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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.

The interaction between serotonin (5-HT)1A and nicotinic cholinergic receptors in the regulation of spatial navigation behavior in the Morris water maze (WM) test was studied. Pretraining intraperitoneal (i.p.) injections of a combination of subthreshold doses of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (a 5-HT1A receptor agonist) at 30 micrograms/kg and mecamylamine (a nicotinic cholinergic receptor antagonist) a 2500 micrograms/kg greatly impaired WM navigation to a hidden platform and slightly, but not statistically significantly, impaired WM navigation to a visible platform. Post-training i.p. injections of this combination had no effect on WM navigation performance. Serotonin depletion induced by p-chlorophenylalanine (PCPA) increased the performance impairing action of pretraining injected combination of 8-OH-DPAT 30 micrograms/kg and mecamylamine 2500 micrograms/kg. In trained rats combined injections of 8-OH-DPAT 30 micrograms/kg and mecamylamine 2500 micrograms/kg given pretraining had no effect on the navigation to a hidden platform located in a familiar or in a novel position. Pretraining trial injected combination of hexamethonium 2000 micrograms/kg (a peripherally acting nicotinic antagonist) and 8-OH-DPAT 30 micrograms/kg had no effect on navigation. These data suggest that a combined treatment with a 5-HT1a receptor agonist and a nicotinic cholinergic receptor antagonist more severely impair non-mnemonic acquisition performance processes than consolidation and retrieval processes.

The present study investigated whether an overactive noradrenergic system is related to the impairment in learning/memory in aged subjects. The effects of partial noradrenaline depletion (using the noradrenergic neurotoxin DSP-4) on the acquisition of a water maze task was investigated in young and aged rats, and hippocampal noradrenaline content was correlated with spatial learning performance in similar rats. DSP-4 treatment impaired markedly the acquisition of the water maze task in aged rats, but improved it slightly in young rats. DSP-4 treatment decreased swimming speed, and this effect tended to be more marked in young rats. In the group of control rats, hippocampal noradrenaline tended to correlate positively with spatial bias in aged rats (the rats with the highest noradrenaline content in the hippocampus tended to have the best spatial learning/memory), but negatively in young rats. These results do not support the hypothesis that spatial learning/memory impairment is due to an overactive noradrenergic system in aged rats. Further studies are needed to clarify the reasons of the marked age-related difference in the effects of DSP-4 on the performance of water maze task in rats.

The present study investigates whether the stimulation of gamma-aminobutyric acid (GABA)ergic system affects spatial navigation deficits induced by the lesioning of the nucleus basalis (NB). Thus, the effect of gamma-vinyl-GABA treatment which elevates the GABA levels in brain was studied on water maze task both in unoperated and NB-lesioned (ibotenic acid) rats. The subchronic administration of gamma-vinyl-GABA aggravated dose-dependently NB lesion-induced deficits, although it did not impair the performance of unoperated rats in this task. The imbalance between GABAergic system and cholinergic or non-cholinergic systems of the NB may contribute to spatial navigation deficits in rats.

We compared the effects on spatial learning of an ibotenic acid lesion of the nucleus basalis magnocellularis (NBM), a 5,7-dihydroxytryptamine lesion of the raphe dorsalis (RD) and a combined NBM and RD lesion. The RD lesion reduced serotonin levels, and the NBM lesion reduced cholineacetyltransferase (ChAT) activity in the cortex. Although RD lesions alone did not affect spatial learning in the water-maze, the lesion aggravated the spatial navigation deficit produced by NMB lesioning. The current results a functional interaction between the RD and NBM in spatial navigation.

In the present study we compared the effects of an ibotenic acid lesion of the nucleus basalis magnocellularis (NBM), a 5,7-dihydroxytryptamine lesion of the raphe dorsalis (RD) and a combined RD and NBM lesion on the regulation of neocortical electrical activity in freely moving rat. NBM lesions (choline acetyltransferase decrease: frontal cortex 29%, occipital cortex 23%) increased both slow wave amplitudes and waking immobility-related high-voltage spindles (HVS). Although RD lesions (serotonin decrease: frontal cortex 67%, occipital cortex 68%) alone did not affect neocortical electrical activity, the lesion aggrevated the increase of HVSs induced by an NBM lesion. The present results demonstrate an interaction between the RD and NBM in regulating cortical functions.

Several experimental models of epilepsy have used kainic acid in animals to induce seizures and neuropathological changes which mimic those observed in human temporal lobe epilepsy. These models differ in the location and manner in which kainic acid is applied. In the present study, we characterized the seizure activity and neuropathological changes that occur in awake rats after kainic acid (25 ng/250 nl) is injected into the entorhinal cortex of freely moving rats. In 91% of the animals, this induced generalized motor seizures. Moreover, all of the animals survived status epilepticus. Animals were perfused two weeks after the injection for neuropathological examination. Silver-impregnation revealed that kainic acid caused pyramidal cell damage which was most severe in the CA1 subfield and to a lesser degree in the CA3c area. A loss of NADPH diaphorase-containing neurons in the hilus and the CA1 area was also consistently seen and, in most cases, a population of somatostatin-immunoreactive neurons was diminished. Our findings show that a minute amount of kainic acid delivered directly to the entorhinal cortex on unanesthetized animals reliably produces generalized seizures as well as a consistent pattern of cell damage in the hippocampus. Therefore, this model may be suitable for investigating the mechanisms underlying temporal lobe epilepsy, and may prove useful in assessing different treatment strategies for preventing seizure-induced structural damage.

The present study investigated the effects of repeated daily administration of a mixture containing free fatty acids (α-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 383¯1 + 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.

The possible coexistence of the calcium-binding protein, parvalbumin, with the major inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), and its synthesizing enzyme, glutamate decarboxylase (GAD), was studied in nonpyramidal cells of the rat medial and lateral entorhinal cortex. The material was analyzed by two different methods, the first of which was a mirror techniques where the possible coexistence of two different antigens was analyzed from cells cut in half at the surface of the adjacent section. The other method consisted of analyzing double immunofluorescent-stained sections with a confocal microscope. The colocalization analysis revealed that all parvalbumin-immunoreactive neurons (mirror technique n = 688 and confocal microscopy n = 644) in all layers of the medial and lateral entorhinal cortex were also immunopositive for GABA or GAD. Parvalbumin-cells made up 52% of the GABA cells in most of the layers in the medial and lateral entorhinal cortex. In layer III of the entorhinal cortex, the proportion was about 40%. Thus, parvalbumin-containing neurons in the entorhinal cortex represent a large GABAergic cell population, which is likely to play an important role in controlling both the input and the output of the entorhinal cortex.

Kainic acid (KA)-induced convulsions are accompanied by histopathological changes that are most prominent in the temporal lobe structures. In the present study, we investigated whether a selective alpha2-adrenoceptor agonist, dexmedetomidine could attenuate KA-induced epileptic convulsions and subsequent neuronal damage in the rat hippocampus. Rats were pretreated 30 min before KA injection (9 mg/kg, i.p.) with dexmedetomidine (3 micrograms/kg, s.c.). The behavior of animals was observed for at least 3 h. Dexmedetomidine suppressed the development (p0.001), generalization (p0.05) and severity (p0.01) of convulsions. In addition, histological analysis revealed that dexmedetomidine-treated animals without convulsions or with only partial convulsions had no neuronal damage in the principal cell layers of the hippocampus. A selective alpha2-antagonist, atipamezole (1 mg/kg, s.c.) potentiated KA-induced convulsions and increased the mortality in status epilepticus. In conclusion, the present study demonstrated that dexmedetomidine, in addition to possessing anticonvulsant properties, has a neuroprotective effect in the KA model of status epilepticus.

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.

Fast cyclic voltammetry was used to monitor the release of dopamine in the caudate nucleus following potassium stimulation of the median forebrain bundle and to determine the characteristics of the small basal oxidation current while dipping of an electrode with a large tip (0.3 mm) in the caudate nucleus. The oxidation current was shown to be greater just after the electrode reached the caudate area than at a time 15–20 s after its arrival. There was less current increase observed when the tip reached the cortex and no current was observed in the white matter or with the electrode returning or with repeated passage along the same track. Potassium stimulation of median forebrain bundle induced an initial low magnitude dopamine release which disappeared within minutes. The basal oxidation current increased step by step after a few potassium stimulations. This effect was not blocked by pargyline (75 mg/kg) whereas l -DOPA (200 mg/kg) was shown to increase it. It is thought that the large tip of the lowered electrode can destroy neurons and induce the release of intracellularly stored compounds into the extracellular space. We consider also dopamine to be responsible for the increase in oxidizable current just after the electrode movement stopped.

The present study investigates the effects of concurrent manipulations of nicotinic cholinergic receptors (mecamylamine 10 mg/kg, i.p.) and serotonin neurons (PCPA, 400 mg on each of 4 days) on spatial navigation (water maze, WM) and passive avoidance (PA) performance. PCPA treatment had no effect on WM navigation or PA performance of intact rats, but greatly aggravated mecamylamine induced performance deficit. Either single or combined treatments with hexamethonium (5.0 mg/kg, s.c.) and PCPA had no effect on WM or PA performance. These findings may suggest that nicotinic cholinergic receptors are also importantly involved in the cholinergic-serotonergic regulation of cognitive functioning.

The present study examines the effects of noradrenergic lesions (either DSP-4 i.p. or 6-hydroxydopamine (6-OHDA) into the dorsal noradrenergic bundle on biochemical (noradrenaline (NA), dopamine (DA), serotonin (5-HT) and choline acetyltransferase (ChAT) activity) and cortical EEG (quantitative EEG (qEEG) and high-voltage spindle (HVS)) activity in young and aged rats. Near complete 6-OHDA NA lesions, but not partial DSP-4 NA lesions, increased HVS activity in young rats. DSP-4 and 6-OHDA lesions produced no significant changes in the 5-HT or DA levels or in the ChAT activity in young rats. In some of the aged rats, DSP-4 produced similar biochemical and HVS effects, as it induced in young rats. In the remainder of the aged rats, NA levels were greatly and 5-HT levels slightly decreased. DA levels and ChAT activity were unaltered in either set of aged rats. HVS activity was increased only in that group of aged rats with the greatly lowered NA content. These results suggest that: (1) some of the aged rats are more sensitive to DSP-4 treatment than young adult rats; and (2) NA depletions have to be complete to produce an increase in HVS activity in young and aged rats.

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 and 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.

Sustained stimulation of the perforant path has been shown to damage the CA1 area and impair spatial memory in rats. The pattern of cell death is similar in human epileptics, who also exhibit memory deficits. In this study we demonstrate that the learning/memory impairment in water maze test and the development of interictal spikes that also followed stimulation-induced damage were antagonized by CGP 39551. Pretreatment with this NMDA receptor antagonist also slightly diminished somatostatin cell loss in the hilus but not CA1 pyramidal cell damage. These results indicate that the impairment of spatial learning/memory seems to be dependent not only on the degree of cell degeneration in the CA1 subfield of the hippocampus but also on the frequency of interictal spikes, at least in this model of epilepsy.

The present study investigates the effects of concurrent manipulations of nicotinic cholinergic receptors (nicotinic cholinergic agonist: nicotine 0.03, 0.1, 0.3 mg/kg, nicotinic cholinergic antagonist: mecamylamine 7.5 mg/kg) and serotonin neurons (p-chlorophenylalanine (PCPA), 400/kg mg on each of 3 days) on spatial navigation (water maze, WM) and passive avoidance (PA) performance. Nicotine did not affect PA performance but at the highest dose slightly impaired WM performance. PCPA did not affect WM navigation or PA performance in saline or nicotine-treated rats. Nicotine restored WM and PA performance defect in mecamylamine pretreated rats. PCPA aggravated the WM defect and decreased the WM performance-improving effect of nicotine in mecamylamine pretreated rats. PCPA did not aggravate the PA performance defect of mecamylamine but completely blocked the PA performance-improving effect of nicotine in mecamylamine pretreated rats. These results suggest that serotonergic and nicotinergic cholinergic systems jointly modulate performance in WM and PA tests.

To investigate changes in the somatostatinergic neurons of patients with Alzheimer's disease (AD), we determined the somatostatin-like immunoreactivity (SLI) in post-mortem brain tissue of histopathologically confirmed AD patients and in CSF of probable AD patients (according to DSM III). The CSF values were then correlated with psychological test scores. In 6 AD patients the SLI values were decreased 42% (P less than 0.005) in the frontal cortex, 28% (P less than 0.05) in the temporal cortex and 42% (P less than 0.01) in the parietal cortex but not in the thalamus and putamen compared to 11 control patients. In some brain areas there were statistical correlations between SLI values and cholinergic markers, choline acetyltransferase and acetylcholine esterase activities, suggesting a relationship between these two neurotransmitter systems. In the CSF among 75 AD patients SLI was 35% lower (P less than 0.001) than in controls. Severely demented power (P less than 0.001) than in controls. Severely demented patients showed lower SLI values than moderately demented individuals, but this difference was not significant. There was a weak but statistically significant correlation between SLI values in CSF and neuropsychological test scores. This study further confirms the involvement of somatostatinergic neurons in AD and suggests that this involvement may be related to the progression of dementia symptoms.

Somatostatin-like immunoreactivity (SLI) was measured in cerebrospinal fluid (CSF) of rats kindled by pentylenetetrazol (PTZ) (35 mg/kg, i.p., daily) and saline-injected controls. Interictally the levels of SLI did not differ between the groups. Five minutes after the PTZ-induced generalized convulsion the amount of SLI released into CSF was higher (173%, P = 0.006) in kindled rats than in controls, which agrees with previous findings about elevated brain levels of SLI in kindling.