Riekkinen P, Jr.

References (42)

Title : Pre-training blocks the improving effect of tetrahydroaminoacridine and D-cycloserine on spatial navigation performance in aged rats - Aura_2000_Eur.J.Pharmacol_390_313
Author(s) : Aura J , Riekkinen P , Riekkinen P, Jr.
Ref : European Journal of Pharmacology , 390 :313 , 2000
Abstract : 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.
ESTHER : Aura_2000_Eur.J.Pharmacol_390_313
PubMedSearch : Aura_2000_Eur.J.Pharmacol_390_313
PubMedID: 10708739

Title : Characterization of learning and memory behaviors and the effects of metrifonate in the C57BL strain of mice - Ikonen_1999_Eur.J.Pharmacol_372_117
Author(s) : Ikonen S , Schmidt BH , Riekkinen P, Jr.
Ref : European Journal of Pharmacology , 372 :117 , 1999
Abstract : 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.
ESTHER : Ikonen_1999_Eur.J.Pharmacol_372_117
PubMedSearch : Ikonen_1999_Eur.J.Pharmacol_372_117
PubMedID: 10395091

Title : Tetrahydroaminoacridine and D-cycloserine fail to alleviate the water maze spatial navigation defect induced by hippocampal inactivation - Riekkinen_1999_Eur.J.Pharmacol_366_13
Author(s) : Riekkinen P, Jr. , Ikonen S , Aura J , Riekkinen M
Ref : European Journal of Pharmacology , 366 :13 , 1999
Abstract : 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.
ESTHER : Riekkinen_1999_Eur.J.Pharmacol_366_13
PubMedSearch : Riekkinen_1999_Eur.J.Pharmacol_366_13
PubMedID: 10064146

Title : THA improves word priming and clonidine enhances fluency and working memory in Alzheimer's disease - Riekkinen_1999_Neuropsychopharmacology_20_357
Author(s) : Riekkinen P, Jr. , Riekkinen M
Ref : Neuropsychopharmacology , 20 :357 , 1999
Abstract : We investigated the effects of a single administration of a cholinesterase inhibitor, tetrahydroaminoacridine (THA, 25 and 50 mg, orally), and an alpha 2-agonist, clonidine (0.5 and 2 micrograms/kg, orally), on neuropsychologic performance in two groups of patients with Alzheimer's disease (AD). Clonidine enhanced a spatial working memory and verbal fluency, but had no effect on spatial span or word priming. THA enhanced word priming, but had no effect on other performance measures. Our data suggests that degeneration of the LC noradrenergic system and the cholinergic cells of the basal forebrain have different functional consequences during the progression of AD. Finally, a combined treatment with noradrenergic and cholinergic drugs might produce a qualitatively broader effect on cognitive functions than either of the treatments alone, and more effectively attenuate clinical dementia.
ESTHER : Riekkinen_1999_Neuropsychopharmacology_20_357
PubMedSearch : Riekkinen_1999_Neuropsychopharmacology_20_357
PubMedID: 10088136

Title : Oxotremorine suppresses thalamocortical oscillations via thalamic muscarinic acetylcholine receptors - Puolivali_1998_Psychopharmacology.(Berl)_140_285
Author(s) : Puolivali J , Jakala P , Koivisto E , Riekkinen P, Jr.
Ref : Psychopharmacology (Berl) , 140 :285 , 1998
Abstract : We investigated whether the local intrathalamic infusion of a muscarinic acetylcholine receptor agonist (oxotremorine) at either the reticular nucleus of thalamus (NRT) or the ventroposteromedial nucleus of thalamus (VPM) suppresses thalamocortically generated neocortical high-voltage spindles (HVSs). In addition, we studied whether the intracerebroventricular (ICV) infusion of a selective muscarinic M2 acetylcholine receptor antagonist (methoctramine) could block the suppression of HVSs induced by either systemic (IP) administration of an anticholinesterase drug [tetrahydroaminoacridine (THA)] or ICV infusion of oxotremorine in rats. Intrathalamic administration of oxotremorine at 3 and 15 microg in the NRT, and at 15 microg in the VPM suppressed HVSs. ICV oxotremorine at 30 and 100 microg and IP THA at 3 mg/kg decreased HVSs. ICV methoctramine at 100 microg increased HVSs and completely blocked the decrease in HVSs produced by oxotremorine 100 microg and THA 3 mg/kg. The results suggest that activation of muscarinic M2 acetylcholine receptors in thalamic nuclei (NRT and VPM) can suppress thalamocortical oscillations and that ICV or systemically administered drugs that activate either directly (oxotremorine and methoctramine) or indirectly (THA) the muscarinic M2 acetylcholine receptors may modulate neocortical HVSs via the thalamus.
ESTHER : Puolivali_1998_Psychopharmacology.(Berl)_140_285
PubMedSearch : Puolivali_1998_Psychopharmacology.(Berl)_140_285
PubMedID: 9877008

Title : Tetrahydroaminoacridine improves the recency effect in Alzheimer's disease - Riekkinen_1998_Neurosci_83_471
Author(s) : Riekkinen M , Soininen H , Riekkinen P, Sr. , Kuikka J , Laakso M , Helkala EL , Partanen J , Riekkinen P, Jr.
Ref : Neuroscience , 83 :471 , 1998
Abstract : We investigated the effects of a single administration of tetrahydroaminoacridine (25 and 50 mg, orally), a cholinesterase inhibitor, on memory function in Alzheimer's disease patients. The recall of memory items from the end of the word list (recency effect) was improved in a subgroup of Alzheimer's disease patients (responders 10 out of 28) by tetrahydroaminoacridine 50 mg. However, tetrahydroaminoacridine 50 mg had no effect on the recall of those words from the beginning or middle of the list. Tetrahydroaminoacridine did not markedly improve non-verbal delayed matching to sample or paired associates learning in any of the Alzheimer's disease patients. The "responders" performed better than the "non-responders" in tests measuring memory and frontal functions. The responders had less severe hippocampal atrophy and less prefrontal blood flow defect, and had a lower frequency of the apolipoprotein E4 allele than the "non-responders". These results suggest that acute tetrahydroaminoacridine treatment may stimulate the recency effect, and that a severe dysfunction of hippocampus and prefrontal regions blocks this effect of tetrahydroaminoacridine on short-term memory performance.
ESTHER : Riekkinen_1998_Neurosci_83_471
PubMedSearch : Riekkinen_1998_Neurosci_83_471
PubMedID: 9460755

Title : Tetrahydroaminoacridine, a cholinesterase inhibitor, and D-cycloserine, a partial NMDA receptor-associated glycine site agonist, enhances acquisition of spatial navigation - Riekkinen_1998_Neuroreport_9_1633
Author(s) : Riekkinen P, Jr. , Ikonen S , Riekkinen M
Ref : Neuroreport , 9 :1633 , 1998
Abstract : The present study examines the efficacy of single and combined treatments with an antiocholinesterase, tetrahydroaminoacridine (THA, i.p.), and a glycine-B site partial agonist, D-cycloserine (DCS, i.p.) to alleviate water maze (WM) spatial navigation defect induced by medial septal (MS) lesion. THA 3 and DCS at 3 or 10 mg/kg improved acquisition of the WM test, but only DCS improved spatial bias. These drugs had no effect on consolidation. A combination of THA 3 and DCS 10 mg/kg enhanced WM acquisition more effectively than either of the treatments on their own. This suggests that combined modulation of acetylcholine and NMDA mechanisms may have greater therapeutic effect to stimulate cognitive dysfunctions.
ESTHER : Riekkinen_1998_Neuroreport_9_1633
PubMedSearch : Riekkinen_1998_Neuroreport_9_1633
PubMedID: 9631478

Title : Tetrahydroaminoacridine and D-cycloserine stimulate acquisition of water maze spatial navigation in aged rats - Aura_1998_Eur.J.Pharmacol_342_15
Author(s) : Aura J , Riekkinen M , Riekkinen P, Jr.
Ref : European Journal of Pharmacology , 342 :15 , 1998
Abstract : We investigated the effect of tetrahydroaminoacridine, a cholinesterase inhibitor and D-cycloserine (a partial glycine-B agonist of the NMDA receptor complex) on the defect of water maze spatial navigation in rats induced by aging. Tetrahydroaminoacridine (3 mg/kg, i.p.) or D-cycloserine (10 mg/kg, i.p.) enhanced acquisition of the water maze task. A combination of subthreshold doses of tetrahydroaminoacridine (1 mg/kg) and D-cycloserine (3 mg/kg) improved water maze acquisition, but a combination of lower subthreshold doses (tetrahydroaminoacridine 0.3 mg/kg + D-cycloserine 1 mg/kg) was ineffective. Consolidation in water maze test was not improved by tetrahydroaminoacridine (3 mg/kg) and/or D-cycloserine (10 mg/kg). The results suggest that tetrahydroaminoacridine and D-cycloserine synergistically enhance acquisition of spatial navigation in aged rats.
ESTHER : Aura_1998_Eur.J.Pharmacol_342_15
PubMedSearch : Aura_1998_Eur.J.Pharmacol_342_15
PubMedID: 9544787

Title : D-cycloserine, a partial NMDA receptor-associated glycine-B site agonist, enhances reversal learning, but a cholinesterase inhibitor and nicotine has no effect - Riekkinen_1998_Neuroreport_9_3647
Author(s) : Riekkinen P, Jr. , Ikonen S , Riekkinen M
Ref : Neuroreport , 9 :3647 , 1998
Abstract : The present study examined the efficacy of single and combined treatments with an anticholinesterase, tetrahydroaminoacridine, nicotine and a glycine-B site partial agonist, D-cycloserine, in alleviating the water maze reversal learning defect induced by a medial septal lesion. D-cycloserine (3 and 10 mg/kg) improved reversal learning. Tetrahydroaminoacridine (1 and 3 mg/kg) and nicotine (0.1 and 0.3 mg/kg) had no effect on reversal learning. A combination of tetrahydroaminoacridine 3 mg/kg or nicotine 0.3 mg/kg and D-cycloserine 10 mg/kg was not more effective than D-cycloserine 10 mg/kg alone in improving reversal learning. This suggests that stimulation of NMDA mechanisms may more effectively improve in medial septal-lesioned rats reversal learning processes than stimulation of cholinergic activity.
ESTHER : Riekkinen_1998_Neuroreport_9_3647
PubMedSearch : Riekkinen_1998_Neuroreport_9_3647
PubMedID: 9858374

Title : Chronic nimodipine and acute metrifonate treatment decreases age- related cortical high voltage spindles in rats - Riekkinen_1997_Psychopharmacology_129_91
Author(s) : Riekkinen P, Jr. , Schmidt B , Jakala P , Koivisto E , Bjorklund M
Ref : Psychopharmacology , 129 :91 , 1997
Abstract : We studied the effect of nimodipine (1000 ppm mixed in food), an L-type calcium-channel antagonist, administered for 4 months, on the cortical EEG activity in young and aged rats. Nimodipine treatment decreased cortical high voltage spindles (HVSs) in aged rats, but did not prevent the diminution of spontaneous locomotor activity. The threshold dose of metrifonate, a cholinesterase inhibitor, for suppression of HVSs was lower in nimodipine compared to placebo treated aged rats (30 mg/kg versus 60 mg/kg; p.o.). In young rats, nimodipine did not decrease HVSs, protect from scopolamine (0.1 or 0.8 mg/kg, i.p.) induced EEG slowing or augment the effect of metrifonate to suppress slow waves induced by scopolamine. The present results suggest that a chronic nimodipine treatment modulates thalamocortical arousal and thereby adds to the therapeutic effects of metrifonate to restore normal cortical electrical arousal in aged rats.
ESTHER : Riekkinen_1997_Psychopharmacology_129_91
PubMedSearch : Riekkinen_1997_Psychopharmacology_129_91
PubMedID: 9122369

Title : Subchronic treatment increases the duration of the cognitive enhancement induced by metrifonate - Riekkinen_1997_Eur.J.Pharmacol_338_105
Author(s) : Riekkinen M , Schmidt BH , Riekkinen P, Jr.
Ref : European Journal of Pharmacology , 338 :105 , 1997
Abstract : The study compared the efficacy of acute versus chronic metrifonate treatment to improve initial and reversal learning of the water maze spatial navigation task in medial septal-lesioned rats. Acute oral administration of 30 mg/kg metrifonate at 30 min, but not at 150 or 360 min, before training improved the initial acquisition of the water maze task. In contrast, improvement of initial learning performance of medial septal-lesioned rats pretreated for 21 days with metrifonate was observed irrespective of the timing of metrifonate treatment relative to behavioral testing. Reversal learning was assessed after a four-day wash-out period. No drug treatment was administered during this part of the study. All the medial septal-lesioned rats that had received only acute treatment with metrifonate during the initial learning stage were now as impaired as vehicle treated medial septal-lesioned rats. However, the group subchronically pretreated with metrifonate performed better than the vehicle-treated medial septal-lesioned controls. These results indicate that both acute and subchronic treatment with metrifonate can facilitate spatial learning in medial septal-lesioned rats and the transient nature of this beneficial effect after single acute administration is transformed into a long-lasting improvement by subchronic treatment.
ESTHER : Riekkinen_1997_Eur.J.Pharmacol_338_105
PubMedSearch : Riekkinen_1997_Eur.J.Pharmacol_338_105
PubMedID: 9455990

Title : Frontal dysfunction blocks the therapeutic effect of THA on attention in Alzheimer's disease - Riekkinen_1997_Neuroreport_8_1845
Author(s) : Riekkinen P, Jr. , Riekkinen M , Soininen H , Kuikka J , Laakso M , Riekkinen P, Sr.
Ref : Neuroreport , 8 :1845 , 1997
Abstract : We evaluated the effect of a single dose of a cholinesterase inhibitor, tetrahydroaminoacridine (THA; 25 and 50 mg, orally), on attention in patients with Alzheimer's disease (AD). THA 50 mg improved performance in attentional measures (Trail Making Test, Big/Little Circle, Simple and Choice Reaction Time) in nine of 28 patients with AD. We analysed retention of 99mTc-labelled ethylene dicysteinate (ECD) in the cortical areas using single photon emission computed tomography. Those patients who benefited from THA treatment had bilaterally higher frontal and prefrontal ECD retention values. We suggest that THA may improve attention in patients with AD, but a severe frontal dysfunction may block the therapeutic effect of THA.
ESTHER : Riekkinen_1997_Neuroreport_8_1845
PubMedSearch : Riekkinen_1997_Neuroreport_8_1845
PubMedID: 9223063

Title : THA disrupts mismatch negativity in Alzheimer disease - Riekkinen_1997_Psychopharmacology_133_203
Author(s) : Riekkinen P, Jr. , Paakkonen A , Karhu J , Partanen J , Soininen H , Laakso M , Riekkine P, Sr.
Ref : Psychopharmacology , 133 :203 , 1997
Abstract : The present study investigates the effects of 25 or 50 mg tetrahydroaminoacridine (THA), a cholinesterase inhibitor, on auditory mismatch negativity (MMN) event-related response in 19 patients with Alzheimer disease (AD). MMN is produced by the deviant tones representing passive attention and automatic detection of stimulus change. In an inattentive task condition, standard (85%) and deviant (15%) tones were represented in a random order with interstimulus interval of 1 s in separate blocks. THA 25 mg had no effect on MMN in AD patients. In contrast, THA 50 mg diminished MMN in AD subjects. The results suggests that acute treatment of AD subjects with a cholinesterase inhibitor disrupts the passive detection of change in an auditory input.
ESTHER : Riekkinen_1997_Psychopharmacology_133_203
PubMedSearch : Riekkinen_1997_Psychopharmacology_133_203
PubMedID: 9342788

Title : The ability of THA treatment to increase cortical alpha waves is related to apolipoprotein E genotype of Alzheimer disease patients - Riekkinen_1997_Psychopharmacology.(Berl)_129_285
Author(s) : Riekkinen P, Jr. , Soininen H , Partanen J , Paakkonen A , Helisalmi S , Riekkinen P, Sr.
Ref : Psychopharmacology (Berl) , 129 :285 , 1997
Abstract : In a previous study, we reported that Alzheimer disease (AD) patients with an apolipoprotein E (APOE) epsilon 4 allele (+ APOE4) show more severe loss of nucleus basalis (NB) cholinergic cells than patients without epsilon 4 alleles (-APOE4). The present study investigates the effects of a single oral administration of THA 25 or 50 mg on cortical spectral EEG activity in + (five APOE4/4, six APOE4/3) and -APOE4 (eight APOE3/3) AD patients. THA 25 mg had no significant effect on EEG activity in any AD patients. However, THA 50 mg increased alpha activity and alpha/theta ratio in -APOE4 patients. In contrast, THA 50 mg had no effect on EEG activity in + APOE4 patients. This result tentatively suggests that in AD patients APOE genotype may affect the response of cortical electrical arousal to cholinergic therapy that enhances the efficacy of presynaptic NB axons.
ESTHER : Riekkinen_1997_Psychopharmacology.(Berl)_129_285
PubMedSearch : Riekkinen_1997_Psychopharmacology.(Berl)_129_285
PubMedID: 9084068

Title : Combined cholinergic and 5-HT2 receptor activation suppresses thalamocortical oscillations in aged rats - Jakala_1997_Pharmacol.Biochem.Behav_56_713
Author(s) : Jakala P , Riekkinen P, Jr.
Ref : Pharmacol Biochem Behav , 56 :713 , 1997
Abstract : The present study investigated whether combined stimulation of the cholinergic system and 5-hydroxytryptamine (5-HT) subtype 2 receptors can suppress neocortical high-voltage spindles (HVSs) reflecting thalamocortical oscillations in aged rats. Cholinesterase inhibitors-tetrahydro-aminoacridine (THA: 1.0 and 3.0 mg/kg i.p.) and physostigmine (0.36 mg/kg i.p.)- and a 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 0.3 and 1.0 mg/kg SC)-suppressed HVSs in aged rats. A combination of subthreshold doses of THA (0.3 mg/kg i.p.) and DOI (0.1 mg/kg s.c.) suppressed HVSs more effectively than either drug alone. Furthermore, a 5-HT2 receptor antagonist, ketanserin (5.0 and 20.0 mg/kg s.c.), reduced the efficacy of THA (1.0 and 3.0 mg/kg i.p.) and physostigmine (0.12 and 0.36 mg/kg i.p.) in decreasing HVSs. THA and ketanserin slightly decreased, physostigmine tended to increase, and DOI significantly increased behavioral activity of the rats, demonstrating that the effects of the drugs on behavioral activity may be separated from their effects on generation of thalamocortical oscillations. The results suggest that activation of the cholinergic system and 5-HT2 receptors has additive effects in the suppression of thalamocortical oscillations in aged rats.
ESTHER : Jakala_1997_Pharmacol.Biochem.Behav_56_713
PubMedSearch : Jakala_1997_Pharmacol.Biochem.Behav_56_713
PubMedID: 9130298

Title : Behavioral characterization of metrifonate-improved acquisition of spatial information in medial septum-lesioned rats - Riekkinen_1997_Eur.J.Pharmacol_323_11
Author(s) : Riekkinen P, Jr. , Schmidt B , Riekkinen M
Ref : European Journal of Pharmacology , 323 :11 , 1997
Abstract : We investigated the effects of acute oral pretraining treatment with an indirect acetylcholinesterase inhibitor, metrifonate, on water maze spatial navigation in medial septum-lesioned rats. We observed that metrifonate (30 mg/kg, orally) (1) does not alter the pattern of exploration of lesioned rats at the water maze pool or retrieval of spatial memory, (2) effectively reverses the acquisition defect, (3) enhances reversal learning, and (4) improves acquisition of water maze navigation by facilitating the encoding of the spatial representation of a specific environment. These results indicate that metrifonate does not improve escape performance to the hidden platform by modulating exploration strategy, but that metrifonate enhances the speed and accuracy of development and durability of spatial memory engrams, and facilitates learning capacity that depends on activity of the septo-hippocampal projection.
ESTHER : Riekkinen_1997_Eur.J.Pharmacol_323_11
PubMedSearch : Riekkinen_1997_Eur.J.Pharmacol_323_11
PubMedID: 9105871

Title : Effects of combined nimodipine and metrifonate on rat cognition and cortical EEG - Jakala_1996_Eur.J.Pharmacol_318_239
Author(s) : Jakala P , Riekkinen M , Bjorklund M , Koivisto E , Schmidt B , Riekkinen P, Jr.
Ref : European Journal of Pharmacology , 318 :239 , 1996
Abstract : The present study investigated if short-term treatment with an L-type Ca2+-channel inhibitor, nimodipine, can stimulate cognitive functioning and cortical electroencephalograph (EEG) arousal, and potentiate the effect of a cholinesterase inhibitor, metrifonate. Pretraining administration of nimodipine (3, 10 and 30 mg/kg, p.o.) had no effect on water maze and passive avoidance behavior of young neurologically intact controls, or water maze and passive avoidance performance failure induced by scopolamine pretreatment (i.p.; 0.4 mg/kg during the water maze and 2.0 mg/kg during the passive avoidance study), medial septal lesioning, or aging. Furthermore, nimodipine (3, 10 and 30 mg/kg, p.o.) had no effect on the improvement by metrifonate (10 mg/kg, p.o.) of the water maze and passive avoidance failure induced by scopolamine pretreatment or medial septal lesioning, nor did it affect the potential of metrifonate (30 mg/kg. p.o.) to improve the water maze or passive avoidance behavior of aged rats. Finally, nimodipine (3, 10 and 30 mg/kg, p.o.) had no effect on spontaneously occurring thalamically generated neocortical high-voltage spindles or spectral EEG activity of young controls, nor did it alleviate the spectral EEG abnormality induced by scopolamine (0.2 mg/kg, i.p.) administration. Also, the combination of nimodipine 3 or 10 mg/kg and a subthreshold dose of metrifonate 10 mg/kg could not suppress high-voltage spindles or scopolamine treatment-induced spectral EEG activity abnormalities. According to the present results, short-term treatment with nimodipine does not stimulate cognitive functions or increase cortical EEG arousal, and does not block or potentiate the propensity of metrifonate to improve cognitive performance of rats.
ESTHER : Jakala_1996_Eur.J.Pharmacol_318_239
PubMedSearch : Jakala_1996_Eur.J.Pharmacol_318_239
PubMedID: 9016911

Title : An indirect cholinesterase inhibitor, metrifonate, increases neocortical EEG arousal in rats - Bjorklund_1996_Neuroreport_7_1097
Author(s) : Bjorklund M , Jakala P , Schmidt B , Riekkinen M , Koivisto E , Riekkinen P, Jr.
Ref : Neuroreport , 7 :1097 , 1996
Abstract : We investigated the ability of a cholinesterase inhibitor, metrifonate, to desynchronize cortical EEG activity. Metrifonate suppressed immobility-related high voltage spindling activity in young and aged rats at doses of 30 and 60 mg kg-1, p.o., and 10, 30 and 60 mg kg-1, p.o., respectively. The increase in EEG 1-20 Hz amplitude induced by scopolamine (0.2 mg kg-1, i.p.) was fully alleviated by metrifonate (30 and 100 mg kg-1, p.o.) and partially alleviated by a reference cholinesterase inhibitor, THA (3 and 6 mg kg-1, i.p.). Nucleus basalis (NB) lesions induced by quisqualic acid decreased frontal cortical choline acetyltransferase activity by 80% and increased cortical EEG slow waves. Metrifonate and THA did not reverse NB lesion-induced EEG abnormality. We conclude that metrifonate enhances cholinergic desynchronization of cortical EEG waves and that a severe defect of presynaptic NB cholinergic fibres limits the therapeutic effects of metrifonate.
ESTHER : Bjorklund_1996_Neuroreport_7_1097
PubMedSearch : Bjorklund_1996_Neuroreport_7_1097
PubMedID: 8804059

Title : Metrifonate improves spatial navigation and avoidance behavior in scopolamine-treated, medial septum-lesioned and aged rats - Riekkinen_1996_Eur.J.Pharmacol_309_121
Author(s) : Riekkinen P, Jr. , Schmidt B , Stefanski R , Kuitunen J , Riekkinen M
Ref : European Journal of Pharmacology , 309 :121 , 1996
Abstract : We investigated the effects of acute p.o. pretraining treatment with an indirect acetylcholinesterase inhibitor, metrifonate, on water maze spatial navigation and passive avoidance behavior. Metrifonate (10-100 mg/kg, orally, p.o.) did not improve the water maze or passive avoidance performance of young intact rats. However, in young rats metrifonate over a broad dosage range (10-100 mg/kg, p.o.) was able to alleviate the adverse effects of scopolamine (a muscarinic acetylcholine receptor antagonist; 0.4 and 2.0 mg/kg in water maze and passive avoidance study, respectively) and medial septum-lesioning on spatial reference and working memory and passive avoidance performance. In old (23-month-old) rats, a defect of water maze and passive avoidance behavior was observed. In old rats, metrifonate improved spatial reference memory function in the water maze and also passive avoidance at 10-30 mg/kg, but the 3 mg/kg dose was ineffective. Very old (27-month-old) rats had a more severe impairment of water maze performance than old rats, and metrifonate 3-30 mg/kg did not improve their spatial navigation. These results show that metrifonate may over a wide range of doses stimulate cognitive functioning, but during advanced aging neurobiological defects develop that may mask some of the therapeutic effects of metrifonate in rats.
ESTHER : Riekkinen_1996_Eur.J.Pharmacol_309_121
PubMedSearch : Riekkinen_1996_Eur.J.Pharmacol_309_121
PubMedID: 8874130

Title : Depletion of serotonin, dopamine and noradrenaline in aged rats decreases the therapeutic effect of nicotine, but not of tetrahydroaminoacridine - Riekkinen_1996_Eur.J.Pharmacol_308_243
Author(s) : Riekkinen M , Aroviita L , Kivipelto M , Taskila K , Riekkinen P, Jr.
Ref : European Journal of Pharmacology , 308 :243 , 1996
Abstract : The present study investigates the effects of nicotine (0.1 and 0.3 mg/kg) and tetrahydroaminoacridine (3 mg/kg) treatment on spatial navigation in aged control and p-chlorophenylalanine (a serotonin (5-hydroxytryptamine, 5-HT) synthesis inhibitor, 400 mg/kg on 3 successive days, i.p.)-treated rats. p-Chlorophenylalanine did not aggravate the water maze failure of aged rats. Nicotine (0.3 mg/kg) was more effective than tetrahydroaminoacridine (3 mg/kg) in promoting water maze navigation by aged control rats. p-Chlorophenylalanine blocked the therapeutic effect of nicotine (0.3 mg/kg),but did not decrease the effect of tetrahydroaminoacridine (3 mg/kg) in aged rats. Frontal cortex dopamine levels and choline acetyltransferase activity were lower in aged rats, but 5-HT and noradrenaline levels were unaltered. p-Chlorophenylalanine decreased selectively 5-HT levels in young rats, but in aged rats 5-HT, dopamine and noradrenaline levels were decreased. These results suggest that aged rats are neurochemically more sensitive to p-chlorophenylalanine treatment and that tetrahydroaminoacridine may more effectively than nicotine stimulate spatial learning if 5-HT, dopamine and noradrenaline systems are severely affected.
ESTHER : Riekkinen_1996_Eur.J.Pharmacol_308_243
PubMedSearch : Riekkinen_1996_Eur.J.Pharmacol_308_243
PubMedID: 8858294

Title : Effects of Alzene and tacrine on water maze reference and working memory function in medial septal-lesioned rats - Riekkinen_1996_Brain.Res_714_118
Author(s) : Riekkinen P, Jr. , Mettinger KL , Karukin M , Riekkinen M
Ref : Brain Research , 714 :118 , 1996
Abstract : The present study investigated the effects of repeated daily administration of a mixture containing free fatty acids (alpha-linolenic/linoleic acid in a 1:4 ratio at 25 mg/kg i.p., Alzene) on medial septal (MS) lesion-induced impairment of water maze (WM) spatial reference and working memory or passive avoidance (PA) behavior in adult rats (250-275 g at the beginning of the study). Alzene treatment was started 7 days before initiation of behavioral testing (WM reference memory testing on treatment days: 7-9 and 28-30 + passive avoidance on treatment days 31-32; WM working memory testing on treatment days: 7-10 and 38-31 + passive avoidance testing on treatment days 32-33) and continued until the end of the study. Alzene improved WM reference memory (treatment days 7-9 and 28-30) and PA behavior (treatment days 31-32) as effectively as an anti-cholinesterase drug, tacrine 3 mg/kg (i.p.). However, in a separate group of MS-lesioned rats we observed that working memory (treatment days 7-10 and 28-31) was not improved by either Alzene or tacrine treatment. The present results suggest that Alzene treatment improves spatial reference memory and inhibitory avoidance in MS-lesioned rats.
ESTHER : Riekkinen_1996_Brain.Res_714_118
PubMedSearch : Riekkinen_1996_Brain.Res_714_118
PubMedID: 8861616

Title : Tetrahydroaminoacridine modulates technetium-99m labelled ethylene dicysteinate retention in Alzheimer's disease measured with single photon emission computed tomography imaging - Riekkinen_1995_Neurosci.Lett_195_53
Author(s) : Riekkinen P, Jr. , Kuikka J , Soininen H , Helkala EL , Hallikainen M , Riekkinen P
Ref : Neuroscience Letters , 195 :53 , 1995
Abstract : The present study investigated if acute treatment with tetrahydroaminoacridine (THA) (25 or 75 mg, p.o.) affects technetium-99m labelled ethylene dicysteinate (ECD) retention abnormalities in patients with mild to moderate Alzheimer's disease (AD; mean age 69 years). THA (75 mg) increased temporal, prefrontal and occipital ECD retention (normalized to cerebellum) in mildly demented AD patients, but 25 mg of THA had no effect on ECD retention. After 75 mg THA, prefrontal and temporal ECD retention correlated with improved executive and memory functioning, respectively. THA (25 or 75 mg) had no measurable effect on ECD retention of moderately demented patients.
ESTHER : Riekkinen_1995_Neurosci.Lett_195_53
PubMedSearch : Riekkinen_1995_Neurosci.Lett_195_53
PubMedID: 7478254

Title : Effects of tetrahydroaminoacridine and nicotine in nucleus basalis and serotonin-lesioned rats - Riekkinen_1995_Eur.J.Pharmacol_279_65
Author(s) : Riekkinen P, Jr. , Riekkinen M
Ref : European Journal of Pharmacology , 279 :65 , 1995
Abstract : The present study was designed to investigate the hypothesis that concurrent degeneration of serotonin and acetylcholine cells may decrease the therapeutic effects of cholinergic drugs on cognitive functioning in Alzheimer dementia. Therefore, we compared the effects of pretraining injections of a cholinesterase inhibitor, tetrahydroaminoacridine (1, 3 and 5 mg/kg i.p.), and nicotine (0.03, 0.1 and 0.3 mg/kg i.p.) on spatial navigation (water maze) and passive avoidance in nucleus basalis- and nucleus basalis+p-chlorophenylalanine-lesioned rats. Nicotine (0.1 and 0.3 mg/kg) promoted passive avoidance performance of nucleus basalis-lesioned rats, but nicotine did not improve performance of combined-lesioned rats. Tetrahydroaminoacridine (3 mg/kg) facilitated passive avoidance performance of nucleus basalis- and combined-lesioned rats. However, tetrahydroaminoacridine-treated nucleus basalis+p-chlorophenylalanine-lesioned rats were not performing better than vehicle-treated nucleus basalis-lesioned rats. Spatial navigation of nucleus basalis and nucleus basalis+p-chlorophenylalanine-lesioned rats was slightly impaired during the first training day and tetrahydroaminoacridine 3 mg/kg restored the performance of combined-lesioned rats. Combined-lesioned rats performed as well as the controls during the other training days. The present results suggest that, in Alzheimer's disease, combined degeneration of nucleus basalis cholinergic and brainstem serotonergic cells decreases the therapeutic effect of nicotine, but not that of tetrahydroaminoacridine.
ESTHER : Riekkinen_1995_Eur.J.Pharmacol_279_65
PubMedSearch : Riekkinen_1995_Eur.J.Pharmacol_279_65
PubMedID: 7556384

Title : Hippocampal atrophy, acute THA treatment and memory in Alzheimer's disease - Riekkinen_1995_Neuroreport_6_1297
Author(s) : Riekkinen P, Jr. , Soininen H , Helkala EL , Partanen K , Laakso M , Vanhanen M , Riekkinen P
Ref : Neuroreport , 6 :1297 , 1995
Abstract : We designed the present study to investigate the hypothesis that progression of hippocampal pathology may decrease the therapeutic effects of anti-cholinesterase drug, tetrahydroaminoacridine, on memory functioning in Alzheimer's disease (AD) patients. Memory, visuoconstructive, executive and vigilance functions were assessed after administration of placebo (p.o.; two placebo sessions) and tetrahydroaminoacridine (one session for 25 and 75 mg, p.o.). Eight patients performed better on list learning test during tetrahydroaminoacridine 75 mg than after placebo or tetrahydroaminoacridine 25 mg. The responders performed during baseline examination better than the non-responders in executive and some declarative memory functions, and had higher MMSE scores than the non-responders. The responders had larger left and right hippocampi than the non-responders. The hippocampal volume correlated with list learning performance. The results suggest that severe hippocampal atrophy may block memory improving effect of an anticholinesterase drug, tetrahydroaminoacridine.
ESTHER : Riekkinen_1995_Neuroreport_6_1297
PubMedSearch : Riekkinen_1995_Neuroreport_6_1297
PubMedID: 7669991

Title : Effects of THA and physostigmine on spatial navigation and avoidance performance in mecamylamine and PCPA-treated rats - Riekkinen_1994_Exp.Neurol_125_111
Author(s) : Riekkinen M , Riekkinen P, Jr.
Ref : Experimental Neurology , 125 :111 , 1994
Abstract : The present study compares the effects of two cholinesterase inhibitors, tetrahydroaminoacridine (THA, 1 and 3 mg/kg) and physostigmine (0.12 and 0.36 mg/kg), on spatial navigation (water maze, WM) and avoidance (step through passive avoidance, PA) performance. THA and physostigmine did not facilitate WM or PA performance in control or p-chlorophenylalanine (PCPA)-treated rats. THA at 3 mg/kg, but not at 1 mg/kg, completely restored the defect in WM and PA performance in rats pretreated with 7.5 mg/kg mecamylamine, a centrally active nicotinic antagonist. Physostigmine completely restored behavior in WM and PA tests at 0.12 and 0.36 mg/kg in mecamylamine-treated rats. In rats pretreated with mecamylamine+PCPA, 3 mg/kg THA to some extent restored WM performance but had no effect on PA retention. Likewise, physostigmine partially restored WM performance but did not facilitate PA retention in mecamylamine+PCPA-pretreated rats. The present study suggests that serotonergic dysfunction may decrease the efficacy of cholinesterase inhibitors to reverse the defect in WM and PA behavior occurring as a consequence of a decrease in activity of nicotinic-mediated functions.
ESTHER : Riekkinen_1994_Exp.Neurol_125_111
PubMedSearch : Riekkinen_1994_Exp.Neurol_125_111
PubMedID: 8307118

Title : Serotonin depletion decreases the therapeutic effect of nicotine, but not THA in medial septal-lesioned rats - Riekkinen_1994_Brain.Res_662_95
Author(s) : Riekkinen P, Jr. , Sirvio J , Riekkinen M
Ref : Brain Research , 662 :95 , 1994
Abstract : The present study compares the effects of systemic pretraining trial injections of a cholinesterase inhibitor, tetrahydroaminoacridine (THA, 1, 3 and 5 mg/kg, i.p.) and nicotine (0.03, 0.1 and 0.3 mg/kg, i.p.) on spatial navigation water maze (WM) and passive avoidance (step-through PA) performance in medial septal (MS)--or MS+p-chlorophenylalanine (PCPA, a serotonin synthesis inhibitor)-lesioned rats. MS-lesion impaired WM and PA acquisition, and serotonin depletion significantly aggravated PA failure of MS-lesioned rats. THA (3 mg/kg) and nicotine (0.1 and 0.3 mg/kg) promoted PA and WM navigation of MS-lesioned rats. THA at a dose of 3 mg/kg improved performance of MS+PCPA-lesioned rats in WM and PA tests, but nicotine did not promote test performance of combined-lesioned rats. This result demonstrates that serotoninergic pathology may decrease the therapeutic effect of nicotine.
ESTHER : Riekkinen_1994_Brain.Res_662_95
PubMedSearch : Riekkinen_1994_Brain.Res_662_95
PubMedID: 7859094

Title : Effects of muscarinic receptor agonists and anticholinesterase drugs on high voltage spindles and slow waves - Riekkinen_1993_Eur.J.Pharmacol_240_1
Author(s) : Riekkinen P, Jr. , Riekkinen M , Fisher A , Ekonsalo T , Sirvio J
Ref : European Journal of Pharmacology , 240 :1 , 1993
Abstract : The effects of muscarinic agonists (AF102B, pilocarpine, oxotremorine) and anticholinesterases (physostigmine, tetrahydroaminoacridine) were investigated on the incidence of thalamically generated rhythmic high voltage spindles and on scopolamine (0.2 mg/kg)-induced neocortical slow wave activity (i.e. increased sum amplitude value of the 1-20 Hz band in a quantitative electroencephalography (qEEG) analysis). AF102B and pilocarpine decreased high voltage spindles and scopolamine increased sum amplitude values at 3 and 9 mg/kg, but not at 1 mg/kg. Oxotremorine was less potent than AF102B or pilocarpine in suppressing high voltage spindles. Oxotremorine had no effect on the scopolamine-induced qEEG changes. Tetrahydroaminoacridine decreased high voltage spindles at 1, 3 and 9 mg/kg and slow waves at 9 mg/kg. Physostigmine decreased high voltage spindles and slow waves at 0.12 and 0.36 mg/kg. Based on the present results we propose that agonists possessing muscarinic M1 receptor activity are effective in decreasing high voltage spindles and scopolamine-induced slow wave activity, but agonists showing predominant muscarinic M2 receptor activity may be less effective in decreasing high voltage spindles and slow waves. Furthermore, tetrahydroaminoacridine decreased high voltage spindles at doses lower than those required to decrease scopolamine-induced slow waves. Physostigmine decreased high voltage spindles and slow waves over the same dose range. This result may indicate that non-cholinergic mechanisms are involved in the tetrahydroaminoacridine-induced decrease in high voltage spindles.
ESTHER : Riekkinen_1993_Eur.J.Pharmacol_240_1
PubMedSearch : Riekkinen_1993_Eur.J.Pharmacol_240_1
PubMedID: 8405117

Title : Effects of nicotine on neocortical electrical activity in rats - Riekkinen_1993_J.Pharmacol.Exp.Ther_267_776
Author(s) : Riekkinen P, Jr. , Riekkinen M , Sirvio J
Ref : Journal of Pharmacology & Experimental Therapeutics , 267 :776 , 1993
Abstract : The present study investigates the effects of acute and repeated nicotine i.p. treatment on cortical EEG activity. Nicotine at 0.3 and 0.9 mg/kg, but not at 0.1 mg/kg, decreased high voltage spindles (HVSs). Nicotine at 2.7 mg/kg suppressed HVSs completely. Mecamylamine, a nicotinic cholinergic antagonist, increased HVSs at 5 and 7.5 mg/kg. Nicotine blocked the HVS induction induced by mecamylamine. Mecamylamine at 1.25 mg/kg antagonized the HVS suppressing action of nicotine at 0.3 mg/kg. The muscarinic cholinergic antagonist, scopolamine (0.2 mg/kg), increased the 1 to 20 Hz amplitude sum value, and this increase was blocked to some extent by the highest dose of nicotine (2.7 mg/kg). However, nicotine did not block the effect of a higher scopolamine (2.0 mg/kg) dose on the sum amplitude values. Mecamylamine at 2.5 and 7.5 mg/kg blocked the effect of nicotine at 2.7 mg/kg on the EEG sum amplitude values in scopolamine (0.2 mg/kg)-treated rats. The peripherally acting nicotinic and muscarinic cholinergic antagonists, hexamethonium and scopolamine methylbromide, had no effect on spectral EEG and HVS values. In quisqualic acid nucleus basalis-lesioned rats, a frontal cortical choline acetyltransferase depletion (-72%) and slowing of the EEG was observed. Nicotine could not restore EEG activity in nucleus basalis-lesioned rats. After repeated (10 days, three injections/day) administration of nicotine, no tolerance to the effects of either nicotine (0.9 mg/kg) on spontaneously occurring HVSs or nicotine (2.7 mg/kg) on the EEG change induced by scopolamine was observed. The present results show that nicotinic receptor stimulation desynchronizes neocortical EEG activity in normal animals, but this action disappears in basal forebrain-lesioned animals. Therefore, it is likely that the effects of nicotine in reversing EEG and behavioral abnormalities observed in Alzheimer's disease may be limited if the basal forebrain cell loss is extensive.
ESTHER : Riekkinen_1993_J.Pharmacol.Exp.Ther_267_776
PubMedSearch : Riekkinen_1993_J.Pharmacol.Exp.Ther_267_776
PubMedID: 8246153

Title : Effects of tetrahydroaminoacridine on spatial navigation of nucleus-basalis- and frontal-cortex-lesioned rats - Riekkinen_1992_Pharmacol.Biochem.Behav_41_637
Author(s) : Riekkinen P, Jr. , Riekkinen M , Sirvio J
Ref : Pharmacol Biochem Behav , 41 :637 , 1992
Abstract : The present study investigates the effects of tetrahydroaminoacridine (THA: 1 and 3 mg/kg) on water maze (WM) spatial learning performance of intact, nucleus-basalis- (NB) lesioned, frontal-cortex- (FR) lesioned, or NB + FR-lesioned rats. NB lesions did not impair WM learning and had no effect on the WM performance deficit in FR-lesioned rats. THA at 1 or 3 mg/kg did not improve WM spatial memory of intact, NB-, FR-, or NB + FR-lesioned rats. These results suggest that 1) the cholinergic NB system is not a prerequisite for frontally mediated acquisition of WM performance, 2) THA treatment does not enhance spatial memory, and 3) THA is not effective in alleviating cognitive deficits induced by degeneration of the frontal cortex.
ESTHER : Riekkinen_1992_Pharmacol.Biochem.Behav_41_637
PubMedSearch : Riekkinen_1992_Pharmacol.Biochem.Behav_41_637
PubMedID: 1584845

Title : Comparative effects of alpha-2 receptor agents and THA on the performance of adult and aged rats in the delayed non-matching to position task - Sirvio_1992_Psychopharmacology.(Berl)_109_127
Author(s) : Sirvio J , Harju M , Riekkinen P, Jr. , Haapalinna A , Riekkinen PJ
Ref : Psychopharmacology (Berl) , 109 :127 , 1992
Abstract : The present study investigated the effects of dexmedetomidine (an alpha-2 adrenoceptor agonist), atipamezole (an alpha-2 adrenoceptor antagonist) and tacrine (an inhibitor of acetylcholinesterase) on the performance of adult and aged rats in a delayed non-matching to position task assessing spatial short-term memory. Most of the aged rats were impaired in the pretraining phases and in the acquisition of the non-delayed version of the task. After a substantial training period of the delayed version of the task, both adult and aged rats reached their asymptotic level of performance. Both adult and aged rats showed a decline in the percent correct responses at the longest delays in this task, and a delay independent decrease in the percent correct responses across the delays (0-30 s) was found in the group of aged rats (25-month-old) as compared to the adults (10-month-old). Dexmedetomidine (0.3, 1.0 or 3.0 micrograms/kg), atipamezole (0.03, 0.3 or 3.0 mg/kg) and tacrine (1.0 or 3.0 mg/kg) did not increase the percent correct responses in adult or aged rats. The highest doses of dexmedetomidine and tacrine decreased behavioural activity of rats during this short-term memory testing. Atipamezole (0.03 mg/kg) increased behavioural activity of rats. The results suggest that acute, systemic administrations of alpha-2 drugs or an anticholinesterase do not improve short-term memory in rats.
ESTHER : Sirvio_1992_Psychopharmacology.(Berl)_109_127
PubMedSearch : Sirvio_1992_Psychopharmacology.(Berl)_109_127
PubMedID: 1365646

Title : Neurophysiological consequences of combined cholinergic and noradrenergic lesions - Riekkinen_1992_Exp.Neurol_116_64
Author(s) : Riekkinen P, Jr. , Riekkinen M , Sirvio J , Riekkinen P
Ref : Experimental Neurology , 116 :64 , 1992
Abstract : The present study investigates the effects of an anti-cholinesterase, tetrahydroaminoacridine (THA), on combined nucleus basalis (NB, quisqualic acid) and dorsal noradrenergic bundle (DNB, 60HDA) lesion-induced high-voltage spindle (HVS) activity. THA at 3 mg/kg, but not at 1 mg/kg, decreased HVS activity in NB- and DNB-lesioned rats. HVS activity in NB- and DNB-lesioned rats treated with THA at 6 mg/kg was lower than in saline-treated controls. In NB-lesioned rats subjected to an additional DNB lesioning, the HVS suppressing effect of THA at 3 mg/kg was decreased. The present results suggest that NB cholinergic and DNB noradrenergic systems interact in the regulation of HVS activity and that the efficacy of an anticholinesterase drug (THA) in reversing NB cholinergic lesion-induced thalamocortical activation deficit is decreased by combined DNB noradrenergic lesion.
ESTHER : Riekkinen_1992_Exp.Neurol_116_64
PubMedSearch : Riekkinen_1992_Exp.Neurol_116_64
PubMedID: 1559565

Title : Tetrahydroaminoacridine inhibits high voltage spindle activity in aged rats after acute and chronic treatment - Riekkinen_1991_Psychopharmacology.(Berl)_103_265
Author(s) : Riekkinen P, Jr. , Aaltonen M , Riekkinen P
Ref : Psychopharmacology (Berl) , 103 :265 , 1991
Abstract : The present study evaluated the ability of tetrahydroaminoacridine (THA) to reverse the age-related increase in high voltage spindles (HVS). THA was injected either 15 or 90 min before EEG recordings were made. A THA dose of 3 mg/kg IP decreased the incidence of HVS, but was ineffective at doses of 0.03 and 1 mg/kg. The HVS suppressing effect of THA (3 mg/kg) declined during a 10-day treatment period. After 10 days chronic THA treatment, a challenge dose of 6 mg/kg of THA reinstated HVS suppressing effect of THA. Our results suggests that (1) THA reverses the age-related deficit of thalamo-cortical activation (2) tolerance develops to THA-induced HVS suppression (3) anti-cholinesterase activity may be important for the efficacy of THA in decreasing HVS because pilocarpine, a muscarinic agonist, also decreased HVS.
ESTHER : Riekkinen_1991_Psychopharmacology.(Berl)_103_265
PubMedSearch : Riekkinen_1991_Psychopharmacology.(Berl)_103_265
PubMedID: 2027925

Title : Tetrahydroaminoacridine alleviates medial septal lesion-induced and age-related spatial reference but not working memory deficits - Riekkinen_1991_Physiol.Behav_49_1147
Author(s) : Riekkinen P, Jr. , Aaltonen M , Sirvio J , Riekkinen P
Ref : Physiol Behav , 49 :1147 , 1991
Abstract : This study examined the effects of tetrahydroaminoacridine (THA, an anticholinesterase) on water-maze (WM) spatial reference (stable platform location during training) and spatial working memory (reversal of platform location) learning in young intact/medial septal (MS)-lesioned and aged rats. THA (1 or 3 mg/kg, IP) had no effect on reference or working memory performance of young intact rats. MS lesions decreased cholineacetyltransferase activity in the hippocampus and also impaired spatial reference and working memory. THA at 3 mg/kg stabilized MS lesion-induced reference memory performance deficit (path length increase), but was ineffective at 1 mg/kg. THA had no effect on the working memory performance of MS-lesioned rats. Aged rats were impaired in spatial reference and working memory tasks. THA at 3 mg/kg partially stabilized the age-induced spatial reference memory deficits, but was ineffective at 1 mg/kg. THA at either 1 or 3 mg/kg did not alleviate the age-related deficit in the working memory version of WM. The present results suggest that some of the age-related WM deficits may be related to the degeneration of the MS-hippocampus cholinergic system and that THA may be effective in stabilizing the reference memory deficits induced by hippocampal cholinergic dysfunction.
ESTHER : Riekkinen_1991_Physiol.Behav_49_1147
PubMedSearch : Riekkinen_1991_Physiol.Behav_49_1147
PubMedID: 1896495

Title : The effects of THA on scopolamine and nucleus basalis lesion-induced EEG slowing - Riekkinen_1991_Brain.Res.Bull_26_633
Author(s) : Riekkinen P, Jr. , Jakala P , Sirvio J , Koivisto E , Miettinen R , Riekkinen P
Ref : Brain Research Bulletin , 26 :633 , 1991
Abstract : The effectiveness of THA (an anticholinesterae) on scopolamine (0.4 mg/kg) and nucleus basalis (NB) lesion-induced change in neocortical spectral electroencephalography (EEG) were investigated. Scopolamine increased the amplitudes of all the spectral components in waking-immobility. In the movement-related EEG spectral values, only the alpha power was increased. THA 7.5 mg/kg, but not THA 3 mg/kg, could reverse scopolamine-induced amplitude change. NB lesioning increased delta and theta amplitudes, but decreased beta amplitude. Delta amplitude was increased during movement recordings in NB-lesioned rats. THA 7.5 mg/kg and pilocarpine 10 mg/kg, but not THA 3 mg/kg, could partially reverse the increase of delta and theta amplitudes induced by NB lesions. However, the beta power decrease could not be restored with cholinomimetics. This study demonstrates that quantitative EEG activity analysis may reflect the THA-induced restoration of the function of the cholinergic nucleus basalis.
ESTHER : Riekkinen_1991_Brain.Res.Bull_26_633
PubMedSearch : Riekkinen_1991_Brain.Res.Bull_26_633
PubMedID: 1868362

Title : Combination of atipamezole and tetrahydroaminoacridine\/pilocarpine treatment suppresses high voltage spindle activity in aged rats - Riekkinen_1991_Brain.Res.Bull_27_237
Author(s) : Riekkinen P, Jr. , Riekkinen M , Jakala P , Sirvioo J , Lammintausta R , Riekkinen P
Ref : Brain Research Bulletin , 27 :237 , 1991
Abstract : The present study evaluated the effects of combined alpha2-antagonist (atipamezole) and anticholinesterase (tetrahydroaminoacridine, THA) or muscarinic agonist (pilocarpine) treatments on the high voltage spindle (HVS) activity in aged rats. On their own, high doses of THA (3 mg/kg), pilocarpine (3 mg/kg) and atipamezole (3 mg/kg) suppressed HVS activity. Low doses of THA (1 mg/kg), pilocarpine (1 mg/kg) and atipamezole (1 mg/kg) did not suppress HVS activity. Combinations of low doses of atipamezole and THA or pilocarpine suppressed HVS activity. Our results suggest that 1) the administration of alpha2-antagonist blocked the age-related deficit of thalamocortical activation, 2) a combination of alpha2-antagonist and a cholinergic drug may more effectively stabilize age-related HVS activity than either of the treatments alone.
ESTHER : Riekkinen_1991_Brain.Res.Bull_27_237
PubMedSearch : Riekkinen_1991_Brain.Res.Bull_27_237
PubMedID: 1683807

Title : Tetrahydroaminoacridine improves passive avoidance retention defects induced by aging and medial septal lesion but not by fimbria-fornix lesion - Riekkinen_1991_Brain.Res.Bull_27_587
Author(s) : Riekkinen P, Jr. , Riekkinen M , Lahtinen H , Sirvio J , Valjakka A , Riekkinen P
Ref : Brain Research Bulletin , 27 :587 , 1991
Abstract : The present study examines whether tetrahydroaminoacridine (THA) can improve the deterioration in passive avoidance (PA) retention performance induced by medial septal (MS) and fimbria-fornix (FF) lesions in young rats or by aging. Retention of young MS-lesioned rats was improved by pretraining injection of THA at 3 mg/kg, but not by THA at 1 mg/kg or by either of the posttraining doses of THA (1 and 3 mg/kg). Pretraining injections of THA at 1 or 3 mg/kg had no effect on the PA retention performance of FF-lesioned rats. Age-induced PA failure was alleviated by pretraining administration of THA at 1 and 3 mg/kg. Posttraining injections of THA (1 or 3 mg/kg) had no effect on PA retention performance of aged rats. These results demonstrate that 1) THA may improve hippocampal cholinergic denervation-induced functional deficits and 2) some of the age-related PA deficits may be due to a cholinergic deficit and can be reversed with THA.
ESTHER : Riekkinen_1991_Brain.Res.Bull_27_587
PubMedSearch : Riekkinen_1991_Brain.Res.Bull_27_587
PubMedID: 1756376

Title : Effects of THA on passive avoidance and spatial performance in quisqualic acid nucleus basalis-lesioned rats - Aaltonen_1991_Pharmacol.Biochem.Behav_39_563
Author(s) : Aaltonen M , Riekkinen P , Sirvio J , Riekkinen P, Jr.
Ref : Pharmacol Biochem Behav , 39 :563 , 1991
Abstract : Bilateral quisqualic acid nucleus basalis (NB) lesions impaired passive avoidance (PA) retention. NB lesions did not impair acquisition performance (stable platform location) in the water maze (WM). However, NB-lesioned rats were impaired in learning the new location of the escape platform in WM. Pretraining injections of tacridine (an anticholinesterase, THA) at 3 mg/kg, but not at 1 mg/kg, slightly improved PA retention performance in NB-lesioned rats. THA (1 or 3 mg/kg) did not alleviate NB lesion-induced WM defect. The results further suggest that loss of NB neurons impair PA acquisition and relearning of the new platform location in WM, and that cholinergic neuron loss may be at least partially involved in the NB lesion-induced performance defect.
ESTHER : Aaltonen_1991_Pharmacol.Biochem.Behav_39_563
PubMedSearch : Aaltonen_1991_Pharmacol.Biochem.Behav_39_563
PubMedID: 1784585

Title : EEG changes induced by acute and chronic quisqualic or ibotenic acid nucleus basalis lesions are stabilized by tacridine - Riekkinen_1991_Brain.Res_559_304
Author(s) : Riekkinen P, Jr. , Sirvio J , Riekkinen M , Riekkinen P
Ref : Brain Research , 559 :304 , 1991
Abstract : The present study investigated the effects of acute (1 week) and chronic (8 months) quisqualic (quis) and ibotenic (ibo) acid nucleus basalis (NB) lesions on the biochemical activity of the NB cholinergic system (choline acetyltransferase (ChAT) activity) and on neocortical EEG activity. Cortical ChAT activity of quis or ibo NB-lesioned rats did not recover during an 8-month period. Acute and chronic quis and ibo NB lesions increased EEG slow waves and high voltage spindles. Tacridine, an anticholinesterase, dose-dependently suppressed acute and chronic quis and ibo NB lesion-induced EEG changes. The present results suggest that NB cholinergic neurons do not recover after excitotoxin-induced damage during an 8-month period and that cholinergic neuron loss is importantly involved in the acute and chronic lesion-induced EEG changes.
ESTHER : Riekkinen_1991_Brain.Res_559_304
PubMedSearch : Riekkinen_1991_Brain.Res_559_304
PubMedID: 1794103

Title : Effects of THA on passive avoidance retention performance of intact, nucleus basalis, frontal cortex and nucleus basalis + frontal cortex-lesioned rats - Riekkinen_1991_Pharmacol.Biochem.Behav_39_841
Author(s) : Riekkinen P, Jr. , Sirvio J , Riekkinen M , Riekkinen P
Ref : Pharmacol Biochem Behav , 39 :841 , 1991
Abstract : Unilateral quisqualic acid lesions of the nucleus basalis magnocellularis (NBM) produced marked choline acetyltransferase depletion (-67% ipsilateral to lesion) and impaired passive avoidance (PA) retention at 24 hours. Pretraining injections of tacrine (THA: 1, 3 and 5 mg/kg), an anticholinesterase, failed to facilitate PA retention in intact rats. However, the retention performance of NBM-lesioned rats was improved by pretraining administration of THA at 3 mg/kg but not at either 1 or 5 mg/kg. Frontal cortex lesioning did not impair PA retention, and THA at 3 mg/kg had no effect on the PA retention of frontal cortex-lesioned rats. THA at 3 mg/kg failed to improve retention performance of NBM + frontal cortex-lesioned rats. After 10 days of chronic treatment with THA, NBM lesion-induced PA retention deficits were partially restored at both 3- and 5-mg/kg doses. The results suggest that 1) the insult to cholinergic neurons in the NBM may be involved in the PA memory consolidation deficit induced by nonselective quisqualic acid lesioning; 2) the beneficial effects of THA on NBM lesion-induced PA retention deficit occur in a narrow dose range; 3) the alleviating effects of THA on NBM lesion-induced PA memory deficits are blocked by frontal cortex lesions; and 4) the dose-response window for THA-induced PA retention performance improvement is broadened by repeated treatment.
ESTHER : Riekkinen_1991_Pharmacol.Biochem.Behav_39_841
PubMedSearch : Riekkinen_1991_Pharmacol.Biochem.Behav_39_841
PubMedID: 1763101

Title : Effects of atipamezole and tetrahydroaminoacridine on nucleus basalis lesion-induced EEG changes - Riekkinen_1991_Brain.Res.Bull_27_231
Author(s) : Riekkinen P, Jr. , Sirvio J , Valjakka A , Riekkinen M , Lammintausta R , Riekkinen P
Ref : Brain Research Bulletin , 27 :231 , 1991
Abstract : In the present study the effect of combined anticholinesterase [tetrahydroaminoacridine (THA)] and alpha2-antagonist (antipamezole) treatment were evaluated on nucleus basalis (NB, quisqualic acid) lesion-induced EEG activity changes. THA (1, 3 and 6 mg/kg; an anticholinesterase) and atipamezole (Ati: 3 and 10 mg/kg; an alpha2-antagonist) suppressed dose-dependently NB lesion-induced high-voltage spindle activity and increase in slow/fast activity ratio. A combination of THA (3 mg/kg) and Ati (3 or 10 mg/kg) more effectively suppressed NB lesion-induced HVS activity than either of the drugs alone did. The present results suggest that alpha2-noradrenergic and NB cholinergic systems interact in the regulation of slow wave and HVS activity and that combined stimulation of these systems more effectively stabilize NB lesion-induced EEG changes.
ESTHER : Riekkinen_1991_Brain.Res.Bull_27_231
PubMedSearch : Riekkinen_1991_Brain.Res.Bull_27_231
PubMedID: 1683806

Title : Modulation of EEG rhythmicity and spike activity in the rat hippocampus by systemically administered tetrahydroaminoacridine, scopolamine and atipamezole - Valjakka_1991_Brain.Res.Bull_26_739
Author(s) : Valjakka A , Lukkarinen K , Koivisto E , Riekkinen P, Jr. , Miettinen R , Airaksinen MM , Lammintausta R , Riekkinen P
Ref : Brain Research Bulletin , 26 :739 , 1991
Abstract : The hippocampal EEG recording electrodes were implanted bilaterally in the hilus of the dentate gyrus (DG) and the stratum radiatum layer of the CA1 area in young (2-3-month-old) and aged (17-20-month-old) rats. In the subgroups of rats, brain noradrenaline (NA) was depleted by DSP-4 neurotoxin (50 mg/kg, IP). The aged animals were included in DSP-4-lesioned group in order to diminish the plastic regeneration of the noradrenergic system which may be more effective in young subjects. All the EEG recordings, after the administration of different agents or vehicle, were made while rats were awake and immobile. Approximately 40% decrease of brain NA had no noticeable effects on the nonrhythmical hippocampal EEG in either age group. In all the rats, compared to the baseline recordings, scopolamine hydrobromide (2 mg/kg, IP, a muscarinic antagonist) increased the incidence of spontaneous EEG spikes, while tetrahydroaminoacridine (THA, 12.5 mg/kg, IP, an acetylcholine esterase inhibitor) decreased the spike activity and induced theta rhythm. Atipamezole (3 mg/kg, SC), a noradrenergic alpha 2-antagonist, increased the baseline amplitude of the nonrhythmical EEG in the DG and increased slightly the spike activity in the CA1 area. The combined blockade of muscarinic receptors by scopolamine (2 mg/kg) and noradrenergic alpha 2-receptors by atipamezole (3 mg/kg) resulted in irregular EEG pattern and corresponding power spectra differed from the scopolamine spectra. The last combination treatment suggests that the effect of atipamezole was not mediated by the secondary cholinergic activation. In the DG, the spectral power increase caused by atipamezole may be related to the increased excitability/bursting liability of granular cells because NA turnover is increased by this agent and NA increases the excitability of granular cells.(ABSTRACT TRUNCATED AT 250 WORDS)
ESTHER : Valjakka_1991_Brain.Res.Bull_26_739
PubMedSearch : Valjakka_1991_Brain.Res.Bull_26_739
PubMedID: 1682015

Title : The effects of THA on medial septal lesion-induced memory defects - Riekkinen_1990_Pharmacol.Biochem.Behav_36_237
Author(s) : Riekkinen P, Jr. , Sirvio J , Riekkinen P
Ref : Pharmacol Biochem Behav , 36 :237 , 1990
Abstract : Electrolytic lesioning of the medial septum (MS) was used to assess the effectiveness of tacrine (THA) in reversing lesion-induced spatial memory deficits in a water-maze. Lesioned animals were injected with either 3 mg/kg or 5 mg/kg of THA intraperitoneally 15 min prior to daily behavioral training. One group of the lesioned and sham-operated animals received saline. All animals underwent two training trials each day for a period of ten days, after which a spatial probe trial was performed and assessed. The accurate placement of MS lesions resulted in lowered acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) activity within the hippocampus of lesioned rats. Lesioning of the MS also impaired the learning performance in locating the escape platform during training and decreased the spatial bias during the probe trial. A lower dose of THA (3 mg/kg) significantly reversed the path length increase and spatial bias decrease induced by MS lesioning, but had no effect on escape latency. However, comparison between the saline- and THA- (5 mg/kg) injected MS-lesioned rats showed no significant differences in either escape latency or spatial bias. The present results support the use of cholinesterase inhibitors in further treatment trials of geriatric memory disorders.
ESTHER : Riekkinen_1990_Pharmacol.Biochem.Behav_36_237
PubMedSearch : Riekkinen_1990_Pharmacol.Biochem.Behav_36_237
PubMedID: 2356195