Minna Riekkinen

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 α2-agonists, clonidine (0.5, 2, and 5 μg/kg) and guanfacine (7 and 29 μg/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 μg/kg and 5 μg/kg doses of clonidine disrupted spatial working memory, but the medium dose had no effect. The 0.5 and 2 μg/kg doses of clonidine increased impulsive responding in the planning test. The 5 μg/kg dose of clonidine slowed responding at effortful levels of planning and attentional set-shifting tests. The 29 μg/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 α2A-adrenoceptor subtype may underlie its differences from clonidine.

Guanfacine and Clonidine, Alpha2-Agonists, Improve Paired Associates Learning, but not Delayed Matching to Sample, in Humans

The present study compares the effects of two alpha2-agonists, clonidine (0.5, 2, and 5 μg/kg, PO) and guanfacine (7 and 29 μg/kg, PO) 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 μg/kg improved the subjects’ performance. In the DMTS test, clonidine at 5 μg/kg delay-dependently impaired performance accuracy, and at 2 and 5 μg/kg it also slowed responses. Guanfacine had no effect on DMTS test performance. Clonidine 5 and guanfacine 29 μg/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 “mnemonic processing” decreasing DMTS accuracy. The greater selectivity of guanfacine for alpha2A-adrenoceptor subtype may explain the different profile of action of the drugs.

Neocortical, hippocampal and septal parvalbumin- and somatostatin-containing neurons in young and aged rats: Correlation with passive avoidance and water maze performance

Aged (26-month-old) rats were impaired compared with young (three-month-old) rats in passive avoidance and water maze tasks. In order to study whether changes in inhibitory circuits are involved in these age-related cognitive impairments, the number of two different subpopulations of GABAergic neurons, i.e. somatostatin- and parvalbumin-containing neurons, were counted in the hippocampal formation, septum and neocortex. We found that the number of parvalbumin-containing neurons was decreased in the entorhinal, somatosensory and motor cortex as well as in the medial septum and vertical limb of the diagonal band of Broca, but not in the hippocampus of aged rats. Somatostatin-containing neurons were affected in the somatosensory and motor cortex, and in the dorsolateral septum, but not in the hippocampus or in the entorhinal cortex. The decreased number of parvalbumin-containing neurons in the entorhinal cortex of the aged rats correlated with their performance deficits in passive avoidance and spatial learning. We propose that impaired functioning of the entorhinal cortex parvalbumin-containing inhibitory neurons may, to some extent, be responsible for the learning and memory defects found in aged rats.

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 Parkinsons 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 Parkinsons 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.

Loss of cholinergic neurons in the nucleus basalis induces neocortical electroencephalographic and passive avoidance deficits.

The present experiments were designed to examine the hypothesis that the degeneration of cholinergic nucleus basalis is related to the cognitive and neurophysiological deficits found in old age. Aged (26 months) rats were impaired both in the acquisition of spatial (water-maze) task and retention of passive avoidance task. During aging, neocortical electroencephalographic fast activity was decreased and high-voltage spindles increased. Loss of choline acetyltransferase-positive neurons correlated with the high-voltage spindle incidence and passive avoidance retention deficit. Unilateral ibotenate nucleus basalis lesioning decreased choline acetyltransferase activity in the cortex and produced a large nonspecific subcortical cell loss in young rats. Ibotenate-lesioned rats were impaired in spatial learning and passive avoidance retention in young rats. Quisqualic acid produced a greater decrease in cortical choline acetyltransferase activity and smaller nonspecific subcortical cell loss than ibotenate lesioning. Spatial learning was not impaired, but passive avoidance performance was disrupted. Slow waves and high-voltage spindles were increased and beta activity decreased on the side of either quisqualate or ibotenate nucleus basalis lesioning. These results demonstrate that age-related neurophysiological and cognitive deficits result partially from the loss of cholinergic neurons in the nucleus basalis and that quisqualic acid nucleus basalis-lesioning in young rats may be used as a pharmacological model of the age-related cholinergic neuron loss.

Effects of scopolamine infusions into the anterior and posterior cingulate on passive avoidance and water maze navigation

We examined the role of anterior and posterior cingulate cortical muscarinic receptors in water maze spatial learning and passive avoidance. Pretraining and posttraining trial scopolamine (a mixed a muscarinic acetylcholine antagonist) infusions into the anterior cingulate cortex dose dependently (3 no effect; 10 and 30 micrograms impaired) impaired passive avoidance performance. Pretesting infusion into the anterior cingulate had no effect on passive avoidance. Scopolamine infusion into the anterior cingulate did not impair spatial navigation. On the contrary, scopolamine (3 micrograms no effect, 10 and 30 micrograms impaired) infusions into the posterior cingulate before daily training trials impaired water maze navigation to a hidden platform, but did not affect navigation to a visible escape platform or passive avoidance. Posttraining and pretesting infusion into the posterior cingulate did not impair WM spatial navigation. The present results indicate that muscarinic acetylcholine receptor antagonist may modulate passive avoidance performance via cholinergic receptors located in anterior cingulate cortex and the ability to develop a spatial navigation strategy via muscarinic receptors located in posterior cingulate.

Metrifonate improves spatial navigation and avoidance behavior in scopolamine-treated, medial septum-lesioned and aged rats

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.

Dorsal hippocampal muscarinic acetylcholine and NMDA receptors disrupt water maze navigation

THE present study investigated the effects of bilateral dorsal hippocampal infusions with muscarinic acetylcholine (scopolamine; 3 and 10 μg per hemisphere) and N-methyl-D-aspartate (NMDA) (CPP; 0.01 and 0.03 μg per hemisphere) antagonists on acquisition (drug delivered before daily training), consolidation (drug delivered after daily training) and retrieval (drug delivered only before spatial bias test) performance in a water maze (WM) spatial navigation test. Scopolamine 10 μg disrupted acquisition, but had no effect on consolidation or retrieval. CPP 0.03 μg disrupted acquisition and retrieval behaviour. A combination of subthreshold doses of CPP (0.01 μg) and scopolamine (3 μg) disrupted acquisition performance. The treatments did not disrupt navigation to a clearly visible escape platform. The present data indicate that dorsal hippocampal NMDA and muscarinic acetylcholine receptors are important for spatial navigation behaviour.

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.

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 Parkinsons 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 μg/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.