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.

Alpha2-adrenergic agonist clonidine for improving spatial working memory in Parkinson's disease.

The loss of dopaminergic cells during Parkinson's disease (PD) produces "frontal"-like impairment in spatial working memory (SWM) and planning functions. This study investigated whether an alpha2-adrenergic agonist, clonidine (0.5 or 2 microg/kg, orally), improves SWM, spatial short-term or spatial recognition memory, and planning functions in PD patients. Clonidine 2 microg/kg decreased errors in SWM, but a lower dose, 0.5 microg/kg, had no effect on performance. Clonidine 0.5 and 2 microg/kg failed to improve the strategy used to solve the SWM test. Clonidine 0.5 and 2 microg/kg had no effect on accuracy of performance in the other tests. These results showed that clonidine improves performance in a test of SWM and that this is not due to improved spatial short-term or spatial recognition memory or planning functions. The authors suggest that stimulation of alpha2-adrenoceptors improves the mnemonic processing required for accurate SWM performance in PD patients.

Clonidine, but not guanfacine, impairs choice reaction time performance in young healthy volunteers.

The present study compares the effects of two alpha 2-adrenoceptor agonists, clonidine (0.5, 2, and 5 micrograms/kg, p.o.), and guanfacine (7 and 29 micrograms/kg, p.o.), in young healthy volunteers on attentional performance. A placebo-controlled double-blind cross-over design (one drug dose/group) was employed. Neither of the drugs affected measures of motor performance or performance at easy levels in an attentional test. However, at the most difficult level in the attentional test, the highest dose of clonidine (5 micrograms/kg), but not guanfacine, decreased the number of correct responses and increased reaction latency. Clonidine 5 and guanfacine 29 micrograms/kg equally increased subjective feelings of sedation and reduced systolic and diastolic blood pressures. Thus, the effects of the drugs on attentional performance could be dissociated from their sedative effects. The results demonstrate that clonidine, but not guanfacine, disrupts performance in an attentional task requiring effortful processing, while leaving performance intact in tests requiring more automatic processing. The lower alpha 2A-vs. alpha 2C-adrenoceptor selectivity ratio of clonidine and the affinity for alpha 1-adrenoceptors of clonidine may be responsible for the different action of these drugs on attention.

Clonidine impairs sustained attention and memory in Alzheimer's disease.

We investigated the effect of the alpha2-agonist, clonidine (orally: 0.5 and 2 microg/kg), administration on parameters assessing attention and short-term recognition memory in Alzheimer's disease patients. Clonidine 2 microg/kg, but not 0.5 microg/kg, disrupted memory accuracy in delayed matching to sample test delay-dependently in nine out of 28 patients. The volumes of the hippocampus and the entorhinal cortex of those Alzheimer's disease patients who were sensitive to clonidine administration were larger than those whose performance was unaffected by clonidine. These two groups of Alzheimer's disease patients performed equally in measures of attention after placebo or clonidine administration. Clonidine 2 microg/kg disrupted attention only at levels of testing that were demanding for the individual patients. Our results suggest that the disruptive effect of clonidine on short-term memory in Alzheimer's disease patients may be mediated via the hippocampus and the entorhinal cortex. Furthermore, the deleterious effect of clonidine on effortful attention is mediated via different brain systems from those involved in the modulation of memory function.

The alpha2 agonist, clonidine, improves spatial working performance in Parkinson's disease.

Previous work has shown that the dopaminergic defect in Parkinson's disease is involved, to some extent, in the "frontal"-like impairment in spatial working memory and attentional set-shifting functions. We investigated whether an alpha2 agonist, clonidine (0.5 and 2 microg/kg, per os), could alleviate spatial working memory and attentional set-shifting defect in Parkinson's disease patients. We observed that 2 microg/kg clonidine stimulated spatial working memory accuracy, but had no effect on attentional set shifting or visual recognition memory. Clonidine was also effective in stimulating spatial working memory after withdrawal of dopaminergic drugs, and when this was done, its effect was greater in severe Parkinson's disease patients. In contrast, clonidine failed to stimulate visual recognition memory. These results suggest that disrupted activation of alpha2 adrenoceptors may contribute to the impairment of spatial working memory in Parkinson's disease.

Guanfacine, but not clonidine, improves planning and working memory performance in humans.

The present study compares, using a double-blind, placebo controlled design the effects of two alpha 2-agonists, clonidine (0.5, 2, and 5 micrograms/kg) and guanfacine (7 and 29 micrograms/kg) on spatial working memory, planning and attentional set-shifting, functions thought to be dependent on the "central executive" of the prefrontal cortex. Blood pressure and the subjective feeling of sedation were affected equally by clonidine and guanfacine. The 0.5 microgram/kg and 5 micrograms/kg doses of clonidine disrupted spatial working memory, but the medium dose had no effect. The 0.5 and 2 micrograms/kg doses of clonidine increased impulsive responding in the planning test. The 5 micrograms/kg dose of clonidine slowed responding at effortful levels of planning and attentional set-shifting tests. The 29 micrograms/kg dose of guanfacine improved spatial working memory and planning. Guanfacine had no effect on attentional set-shifting. These data indicate that guanfacine improved planning and spatial working memory, but clonidine dose-dependently disrupted performance. It is possible that the greater selectivity of guanfacine for alpha 2A-adrenoceptor subtype may underlie its differences from clonidine.

THA improves word priming and clonidine enhances fluency and working memory in Alzheimer's disease.

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.

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.

Guanfacine and clonidine, alpha 2-agonists, improve paired associates learning, but not delayed matching to sample, in humans.

The present study compares the effects of two alpha 2-agonists, clonidine (0.5, 2, and 5 micrograms/kg, p.o.) and guanfacine (7 and 29 micrograms/kg, p.o.) in young healthy volunteers on their performance in visual paired associates learning (PAL) and delayed matching to sample (DMTS) visual short-term recognition memory tests. In the PAL test, clonidine 2 and guanfacine 29 micrograms/kg improved the subjects' performance. In the DMTS test, clonidine at 5 micrograms/kg delay-dependently impaired performance accuracy, and at 2 and 5 micrograms/kg it also slowed responses. Guanfacine had no effect on DMTS test performance. Clonidine 5 and guanfacine 29 micrograms/kg equally increased subjective feelings of sedation and reduced blood pressure. The results suggest that both clonidine and guanfacine facilitated PAL learning by improving "frontal strategies," but only clonidine disrupted "mneomonic processing" decreasing DMTS accuracy. The greater selectivity of guanfacine for alpha 2A-adrenoceptor subtype may explain the different profile of action of the drugs.

D-cycloserine, a partial NMDA receptor-associated glycine-B site agonist, enhances reversal learning, but a cholinesterase inhibitor and nicotine has no effect.

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.

Reduction of noradrenaline impairs attention and dopamine depletion slows responses in Parkinson's disease.

We investigated the role dopamine and noradrenaline in the modulation of attention in Parkinson's disease (PD) patients. We observed that PD patients with mild and moderate motor disability did not differ in their attentional accuracy in easy tests, but the severe PD group was slightly disrupted in a more arduous test of attention. Attentional accuracy was not affected by withdrawal of dopaminergic drugs in mild or severe PD patients. The movements of severe PD patients were slower, and withdrawal of dopaminergic drugs aggravated motor slowing more in severe PD patients. Clonidine (0.5 and 2 microg/kg) retarded accuracy of performance in the most difficult attention test in mild PD patients, but had no effect in the severe PD group. Clonidine had no effect on movement times. These data suggest that a defect in noradrenaline release may contribute to the impaired accuracy of attention in severe PD patients and that dopamine may be important for maintaining rapid motor responding.

Hippocampal atrophy is related to impaired memory, but not frontal functions in non-demented Parkinson's disease patients.

We investigated the neuropsychological correlates of hippocampal atrophy in Parkinson's disease (PD) patients. The memory impaired PD patients had smaller hippocampi than other PD patients. The performance of PD patients in spatial working memory and attentional set-shifting correlated with the severity of motor defect, and not with hippocampal atrophy. Our results suggests that failure of verbal/visual memory may be related to hippocampal atrophy in Parkinson's disease. On the contrast, the defect in spatial working memory and attentional set-shifting may be sensitive to dysfunction of 'fronto-striatal' systems in PD patients.

Tetrahydroaminoacridine, a cholinesterase inhibitor, and D-cycloserine, a partial NMDA receptor-associated glycine site agonist, enhances acquisition of spatial navigation.

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.

Tetrahydroaminoacridine and D-cycloserine stimulate acquisition of water maze spatial navigation in aged rats.

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.

The role of the dorsal raphe-serotonergic system and cholinergic receptors in the modulation of working memory.

The present study investigated the role of the dorsal raphe-serotonergic system and its interaction with muscarinic or nicotinic receptors in the modulation of working memory and motor activity by assessing the effects of serotonin lesion with pCA and cholinergic receptor blockade on the performance of rats in a working memory (delayed non-matching to position, DNMTP) task. The pCA lesion did not impair the choice accuracy or motor activity of rats in the DNMTP-task. The lower dose of scopolamine (0.075 mg/kg) impaired percent correct responses already at the shortest delay which is not indicative of a working memory impairment per se. Scopolamine also disrupted motor activity markedly. The effects of scopolamine 0.075 mg/kg on the choice accuracy were aggravated by pCA treatment. Furthermore, the effects of N-methylscopolamine (0.150 mg/kg) were comparable with scopolamine. The higher dose of mecamylamine (3.0 mg/kg) also interfered with motor activity and it decreased the choice accuracy. The performance disruption induced by mecamylamine was not as severe as that seen with scopolamine. Mecamylamine did not reveal any interaction with the serotonergic lesion. Hexamethonium slightly decreased the percent correct responses, while not interfering with motor activity of rats. The present results suggest that: (i) lesion of serotonergic fibers with pCA does not significantly impair the choice accuracy or interfere with motor activity of rats; (ii) the blockade of cholinergic receptors does not impair working memory per se, but disrupts motor activity, and (iii) pCA lesion of serotonergic fibers aggravates the non-mnemonic choice accuracy impairment induced by central muscarinic blockade, while not interacting with the cholinolytics in modulation of motor activity.

Tetrahydroaminoacridine improves the recency effect in Alzheimer's disease.

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.

Frontal dysfunction blocks the therapeutic effect of THA on attention in Alzheimer's disease.

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.

Effects of stimulation of alpha 1-adrenergic and NMDA/glycine-B receptors on learning defects in aged rats.

The present study was designed to investigate the efficacy of stimulation of alpha1-adrenoceptors and the strychnine insensitive glycine-B binding sites of the N-methyl-D-aspartate (NMDA) receptor complex to alleviate the age-related defect in water maze (WM) spatial (hidden platform) navigation. We found that daily pretraining IP treatment with 2-(2-chloro-5-trifluoromethylphenylamino) imidazole nitrate (ST 587), an alpha1-adrenoceptor agonist, at 3000 micrograms/kg, but not at 1000 micrograms/kg, facilitated acquisition of water maze spatial navigation in aged rats. However, ST 587 3000 micrograms/kg (IP) did not stimulate WM spatial reversal learning or cue navigation to a visible platform in aged rats. A partial strychnine insensitive glycine-B binding site agonist, D-cycloserine (DCS) at 10000 micrograms/kg stimulated acquisition of WM navigation, but had no effect on reversal learning or cue navigation. DCS at 1000 or 3000 micrograms/kg (IP) had no marked effect on WM spatial navigation, and did not enhance the WM performance improving effect of ST 587 in aged rats. A subthreshold dose of ST 587 1000 micrograms/kg did not enhance the therapeutic effect of DCS 1000 micrograms/kg. The present results indicate that activation of alpha1-adrenoceptors and glycine binding sites of NMDA receptor may to some extent alleviate the age-related defect in spatial navigation. DCS treatment does not enhance the therapeutic effects of ST 587 and vice versa.

Behavioral characterization of metrifonate-improved acquisition of spatial information in medial septum-lesioned rats.

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.

Effects of combined chronic nimodipine and acute metrifonate treatment on spatial and avoidance behavior.

The present experiment was designed to elucidate whether chronic dietary treatment with nimodipine (3 months, 1000 ppm) enhances water maze spatial navigation, passive avoidance behavior and locomotor activity, and whether such a treatment with nimodipine would interact with the therapeutic effect of acute metrifonate treatment. In young medial septum-lesioned rats, nimodipine had no effect by its own on cognitive or motor behavior, and did not enhance the water maze and passive avoidance behavior improving action of metrifonate (3 and 10 mg/kg. p.o.). Nimodipine treatment of aged rats did not markedly affect the deficit in motor performance. Single and combined nimodipine and metrifonate (3 and 10 mg/kg, p.o.) treatment of aged rats resulted in shorter escape distance values to the hidden water maze escape platform compared to those of control aged rats. The passive avoidance performance of aged rats was more effectively facilitated by a combined nimodipine and metrifonate treatment than by either of the drugs on their own. Following a washout period of 2.5 months the rats that were treated previously with nimodipine no longer performed better than aged controls in the water maze test. Furthermore, after the washout period metrifonate 10 mg/kg was no longer effective in improving the water maze behavior of the now 26-month-old rats irrespective of their chronic pretreatment. Taken together, these findings indicate that chronic nimodipine and acute metrifonate treatment may more effectively stimulate cognitive functioning than either of the treatments on their own.