Nicotine improves AF64A-induced spatial memory deficits in Morris water maze in rats.

Ethylcholine mustard aziridinium ion (AF64A) is a neurotoxic derivative of choline that produces not only long-term presynaptic cholinergic deficits, but also various memory deficits in rats similar to some characteristics observed in Alzheimer's disease patients. This study investigated whether nicotine (NCT) administration attenuated spatial learning deficits induced by intracerebroventricular AF64A treatment. AF64A (6 nmol/6 microl)-or saline (SAL)-treated rats were trained in Morris water maze task. NCT (0.025-0.25mg/kg) was subcutaneously injected 5 min before the training every day. The results showed that moderate dose (0.10mg/kg) of NCT attenuated AF64A-induced prolongation of escape latency. Furthermore, NCT dose-dependently recovered the AF64A-induced decrease of time spent in the target quadrant in the probe test. These results suggest that NCT improves AF64A-induced spatial memory deficits, and thus it is a potential therapeutic agent for the treatment of memory deficits in dementia.

Functional difference between rat perirhinal cortex and hippocampus in object and place discrimination tasks.

The present study was designed to determine the degree of functional dissociation between the rat perirhinal cortex and hippocampus for reference memory performance on object and place discrimination tasks. In one experiment, 30 rats were trained on a two-pair concurrent object discrimination task in an elevated radial arm maze. Rats with a perirhinal cortex lesion needed significantly more days to attain the criterion in the relearning of a pre-operatively acquired object discrimination task than the control rats and rats with a hippocampal lesion. However, there were no significant differences between the three groups in the days to attain the criterion in learning post-operatively the original object discrimination task with new discriminanda and its relearning. The rats with a hippocampal lesion did not show any impairment in object discrimination. In a second experiment, 27 rats were trained on a place discrimination task in the same maze. Rats with a hippocampal lesion required more days to attain the criterion than the control rats to relearn the pre-operatively acquired place discrimination task, and they had fewer correct responses in the first three sessions with new discriminanda than the control rats. Rats with a perirhinal cortex lesion, on the other hand, showed mild relearning impairment. These results suggest that there is a functionally single dissociation between the perirhinal cortex and hippocampus for reference memory performance on object and place discrimination tasks. They also suggest the possible involvement of the perirhinal cortex in spatial reference memory performance.

Repeated treatment with N-methyl-d-aspartate antagonists in neonatal, but not adult, rats causes long-term deficits of radial-arm maze learning.

Brain glutamatergic system is involved in synaptic plasticity as a base for learning and neural development. This study investigated the effects of neonatal and adult chronic antagonism of N-methyl-d-aspartate (NMDA) receptors, a subtype of glutamate receptors, on learning and/or memory. Rats were trained in the radial-maze learning, which is known as a measure of spatial working memory capacities, in adulthood after neonatal or adult repeated treatment of MK-801 (dizocilpine; 5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine), a non-competitive antagonist, or neonatal repeated treatment of CGS 19755 (cis-4-phosphonomethyl-2-piperadine carboxilic acid), a competitive antagonist. Neonatal repeated treatment of MK-801 or CGS 19755 markedly impaired the radial-arm maze learning. In addition, the treatment altered activities differently in the radial-maze and in the open-field. On the other hand, adult repeated treatment with MK-801 affected neither the radial-maze learning nor activities. Results suggest that chronic blockade of NMDA receptors in a neonatal stage may produce long-lasting deteriorative effects on spatial working memory in adulthood.

Compensatory increase in extracellular dopamine in the nucleus accumbens of adult rats with neonatal 6-hydroxydopamine treatment.

To characterize a compensatory function of the dopaminergic system of residual dopamine (DA) neurons in the mesolimbic pathway with DA-depleting lesions, we compared tissue and extracellular concentrations of DA and its metabolites in the nucleus accumbens (NACC) of adult rats with neonatal 6-hydroxydopamine (6-OHDA) treatment with those of control rats with neonatal vehicle treatment using high-performance liquid chromatography. The tissue concentration of DA for 6-OHDA-treated rats was 26.9% of that for the control rats, whereas the extracellular DA was not significantly different from the controls. Furthermore, the extracellular DA concentration in the NACC of 6-OHDA-treated rats was significantly increased compared to the controls following neurotensin (NT) microinjection into the ventral tegmental area (VTA). These results suggest that the extracellular DA of the adult rat brain following neonatal 6-OHDA treatment was compensated for by increasing the release of DA from terminals in the NACC of remaining DA neurons through increased mesolimbic pathway afferents (increased demand), as well as by decreasing the synaptic DA reuptake sites and/or D4 receptors. This study supports our hypothesis that the compensatory mechanism(s) of remaining DA neurons in the mesolimbic system are underlying in behavioral characteristics of adult rats with neonatal depletion of brain DA.

[Rewarding property of nicotine and methamphetamine tested by conditioned place preference in rats: effect of chronic nicotine pretreatment].

Nicotine is classified as a dependence-producing drug. This study investigated the rewarding property of nicotine employing the conditioned place preference (CPP) paradigm in a three-compartment box, and compared it with that of methamphetamine (MAP). In place conditioning using a biased method, rats were placed in one (white or black) compartment under the drug treatment and placed in the other compartment without drug. In the preference test conducted after conditioning, the time spent in the nicotine-paired compartment significantly increased compared with that in the baseline test, suggesting nicotine's rewarding property, although the property was weaker compared with that of MAP. Chronic nicotine pretreatment by a subcutaneous osmotic mini-pump for 7days before place conditioning tended to increase the rewarding property of nicotine, and the possible mechanism of this effect was discussed.

[Effects of neurotensin microinjected into ventral tegmental area on spontaneous motor activity in neonatal 6-hydroxydopamine-treated rats].

Intracerebroventricular treatment of the catecholamine neurotoxin, 6-hydroxydopamine (6-OHDA) after desmethylimipramine pretreatment results in semipermanent brain dopamine (DA) depletion. It has been shown that rats neonatally treated with 6-OHDA show hyperactivity in an open-field test. The purpose of this study was to investigate the spontaneous motor activity in neonatal 6-OHDA-treated rats following bilateral saline (SAL; 0.25 microliter) or neurotensin (NT; 1.25, 2.50, 5.00 micrograms/0.25 microliter/side) microinjection into the ventral tegmental area. Each dose of NT significantly augmented locomotor activity in 6-OHDA-treated rats. On the other hand, controls did not show significant increase in lower dose of NT. Effect of NT microinjection on number of rearings in the 6-OHDA-treated group was not significantly altered compared to the vehicle-treated group. These results suggest that the responses in locomotor activity to NT the ventral tegmental area increase in neonatal 6-OHDA-treated rats, and imply that residual activity in mesolimbic DA neurons which is mediated by NT receptors contributes to a part of the hyperactivity seen after neonatal 6-OHDA lesion.

Perirhinal N-methyl-D-aspartate and muscarinic systems participate in object recognition in rats.

To determine the possible involvement of N-methyl-d-aspartate (NMDA) and muscarinic activation of the perirhinal cortex in object recognition, an NMDA antagonist (d,l-2-amino-5-phosphonopentanoic acid (AP5)) and a muscarinic antagonist (scopolamine) were injected into the perirhinal cortex of rats. A high dose of AP5 (60 mM) and two doses of scopolamine (20 and 80 mM), but not a low dose of AP5 (30 mM) alone, significantly impaired discrimination between novel and familiar objects in a spontaneous object recognition task, which is one of the recognition memory tasks. These results suggest that activation of both NMDA and muscarinic receptors in the perirhinal cortex contributes to object recognition.

[Anxiety-like behavior in rats neonatally and adultly treated with 5,7-dihydroxytryptamine].

A large body of evidence has shown the involvement of serotonin (5-HT) in anxiety. The administration of serotonergic neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) into adult rats has been shown to produce a prolonged reduction in the content of brain 5-HT along with anxiolytic effects. In this experiment, 5,7-DHT was administrated intraventricularly to neonatal and adult rats. All rats were tested in an elevated plus maze at 30, 50, 70, and 90 days old to evaluate the anxiety level. Adult treatment increased the time spent in open-arm, and decreased the brain 5-HT content in all the regions measured. In contrast, neonatal treatment decreased the time spent in open-arm, and 5-HT contents in these animals did not decrease in the hypothalamus and medulla oblongata. A 5-HT syndrome test was conducted once when the rats were 91 to 97 days old to evaluate the sensitivity of 5-HT recepotors. It was found that 5-HTP (25 mg/kg) produces a severe serotonin syndrome in the adult 5,7-DHT-treated rats, but only a moderate syndrome in the neonatal-treated animals. Significant negative correlation coefficients were obtained between the score of serotonin syndrome and 5-HT content in the hypothalamus, midbrain, medulla oblongata, and cerebellum of the neonatal 5,7-DHT-treated rats. The results suggest that neonatal 5,7-DHT treatment produces an anxiogenic effect in contrast with the anxiolytic effect with adult treatment.

Residential maze as a task for testing rats' maze learning ability: effects of hippocampal lesions and cholinergic receptor antagonists.

We investigated whether rats can learn mazes by a procedure in which rats were left in the maze (residential maze) in groups for 1 h a day. Water and food locations, which served as the start and goal boxes respectively in the test trial, were at the opposite ends of the maze. On the test trial conducted everyday before the residence period, animals put in the start box showed a significant decrease of the error response into the blind alleys and running time to reach the goal box. Systemic administration of scopolamine (0.25, 0.5 mg/kg), a muscarinic receptor antagonist, dose-dependently increased the number of errors, but mecamylamine, a nicotinic receptor antagonist, had no effect. Bilateral hippocampal lesions retarded both the acquisition and retention of this maze learning. The results suggest that this residential maze procedure is useful for testing maze learning ability in rats.