with the age at death greater than 75 years compared to those dying younger and higher, although not statistically significantly, in AD patients with the apolipoprotein E (ApoE) epsilon4 allele compared to those patients not carrying this allele. In contrast to the situation in AD patients, in the control cases the HLA DR expression was higher in males compared to females. Furthermore, in the very old non-demented patients (age at death > 80 years), a decrease in the up-regulation of HLA DR expression was observed. A significant correlation between activated microglia and neurofibrillary tangles was seen in female AD patients compared to males, in AD cases without ApoE epsilon4 allele compared to those with this allele, in sporadic cases compared to familial and in cases with senile rather than presenile onset of the disease. Our results indicate that there is an age- and/or sex-related variability in up-regulation of HLA DR expression of microglia and that the linkage between this up-regulation and AD lesions is significantly influenced by the ApoE epsilon4 allele, gender of subjects, age at onset and familiality of the disease.

Age Factors↗

PubMed1999

Alpha2C-adrenoceptor overexpression disrupts execution of spatial and non-spatial search patterns.

We investigated the role of alpha2C-adrenoceptors in the modulation of spatial and non-spatial navigation behaviour. Alpha2C-adrenoceptor overexpressing mice developed an ineffective thigmotaxic search pattern characterized by swimming close to the pool walls during both spatial and non-spatial water maze training. A subtype-non-selective alpha2-adrenoceptor antagonist, atipamezole (1000 microg/kg, s.c.), fully reversed this impairment in their search strategy. Withdrawal of atipamezole at the end of spatial training resulted in an immediate disruption of the search pattern in alpha2C-adrenoceptor overexpressing mice. The swimming pattern of alpha2C-adrenoceptor overexpressing mice during a five day free swimming period was normal, when no cognitive component was required. Diazepam (0.3 and 1.0 mg/kg, i.p.), neither improved the accuracy in finding the platform nor decreased thigmotaxis. These results suggest that alpha2C-adrenoceptors may modulate the execution of complex navigation patterns.

Adrenergic alpha-Antagonists↗