Deficits In Radial Maze Performance Research Articles

S32212, a Novel Serotonin Type 2C Receptor Inverse Agonist/α2-Adrenoceptor Antagonist and Potential Antidepressant: II. A Behavioral, Neurochemical, and Electrophysiological Characterization

The present studies characterized the functional profile of N-[4-methoxy-3-(4-methylpiperazin-1-yl)phenyl]-1,2-dihydro-3-H-benzo[e]indole-3-carboxamide) (S32212), a combined serotonin (5-HT)(2C) receptor inverse agonist and α(2)-adrenoceptor antagonist that also possesses 5-HT(2A) antagonist properties (J Pharmacol Exp Ther 340:750-764, 2012). Upon parenteral and/or oral administration, dose-dependent (0.63-40.0 mg/kg) actions were observed in diverse procedures. Both acute and subchronic administration of S32212 reduced immobility time in a forced-swim test in rats. Acutely, it also suppressed marble burying and aggressive behavior in mice. Long-term administration of S32212 was associated with rapid (1 week) and sustained (5 weeks) normalization of sucrose intake in rats exposed to chronic mild stress and with elevated levels of mRNA encoding brain-derived neurotrophic factor in hippocampus and amygdala (2 weeks). S32212 accelerated the firing rate of adrenergic perikarya in the locus coeruleus and elevated dialysis levels of noradrenaline in the frontal cortex and hippocampus of freely moving rats. S32212 also elevated the frontocortical levels of dopamine and acetylcholine, whereas 5-HT, amino acids, and histamine were unaffected. These neurochemical actions were paralleled by "promnemonic" properties: blockade of scopolamine-induced deficits in radial maze performance and social recognition and reversal of delay-induced impairments in social recognition, social novelty discrimination, and novel object recognition. It also showed anxiolytic actions in a Vogel conflict procedure. Furthermore, in an electroencephalographic study of sleep architecture, S32212 enhanced slow-wave and rapid eye movement sleep, while decreasing waking. Finally, chronic administration of S32212 neither elevated body weight nor perturbed sexual behavior in male rats. In conclusion, S32212 displays a functional profile consistent with improved mood and cognitive performance, together with satisfactory tolerance.

Effect of Histamine on Muscimol-Induced Working Memory Deficits in Radial Maze Performance

We investigated the participation of γ-aminobutyric acid (GABA) neurons of the medial septal area in eight-arm radial maze performance in rats. The intra-septal injection of muscimol, a GABAA agonist, caused an increase in total error and working memory error. On the other hand, no significant effect was observed with reference memory error. Donepezil and tacrine (cholinesterase inhibitors) antagonized the muscimol-induced spatial memory deficits. Histidine (1500 mg/kg, i.p.) also improved the total error and working memory error induced by muscimol. At this dose, histidine caused a significant increase in the histamine content of the cortex, hippocampus, and hypothalamus in rats. In addition, the intra-hippocampal injection of histamine also antagonized muscimol-induced spatial memory deficits. The practical conclusion is that the GABAA receptor of the medial septal area plays an important role in working memory, and also, the disturbance of working memory induced by muscimol is mediated not only by cholinergic but also by histaminergic systems in the spatial memory of rats.

This Month in ANESTHESIOLOGY

This Month in ANESTHESIOLOGY

Long-term impairment of acquisition of a spatial memory task following isoflurane-nitrous oxide anesthesia in rats.

The authors demonstrated previously that isoflurane-nitrous oxide anesthesia attenuates performance improvement on an already-learned spatial memory task and that the effect persists for weeks. This experiment was designed to test the hypothesis that learning of new information is particularly susceptible to prolonged disruption after general anesthesia. Six- (n = 5) and 20- (n = 5) month-old male Fischer 344 rats were anesthetized for 2 h with 1.2% isoflurane, 70% nitrous oxide, and 30% oxygen. Age-matched control rats received 30% oxygen and 70% nitrogen (n = 5 per group). Rats breathed spontaneously, and anesthetic and oxygen concentrations were measured. Spatial learning was assessed daily for 21 days on a 12-arm radial maze (RAM) beginning 48 h after anesthesia. In a post hoc experiment to examine locomotion, swim speed was assessed in a separate group of identically treated rats (n = 3 per group) for 4 days beginning 48 h after anesthesia. Aged rats were slower to complete the maze, made fewer correct choices before first error, and made more errors at baseline than young rats (P < 0.05). Anesthesia worsened maze performance in both age groups, as evidenced by increased time to complete the maze and a decreased number of correct choices before first error (P < 0.05), but there were no statistically significant differences in total number of errors. Interestingly, there were no age-by-anesthesia interactions. Aged rats swam slower than adult rats (P < 0.001), but there were no differences between the control and anesthesia groups. Isoflurane-nitrous oxide anesthesia is associated with a persistent deficit in RAM performance that is not explained by impaired locomotion. This impairment occurs in adult and aged rats, indicating that it is not an age-specific phenomenon. Thus, RAM performance is altered after general anesthesia for longer than predicted by the pharmacology of the drugs used, which, by inference, suggests a long-term deficit in learning/memory.

Ameliorative effects of histamine on 7-chlorokynurenic acid-induced spatial memory deficits in rats.

Histamine plays an important role in modulating acquisition and retention in learning and memory process in experimental animals. We examined the effects of polyamine and histamine on the N-methyl- d-aspartate (NMDA) receptor glycine site antagonist 7-chlorokynurenic acid-induced spatial memory deficits in radial maze performance in rats. Effects of histamine (0.5 or 1 nmol/site intracerebroventricularly), spermidine (1 nmol/site, intracerebroventricularly) and spermine (1 nmol/site, intracerebroventricularly) on spatial memory deficit in 9-week-old-male Wistar rats were observed. Both reference and working memory errors occurred in radial maze performance in rats, following intracerebroventricular injection of 7-chlorokynurenic acid (10 nmol/site). Spermidine (1 nmol/site, intracerebroventricularly) or spermine (1 nmol/site, intracerebroventricularly) antagonized 7-chlorokynurenic acid-induced deficits on working memory but not on reference memory errors. Intracerebroventricular histamine (0.5 or 1 nmol/site) or thioperamide (100 nmol/site) also ameliorated 7-chlorokynurenic acid-induced working memory deficits. To determine whether the effects of histamine involve histamine receptors, the effects of some methylhistamines were examined. The effects of R-alpha-methylhistamine on radial maze performance were mimicked by histamine. N(alpha)-methylhistamine had no effect on 7-chlorokynurenic acid-induced memory deficits, whereas 1-methylhistamine, but not 3-methylhistamine reversed 7-chlorokynurenic acid-induced working memory deficits. These results suggest that the amelioration of 7-chlorokynurenic acid-induced working memory deficits by histamine may involve a direct action of histamine at the polyamine sites on NMDA receptors.

Effects of histamine on MK-801-induced memory deficits in radial maze performance in rats

The effects of histamine on the spatial memory deficits induced by MK-801 were investigated using the eight-arm radial maze paradigm in rats. Intracerebroventricular (i.c.v.) injection of histamine or thioperamide, and intraperitoneal (i.p.) injection of histidine improved the spatial memory deficits induced by MK-801. Similar results were obtained with 2-thiazolylethylamine. In contrast, 4-methylhistamine showed no significant effect. Based on these observations, it seems likely that the protective effect of histamine on MK-801-induced spatial memory deficit is mediated by H 1-receptors.

Counteractive effects of a partial (Sabcomeline) and a full (RS86) muscarinic receptor agonist on deficits in radial maze performance induced by S-AMPA lesions of the basal forebrain and medial septal area

After S-AMPA (8.0 mM) lesions to the nucleus basalis and medial septal regions, at the source of the cortical and hippocampal branches of the forebrain cholinergic projection system, rats displayed long-lasting and relatively stable impairment in long-term reference and short-term working memory in both spatial (place) and associative (cue) radial maze tasks. Treatment with four doses of the partial agonist at the M 1 cholinergic muscarinic receptor, sabcomeline (formerly known as SB 202026: 0.01–0.156 mg/kg), substantially reduced working and reference memory errors in both tasks in lesioned rats, in a mainly dose-related manner. These effects were more consistent than those found with the direct muscarinic agonist RS86 (0.05–0.781 mg/kg). The performance of non-lesioned controls was largely unaffected by either treatment. These findings are consistent with previous evidence for cholinergic participation in the radial maze deficits induced by excitotoxic lesions to the forebrain cholinergic projection system. They show that with a relatively selective lesion, which respectively, reduced choline acetyltransferase activity to 36.5 and 22.5% of control level in frontal and dorsolateral cortex, and to 61.8 and 69.2% of control level in dorsal and ventral hippocampus, lesioned rats were responsive to pharmacological treatments aimed to enhance cholinergic function by full or partial agonist activity at M 1 receptors. Findings that nicotine (0.1 mg/kg) also reduced radial maze errors in the lesioned animals supports the suggestion that lesion-induced deficits in radial maze performance were amenable to improvement by cholinergic receptor manipulation. However, given the potential adverse side effects of full receptor agonists, which nonselectively target cholinergic receptors throughout the organism, the functional efficacy of sabcomeline, which shows regional selectivity for the central M 1 receptor subtypes, suggests that deleterious effects of cholinergic depletion on cognition can be counteracted without incurring the risk of unwanted side effects.

Reversal of scopolamine-induced deficits in radial maze performance by (−)-huperzine A: comparison with E2020 and tacrine

The effects of (−)-huperzine A ((5 R,9 R,11 E)-5-amino-11-ethylidene- 5,6,9,10-tetrahydro-7-methyl-5,9-methanocycloocta[ b]pyridin-2(1 H)-one), and of the hydrochloride salt of E2020 (( R, S)-1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]-methyl piperidine) and tacrine (9-amino-1,2,3,4-tetrahydroacridine), on the scopolamine-induced memory deficits in rats were compared in a radial maze, using a 4-out-of-8 baiting procedure. Scopolamine (0.15 mg/kg, i.p.) caused significant impairment in the rats' ability to fulfil the radial maze task. (−)-Huperzine A (0.2–0.4 mg/kg, p.o.; 0.1–0.4 mg/kg, i.p.) had greater efficacy than E2020 (0.6–0.9 mg/kg, p.o.; 0.3–0.6 mg/kg, i.p.) and tacrine (1.5–2.5 mg/kg, p.o.; 0.3–0.6 mg/kg, i.p.) on the improvement of scopolamine-induced working and reference memory errors, respectively. There appeared to be an inverse bell-shape dose-dependent effect for all three compounds tested. The compared data demonstrate that (−)-huperzine A is the most potent and orally active acetylcholinesterase inhibitor of the three, and fits more closely the established criterions for an ideal acetylcholinesterase inhibitor to be used in clinical studies.

Behavioural and neurochemical effects of superior cervical ganglionectomy in rats with septo-hippocampal lesions.

This longitudinal study, extending over 12 months, assessed the behavioural and biochemical effects of hippocampal sympathetic ingrowth (HSI) into the partially denervated hippocampus. Male Long-Evans rats received fimbria-fornix lesions (FIFO) or sham operations at 90 days of age. At the same time half of the rats from each group sustained bilateral ablation of the superior cervical ganglia (SCGX). A battery of behavioural tests, measuring spontaneous alternation, activity in the open field and home cage, and radial-maze performance, were employed, starting after one very short (16 days) and one extended (216 days) post-operative delay. Neurochemical analyses measuring choline acetyltransferase (ChAT) activity, high-affinity choline (HACU) and noradrenaline uptake by hippocampal synaptosomes (HANU), hippocampal noradrenaline ([NA]), serotonin ([5-HT]) and 5-hydroxyindoleacetic acid ([5-HIAA]) concentrations were carried out in a dorsal, a "middle" and a ventral region of the hippocampus. Lesion of the FIFO induced a significant and enduring deficit in radial-maze performance, in addition to a persistent locomotor hyperactivity. ChAT and HACU were significantly depleted in all three regions of the hippocampus at 12 months, and these deficits were negatively correlated with maze performance. SCGX in the presence of the FIFO lesion significantly reduced [NA] in the middle region of the hippocampus, as compared to SCGX rats, and contributed to a restoration of lesion-induced depletions in [5-HT] and [5-HIAA] in the middle and ventral hippocampal regions, whilst failing to elicit any behavioural changes at either time point. It is concluded that if lesion-induced HSI indeed occurred, as is suggested by neurochemical evidence, it had no effect upon the observed behavioural deficits elicited by transection of the FIFO in the rat.

Comparison of the Anticonflict Effect of Buspirone and Its Major Metabolite l-(2-Pyrimidinyl)-Piperazine (1-PP) in Rats

Paeoniflorin, a major constituent of peony root (1 mg/kg, p.o.), attenuated scopolamine-induced deficit in radial maze performance. Both prazosin (0.5 mg/kg, i.p.) and yohimbine (0.3 mg/kg, i.p.) neither impaired radial maze performance by itself nor augmented the scopolamine-induced performance deficit. Prazosin significantly blocked the antagonizing effect of paeoniflorin on the scopolamine deficit, whereas yohimbine did not affect the paeoniflorin effect. These data suggest that the alpha 1-adrenergic but not alpha 2-adrenergic systems are involved in the antagonizing effect of paeoniflorin on the scopolamine deficit in radial maze performance in rats.

Effects of NG-Nitro-L-Arginine on Isolated Rabbit Afferent Arterioles

Paeoniflorin, a major constituent of peony root, has been demonstrated to attenuate the radial maze performance deficit produced by scopolamine. In the present study, to investigate the possible involvement of beta-adrenergic systems in the paeoniflorin antagonism of the scopolamine deficit, the effects of two beta-adrenoceptor antagonists, propranolol and atenolol, on the paeoniflorin effect were examined in male Wistar rats. Paeoniflorin (1 mg/kg, p.o.) significantly attenuated the scopolamine HBr (0.3 mg/kg, i.p.)-induced deficit in the choice accuracy in radial maze performance without changing the running time prolonged by scopolamine. Neither D,L-propranolol HCl, a lipophilic beta-antagonist, at 3 mg/kg, i.p. nor atenolol, a hydrophilic beta 1-antagonist that is known to hardly ever cross the blood-brain barrier, at 1 mg/kg, i.p. impaired maze performance by itself or aggravated the scopolamine-induced deficit in radial maze performance. Both antagonists, however, completely blocked the antagonizing effect of paeoniflorin on the scopolamine deficit. These data suggest that the beta-adrenergic systems, especially peripheral beta 1-adrenergic systems, are involved in the antagonizing effect of paeoniflorin on the scopolamine deficit in radial maze performance in rats.

Involvement of β-Adrenergic Systems in the Antagonizing Effect of Paeoniflorin on the Scopolamine-Induced Deficit in Radial Maze Performance in Rats

Whether anaphylactic histamine release from rat peritoneal mast cells is influenced by betahistine, a histamine H1-receptor agonist/H3-antagonist, and dimaprit, an H2-agonist, was examined. Treatment with dimaprit at 6 and 60 microM for 20 min significantly inhibited the anaphylactic histamine release, whereas betahistine at up to 80 microM under the same conditions did not affect it. Treatment with dimaprit at 6 and 60 microM for 1 to 20 min and for 5 to 20 min, respectively, caused a time-dependent inhibition of the release, but up to 30 min treatment with 8 and 80 microM betahistine had no effect. The decreased histamine release induced by dimaprit was recovered by neither mepyramine nor cimetidine. However, thioperamide, an H3-selective antagonist, dose-dependently restored the diminished release. From these results, the inhibition of anaphylactic histamine release by dimaprit is not produced by the stimulation of H2-receptors, but involves the stimulation of H3-like receptors or H3-subtype receptors, which are distinct from the H3-receptors located in brain, and suggests that the receptor plays an important role in the negative feedback regulation of histamine release.

Involvement of α1-but Not α2-Adrenergic Systems in the Antagonizing Effect of Paeoniflorin on Scopolamine-Induced Deficit in Radial Maze Performance in Rats

The effects of the novel calcium channel antagonist KB-2796, other calcium channel antagonists, an N-methyl-D-aspartate (NMDA) antagonist, non-NMDA antagonists, Mg2+, a Ca(2+)-chelator and a calcium channel agonist on neurotoxicity induced by a 10-min application of 100 microM glutamate were studied in rat hippocampal primary cell cultures. KB-2796 (0.1 and 1 microM), flunarizine (1 microM), nimodipine (10 microM), MK-801 (0.01-1 microM), Mg2+ (10 mM) and EGTA (10 mM) significantly prevented the neurotoxicity, but 6-cyano-7-nitro-quinoxalinedione (CNQX) (10 microM) and 6, 7-dinitro-quinoxalinedione (DNQX) (10 microM) did not. Bay K 8644 (10 and 100 nM) enhanced the neurotoxicity. These findings indicate that KB-2796 protects the neuronal cell from the glutamate-induced neurotoxicity, presumably by blocking the Ca2+ influx into brain neurons.

P-27 - Involvement of β-adrenergic systems in the enhancing effect of paeoniflorin on scopolamine-induced deficit in radial maze performance in rats.

P-27 - Involvement of β-adrenergic systems in the enhancing effect of paeoniflorin on scopolamine-induced deficit in radial maze performance in rats.

The effects of cholinergic drugs and cholinergic-rich foetal neural transplants on alcohol-induced deficits in radial maze performance in rats

Chronic alcohol (20% v/v in drinking water for 28 weeks) impaired acquisition of radial maze spatial and associative tasks by increasing both within-trial working and long-term reference memory errors; animals with high (above the median of 100 mg/100 ml) blood alcohol concentrations (BACs) during treatment were significantly more impaired than those with BACs below the median. Alcohol-treated rats showed improvements in radial maze performance after treatment with cholinergic agonists (arecoline and nicotine) and disruption with antagonists (scopolamine and mecamylamine) at low doses which did not affect controls. These effects were more pronounced for working than reference memory, and not manifest with the peripherally acting antagonists hexamethonium and N-methylscopolamine. Transplants into cortex and hippocampus of cholinergic-rich basal forebrain (BF) and ventral mesencephalon (VM) foetal neural tissue improved radial maze performance of alcohol-treated rats to control level over a period of 9-12 weeks after grafting. Cholinergic-poor foetal hippocampal (HC) grafts were without effect. BF and VM, but not HC, grafts showed dense acetylcholinesterase (AChE) staining, tyrosine-hydroxylase staining was most pronounced in VM sections and dopamine-beta-hydroxylase staining was minimal in all grafts. Choline acetyltransferase (ChAT) activity was significantly reduced in cortex and hippocampus of alcohol-treated rats, except those given cholinergic-rich transplants. Alcohol treatment also significantly reduced AChE-positive cell counts in the nucleus basalis, medial septal and diagonal band brain areas, at the sources of the forebrain cholinergic projection system (FCPS). Cortical levels of noradrenaline were significantly reduced in all alcohol-treated rats, regardless of transplant, whereas cortical dopamine content was significantly elevated in all rats receiving transplants, regardless of behavioural effect, but not in alcohol-treated controls. Forebrain serotonin levels were not significantly altered by grafting or alcohol treatment. These results suggest that damage to the FCPS, as shown by reduced ChAT activity in target areas, and reduced AChE cell counts in projection areas, played an important part in the radial maze deficits displayed by alcohol-treated rats, since these animals were sensitive to cholinergic drug challenge, and cholinergic-rich transplants from two different sites in foetal brain elevated ChAT activity and restored cognitive function. In contrast alcohol- or graft-induced alterations in other transmitter systems did not correlate with the pattern of behavioural deficit and recovery.

Radial maze performance following hippocampal kindling

The relation between hippocampal epileptiform activity and 8-arm radial maze performance was assessed following repetitive afterdischarges (ADs) evoked by stimulation of the hippocampal CA1 region (kindling). Hippocampal kindling, whether to stage V (generalized) convulsions or to a preconvulsive stage, induced deficits in radial maze performance, evaluated by correct arm entries in 8 choices or total maze run (trial) time. The deficits persisted at least until 21 days after the last AD. Hippocampal interictal spikes (ISs) were induced by kindling, but the rate of ISs declined to near zero in a few days. The rate or presence of ISs was not related to maze performance.

Age-dependent deficits in radial maze performance in the rat: Effect of chronic treatment with acetyl- l-carnitine

1. An eight-arm radial maze was the experimental model used to investigate spatial learning in rats of different ages and in old rats treated with Acetyl-L-Carnitine. 2. Extramaze visual cues were minimized in order to study the rat's ability to perform using a strategy. 3. The experimental findings indicated a deterioration of the old rat's ability to learn and solve the radial maze. 4. Long-term treatment (8 months) with Acetyl-L-Carnitine was found to antagonize such a deterioration.