Phenobarbital pre-treatment prevents kainic acid-induced impairments in acquisition learning

This study examined the protective effect of phenobarbital on kainic acid-induced deficits in acquisition learning. A single kainic acid injection (9 mg/kg i.p.) was administered five days prior to testing using the Morris water maze test. Kainic acid produced deficits in the acquisition of spatial information observed as an increase in latency to a hidden escape platform. Daily phenobarbital treatment (20 mg/kg i.p.) initiated 45 minutes prior to the kainic acid injection blocked the kainic acid-induced deficits in acquisition learning. When daily phenobarbital treatment was initiated 2-3 hours after kainic acid seizure development it did not block the kainic acid induced-deficits in water maze performance. Daily administration of phenobarbital alone at the moderate concentration used in this study did not cause alterations in behavioral performance in the Morris water maze. These studies indicate that phenobarbital pre-treatment results in a behavioral neuroprotection against kainic acid-induced neurotoxicity.     

Kainic Acid-Induced Decrease in Hippocampal Corticosteroid Receptors

The potential role of excitatory amino acids in the regulation of brain corticosteroid receptors was examined using systemic administration of kainic acid. Administration of kainic acid (5, 10, and 15 mg/kg) to 24-h adrenalectomized rats that were killed 3 h later produced large, dose-related decreases in glucocorticoid receptors (GR) in hippocampus (23-63%), frontal cortex (22-76%), and striatum (41-49%). Kainic acid did not decrease hypothalamic GR. Hippocampal mineralocorticoid receptors (MR) were also markedly decreased (50-71%) by kainic acid. Significant decreases in corticosteroid receptors could be detected as soon as 1 h after kainic acid (10 mg/kg) administration. Decreases in hippocampal, cortical, and hypothalamic GR as well as hippocampal MR were observed 24 h after administration of kainic acid (10 mg/kg) to adrenalectomized rats. Kainic acid (10 mg/kg) also significantly decreased hippocampal GR and MR as well as GR in the other three brain regions when administered to adrenal-intact rats that were subsequently adrenalectomized and killed 48 h after drug administration. The kainic acid-induced decreases in hippocampal GR and MR binding were due to decreases in the maximum number of binding sites (Bmax) with no change in the apparent affinity (KD). Kainic acid when added in vitro did not displace the GR and MR radioligands from their respective receptors. These studies demonstrate that excitatory amino acids play a prominent role in the regulation of hippocampal corticosteroid receptors. In addition, the data indicate that noncorticosterone factors are involved in corticosteroid receptor plasticity.     

Modelling of the parkinsonian syndrome by the administration of kainic acid into the caudate nucleus

The experiments on rats have shown that bilateral administration of kainic acid (0.1-0.15 microgram) into the rostral parts of caudate nuclei led to the development of hypokinesia and rigidity. An increase in the electrical activity--the formation of the generator of pathologically increased excitement (GPIE) was noted in a zone of kainic acid injection. Rigidity and hypokinesia were attenuated and the GPIE activity was depressed after cyclodol (1-10 mg/kg) or L-DOPA (100-200 mg/kg) administration. Combined administration of cyclodol (2 mg/kg) and L-DOPA (50 mg/kg) induced potentiated antiparkinsonian effect. Dopamine microinjections into the GPIE area depressed its activity and abolished rigidity and hypokinesia. These data suggest that the Parkinson syndrome develops under the influence of GPIE induced by kainic acid administration into caudate nuclei.     

Systemic Injection of Kainic Acid Differently Affects LTP Magnitude Depending on its Epileptogenic Efficiency

Seizures have profound impact on synaptic function and plasticity. While kainic acid is a popular method to induce seizures and to potentially affect synaptic plasticity, it can also produce physiological-like oscillations and trigger some forms of long-term potentiation (LTP). Here, we examine whether induction of LTP is altered in hippocampal slices prepared from rats with different sensitivity to develop status epilepticus (SE) by systemic injection of kainic acid. Rats were treated with multiple low doses of kainic acid (5 mg/kg; i.p.) to develop SE in a majority of animals (72–85% rats). A group of rats were resistant to develop SE (15–28%) after several accumulated doses. Animals were subsequently tested using chronic recordings and object recognition tasks before brain slices were prepared for histological studies and to examine basic features of hippocampal synaptic function and plasticity, including input/output curves, paired-pulse facilitation and theta-burst induced LTP. Consistent with previous reports in kindling and pilocapine models, LTP was reduced in rats that developed SE after kainic acid injection. These animals exhibited signs of hippocampal sclerosis and developed spontaneous seizures. In contrast, resistant rats did not become epileptic and had no signs of cell loss and mossy fiber sprouting. In slices from resistant rats, theta-burst stimulation induced LTP of higher magnitude when compared with control and epileptic rats. Variations on LTP magnitude correlate with animals’ performance in a hippocampal-dependent spatial memory task. Our results suggest dissociable long-term effects of treatment with kainic acid on synaptic function and plasticity depending on its epileptogenic efficiency.     

Selective estrogen receptor modulators protect hippocampal neurons from kainic acid excitotoxicity: differences with the effect of estradiol

Neuroprotective effects of estradiol are well characterized in animal experimental models. However, in humans, the outcome of estrogen treatment for cognitive function and neurological diseases is very controversial. Selective estrogen receptor modulators (SERMs) may represent an alternative to estrogen for the treatment or the prevention of neurodegenerative disorders. SERMs interact with the estrogen receptors and have tissue-specific effects distinct from those of estradiol, acting as estrogen agonists in some tissues and as antagonists in others. In this study we have assessed the effect of tamoxifen, raloxifene, lasofoxifene (CP-336,156), bazedoxifene (TSE-424), and 17beta-estradiol on the hippocampus of adult ovariectomized rats, after the administration of the excitotoxin kainic acid. Administration of kainic acid induced the expression of vimentin in reactive astroglia and a significant neuronal loss in the hilus. SERMs did not affect vimentin immunoreactivity in the hilus, while 17beta-estradiol significantly reduced the surface density of vimentin immunoreactive profiles. Estradiol, tamoxifen (0.4-2 mg/kg), raloxifene (0.4-2 mg/kg), and bazedoxifene (2 mg/kg) prevented neuronal loss in the hilus after the administration of kainic acid. Lasofoxifene (0.4-2 mg/kg) was not neuroprotective. These findings indicate that SERMs present different dose-dependent neuroprotective effects. Furthermore, the mechanisms of neuroprotection by SERMs and estradiol are not identical, because SERMs do not significantly affect reactive gliosis while neuroprotection by estradiol is associated with a strong down-regulation of reactive astroglia.     

Glycine modulates N-methyl-D-aspartic acid induced learning facilitation in rats

Summary Pretraining i.p. administration of N-methyl-D-aspartic acid (NMDA) at doses of 10 and 20mg/kg dose-dependently facilitated performance in a water T-maze learning task in rats. The effect of NMDA was inhibited by the competitive NMDA receptor antagonist CGP37849 [(DL)-E(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid] (CGP) at a dose of 6mg/kg, and by the NMDA receptor complex glycine site antagonist 1-hydroxy-3-amino-2-pyrrolidone (HA-966) at a dose of 10mg/kg. The NMDA site antagonist, when given alone, did not impair learning. The glycine precursor milacemide (2-N-pentylaminoacetamide HCl), at doses of 5 and 10mg/kg accelearted learning acquisition and its effect was antagonized by HA-966. The learning rate was impaired following the administration of NMDA 10mg/kg together with milacemide 5mg/kg when compared with the effect of 10mg/kg NMDA alone.The administration of 5mg/kg NMDA was associated with an elevated tissue concentration of aspartate in the hippocampus, an effect which was antagonized by 6mg/kg of CGP. NMDA at doses of 10 and 20mg/kg elevated the concentration of glycine but decreased the concentration of aspartate, glutamate and glutamine in the cortex and aspartate in the hippocampus. The cortical effects of NMDA 10mg/kg were antagonized by 6mg/kg of CGP. Milacemide at the dose of 10mg/kg elevated glycine, aspartate, glutamate and taurine concentrations. The coadministration of 5 mg/kg NMDA with 5mg/kg milacemide elevated the concentrations of glycine, glutamate and glutamine in the cortex and taurine in the hippocampus. These amino acid levels were higher than after administration of 5mg/kg either agent alone. The results demonstrate a dose-dependent facilitation effect on learning performance by NMDA and glycine receptor agonists. Antagonists at the NMDA and glycine sites counteracted the learning improvement of NMDA, and the glycine site antagonist the effect of milacemide.     

Evaluation of the neuroprotective activity of stansin 6, a resin glycoside from Ipomoea stans

Stansin 6 a tetrasaccharide resin glycoside isolated from the root of Ipomoea stans was evaluated as anticonvulsant and neuroprotective in kainic acid-induced seizures of rats. Intraperitoneal injection of kainic acid (10 mg/kg) induced typical behavioral seizures such as wet dog shakes and limbic seizures, and histopathological changes in the hippocampus (degeneration and loss of pyramidal cells in CA1 to CA4 areas). Stansin 6 (10–80 mg/kg) had no effect on the behavior of rats and did not induce hippocampal damage. Pretreatment with stansin 6 inhibited convulsions in rats from kainic acid-induced seizures, reduced the degeneration pattern in the CA3 region, decreased astrocytic reactivity, and reduced the expression of IL-1β and TNF-α induced by kainic acid. These results suggest that stansin 6 possesses neuroprotective and anticonvulsant activities.     

Kainic acid-induced seizures: changes in brain extracellular ions as assessed by intracranial microdialysis

The effect of kainic acid on extracellular [K+], [Ca2+], and [Na+] in the rat piriform cortex and hippocampus was studied by means of intracranial microdialysis. Either a dialysis fiber loop or horizontal Vita fiber were stereotaxically implanted within the piriform cortex or hippocampus, respectively. About 24 h later, fibers were perfused (1 ml/min) with Krebs-Ringer bicarbonate solution. Effluent samples were collected before (four at 30 min intervals), and after (six at 30 min intervals) administration of kainic acid (16 mg/kg, i.p.) or kainic acid vehicle. Kainic acid induced sequential signs of lethargy, staring, "wet-dog shakes," forepaw clonus, and tonic-clonic convulsions. In these awake free-moving rats, kainic acid induced a rapid and prolonged increase in extracellular [K+] and an apparent, but not statistically significant, decrease in extracellular [Ca2+] within the hippocampus. In the piriform cortex, kainic acid induced increases in extracellular [K+] and [Na+], which were associated with early pre-convulsive signs. In contrast to the pronounced ion changes commonly seen when the brain is activated by factors such as local application of excitatory substances or when the brain is made ischemic or hypoxic, extracellular ion concentrations are relatively well maintained during parenteral kainic acid-induced seizures.     

Changes in Cholinergic but Not in GABAergic Markers in Amygdala, Piriform Cortex, and Nucleus Basalis of the Rat Brain Following Systemic Administration of Kainic Acid

Three days after systemic administration of kainic acid (15 mg/kg, s.c.), selected cholinergic markers (choline acetyltransferase, acetylcholinesterase, muscarinic acetylcholine receptor, and high-affinity choline uptake) and GABAergic parameters [benzodiazepine and gamma-aminobutyric acid (GABA) receptors] were studied in the frontal and piriform cortex, dorsal hippocampus, amygdaloid complex, and nucleus basalis. Kainic acid treatment resulted in a significant reduction of choline acetyltransferase activity in the piriform cortex (by 20%), amygdala (by 19%), and nucleus basalis (by 31%) in comparison with vehicle-injected control rats. A lower activity of acetylcholinesterase was also determined in the piriform cortex following parenteral kainic acid administration. [3H]Quinuclidinyl benzilate binding to muscarinic acetylcholine receptors was significantly decreased in the piriform cortex (by 33%), amygdala (by 39%), and nucleus basalis (by 33%) in the group treated with kainic acid, whereas such binding in the hippocampus and frontal cortex was not affected by kainic acid. Sodium-dependent high-affinity choline uptake into cholinergic nerve terminals was decreased in the piriform cortex (by 25%) and amygdala (by 24%) after kainic acid treatment. In contrast, [3H]flunitrazepam binding to benzodiazepine receptors and [3H]muscimol binding to GABA receptors were not affected 3 days after parenteral kainic acid application in any of the brain regions studied. The data indicate that kainic acid-induced limbic seizures result in a loss of cholinergic cells in the nucleus basalis that is paralleled by degeneration of cholinergic fibers and cholinoceptive structures in the piriform cortex and amygdala, a finding emphasizing the important role of cholinergic mechanisms in generating and/or maintaining seizure activity.     

Nicotine improves morphine-induced impairment of memory: possible involvement of N-methyl-D-aspartate receptors in the nucleus accumbens

The possible involvement of N-methyl-D-aspartate (NMDA) receptors in the nucleus accumbens (NAc) in nicotine's effect on impairment of memory by morphine was investigated. A passive avoidance task was used for memory assessment in male Wistar rats. Subcutaneous (s.c.) administration of morphine (5 and 10 mg/kg) after training impaired memory performance in the animals when tested 24 h later. Pretest administration of the same doses of morphine reversed impairment of memory because of post-training administration of the opioid. Moreover, administration of nicotine (0.2 and 0.4 mg/kg, s.c.) before the test prevented impairment of memory by morphine (5 mg/kg) given after training. Impairment of memory performance in the animals because of post-training administration of morphine (5 mg/kg) was also prevented by pretest administration of a noncompetitive NMDA receptor antagonist, MK-801 (0.75 and 1 microg/rat). Interestingly, an ineffective dose of MK-801 (0.5 microg/rat) in combination with low doses (0.075 and 0.1 mg/kg) of nicotine, which had no effects alone, synergistically improved memory performance impaired by morphine given after training. On the other hand, pretest administration of NMDA (0.1 and 0.5 microg/rat), which had no effect alone, in combination with an effective dose (0.4 mg/kg, s.c.) of nicotine prevented the improving effect of nicotine on memory impaired by pretreatment morphine. The results suggest a possible role for NMDA receptors of the NAc in the improving effect of nicotine on the morphine-induced amnesia.     

Effects of kainic acid on messenger RNA levels of IL-1 beta, IL-6, TNF alpha and LIF in the rat brain.

We examined the kainic acid-induced changes of mRNA levels of several cytokines such as IL-1 beta, IL-6, TNF alpha and LIF in the rat brain regions using semiquantitative RT-PCR method. IL-1 beta mRNA was markedly increased in the cerebral cortex (CC), thalamus (THL) and hypothalamus (HT) 2 h after the injection of kainic acid in a convulsive dose (12 mg/kg i.p.), and tended to decrease 4 h after the injection. IL-6 mRNA was weakly induced in the hippocampus (HPP) 2 h after the injection of kainic acid and was markedly increased in the CC, HPP, THL, and HT at 4 h. The level of TNF alpha mRNA was highly elevated in the CC, HPP, striatum (STR), THL and HT at 2 and 4 h after the injection. LIF mRNA apparently expressed in the CC and HPP of control rats and was increased in the CC, HPP and HT by the treatment with kainic acid. These results indicate that mRNAs of several cytokines are increased in various brain regions with different time-courses by kainic acid.     

Adrenalectomy Attenuates Kainic Acid-Induced Spectrin Proteolysis and Heat Shock Protein 70 Induction in Hippocampus and Cortex

Abstract: Glucocorticoids have been shown to exacerbate the damaging effects of a variety of neurotoxic insults in the hippocampus and other brain areas. Evidence suggests that the endangering effects of glucocorticoids may be due to augmenting the cascade of events, such as elevations in intracellular calcium levels, because of excitatory amino acid (EAA) receptor stimulation. A potential mechanism responsible for EAA-induced neuronal damage is activation of calcium-sensitive proteases, such as calpain, which then proteolytically degrade cytoskeleton structural proteins, such as spectrin. The present study was designed to determine if glucocorticoids can regulate the spectrin proteolysis produced by the EAA agonist, kainic acid. Rats were adrenalectomized (ADX) or sham operated and 7 days later injected with kainic acid (10 mg/kg). Twenty-four hours later rats were killed and tissues obtained for western blot analyses of the intact spectrin molecule and the proteolytically derived breakdown products. Kainic acid produced an approximate sevenfold increase in the 145–155-kDa spectrin breakdown products in the hippocampus relative to ADX or sham rats injected with vehicle. ADX attenuated the kainic acid-induced increase in breakdown products by 43%. In a similar way, kainic acid produced a large 10-fold increase in spectrin breakdown products in the frontal cortex, which was also significantly attenuated (?80%) by ADX. Induction of heat shock protein 70 (hsp70) by neurotoxic insults has been suggested to be a sensitive indicator of cellular stress in neurons. Kainic acid induced large amounts of hsp70 in both hippocampus and frontal cortex of sham-operated rats that was markedly attenuated (85–95%) by ADX. There was a strong positive correlation between the amount of spectrin proteolysis and the degree of hsp70 induction in both the hippocampus and frontal cortex. In contrast, kainic acid did not significantly produce spectrin proteolysis and induced only a very modest and inconsistent increase of hsp70 in the hypothalamus. This is consistent with the observation that the hypothalamus is relatively insensitive to the neurotoxic effects of systemically administered kainic acid. The dose of kainic acid (10 mg/kg) used in this experiment produces a 10-fold elevation in circulating corticosterone levels at both 1 and 3 h after administration. These results suggest that part of the endangering effects of glucocorticoids on hippocampal and cortical neurons may be due to augmentation of calpain-induced spectrin proteolysis. The attenuation of kainic acid-induced synthesis of hsp70 by ADX indicates that the cellular stress produced by EAAs is regulated in part by glucocorticoids. In addition, the elevation in endogenous corticosterone levels produced by kainic acid appears to be a significant factor contributing to the neuronal damage produced by this agent.     

Comparison of anticonvulsant effect of ethanol against NMDA-, kainic acid- and picrotoxin-induced convulsions in rats

The anticonvulsant effect of ethanol against N-methyl-D-aspartic acid-(NMDA), kainic acid-, and picrotoxin-induced convulsions was studied in rats. Ethanol (2 g/kg, ip) offered protection against these agents, and it was most effective against picrotoxin and least effective against kainic acid. MK801, NMDA receptor antagonist, also provided protection against these agents. However, it was most effective against NMDA and least effective against kainic acid. Ineffective doses of MK801 (0.1 mg/kg, ip) and ethanol (0.5 g/kg, ip), when administered concurrently, had a facilitatory anticonvulsant effect, thereby providing protection against mortality following severe convulsions induced by NMDA or picrotoxin, but not against kainic acid. The protective effect of ethanol against NMDA- and kainic acid-induced neurotoxicity, in contrast to picrotoxin-induced toxicity, was not reversed by imidazodiazepine, Ro 15-4513, an ethanol antagonist. Furthermore, Ro 15-4513 did not produce any proconvulsant effect with NMDA or kainic acid. These findings suggested that the anticonvulsant actions of ethanol may be attributed to its ability to antagonize NMDA-mediated excitatory responses and facilitate the GABAergic transmission.     

An Electron Spin Resonance Study for Real-time Detection of Ascorbyl Free Radicals After Addition of Dimethyl Sulfoxide in Murine Hippocampus or Plasma During Kainic Acid-Induced Seizures

Electron spin resonance (ESR)-silent ascorbate solutions generate a detectable, likely concentration-dependent signal of ascorbyl free radicals (AFR) immediately upon addition of a molar excess of dimethyl sulfoxide (DMSO). We aimed to perform quantitative ESR analysis of AFR in real time after addition of DMSO (AFR/DMSO) to evaluate ascorbate concentrations in fresh hippocampus or plasma following systemic administration of kainate in mice. Use of a special tissue-type quartz cell allowed immediate detection of AFR/DMSO ESR spectra in fresh tissues from mice. AFR/DMSO content was increased significantly in fresh hippocampus or plasma obtained during kainate-induced seizures of mice, reaching maximum levels at 90 min after intraperitoneal administration of 50 mg/kg kainic acid. This suggests that oxidative injury of the hippocampus resulted from the accumulation of large amounts of ascorbic acid in the brain after kainic acid administration. AFR/DMSO content measured on an ESR spectrometer can be used for real-time evaluation of ascorbate content in fresh tissue. Due to the simplicity, good performance, low cost and real-time monitoring of ascorbate, this method may be applied to clinical research and treatment in the future.     

Characterisation of learning and memory deficits following NMDA receptor antagonism

Summary The effects of the non-competitive NMDA antagonist dizocilpine in tests of cognitive function have been compared with its effects on motor function in rats. Severe motor impairments were observed at doses above 0.1 mg/kg. Dizocilpine (0.075 mg/kg) had no effect on the acquisition of a spatial discrimination task in a Y-maze, but disrupted reversal learning. Both the acquisition and reversal of a visual discrimination task were impaired following dizocilpine (0.075 mg/kg). Dizocilpine (0.04 mg/kg) also disrupted performance of a fivechoice visual reaction time task. It is clear that dizocilpine can impair cognitive function at doses which do not induce pronounced motor dysfunction. The impairment induced by dizocilpine includes a disruption of spatial discrimination learning and a deficit in tasks with sustained attentional demands.     

Impact of estrogen receptor alpha and beta agonists on delayed alternation in middle-aged rats

Estrogens act in the adult brain to modulate cognition, enhancing performance on some learning tests and impairing performance on others. Our previous research has revealed an impairing effect of chronic 17β-estradiol treatment in young and aged rats on a prefrontally-mediated working memory task, delayed spatial alternation (DSA). Little is known about the mechanisms of these impairing effects. The current study examined the effects of selective estrogen receptor (ER) α or ERβ activation on DSA performance in middle-aged female rats. Ovariectomized 12 month old Long–Evans (LE) rats were treated by subcutaneous injection with the ERα agonist propyl pyrazole triol (PPT) or the ERβ agonist diarylpropionitrile (DPN) at 0.02, 0.08, or 0.20 mg/kg/day, or with oil vehicle and tested on an operant variable delay DSA task. A 17β-estradiol group (10% in cholesterol) was included as a positive control group. We replicated our previous finding of a 17β-estradiol induced deficit on DSA performance and this effect was paralleled by low dose (0.02 mg/kg/day) DPN treatment. Higher doses of DPN failed to produce a significant change in performance. The highest dose of PPT (0.20 mg/kg/day) also impaired performance, but this effect was subtle and limited to the longest delay during the final block of testing. These data confirm our earlier findings that chronic 17β-estradiol treatment has an impairing effect on the DSA task, and suggest that ERβ activation may underlie the deficit.     

Impact of estrogen receptor alpha and beta agonists on delayed alternation in middle-aged rats

Estrogens act in the adult brain to modulate cognition, enhancing performance on some learning tests and impairing performance on others. Our previous research has revealed an impairing effect of chronic 17β-estradiol treatment in young and aged rats on a prefrontally-mediated working memory task, delayed spatial alternation (DSA). Little is known about the mechanisms of these impairing effects. The current study examined the effects of selective estrogen receptor (ER) α or ERβ activation on DSA performance in middle-aged female rats. Ovariectomized 12 month old Long–Evans (LE) rats were treated by subcutaneous injection with the ERα agonist propyl pyrazole triol (PPT) or the ERβ agonist diarylpropionitrile (DPN) at 0.02, 0.08, or 0.20 mg/kg/day, or with oil vehicle and tested on an operant variable delay DSA task. A 17β-estradiol group (10% in cholesterol) was included as a positive control group. We replicated our previous finding of a 17β-estradiol induced deficit on DSA performance and this effect was paralleled by low dose (0.02 mg/kg/day) DPN treatment. Higher doses of DPN failed to produce a significant change in performance. The highest dose of PPT (0.20 mg/kg/day) also impaired performance, but this effect was subtle and limited to the longest delay during the final block of testing. These data confirm our earlier findings that chronic 17β-estradiol treatment has an impairing effect on the DSA task, and suggest that ERβ activation may underlie the deficit.     

Morphological changes in the hippocampus following nicotine and kainic acid administration

Using histochemical analysis (NADPH-diaphorase, Fluoro-Jade B dye and bis-benzimide 33,342 Hoechst) we studied the influence of intraperitoneal administration of nicotine (NIC), kainic acid (KA) and combination of both these substances on hippocampal neurons and their changes. In experiments, 35-day-old male rats of the Wistar strain were used. Animals were pretreated with 1 mg/kg of nicotine 30 min prior to the kainic acid application (10 mg/kg). After two days, the animals were transcardially perfused with 4 % paraformaldehyde under deep thiopental anesthesia. Cryostat sections were stained to identify NADPH-diaphorase positive neurons that were then quantified in the CA1 and CA3 areas of the hippocampus, in the dorsal and ventral blades of the dentate gyrus and in the hilus of the dentate gyrus. Fluoro-Jade B positive cells were examined in the same areas in order to elucidate a possible neurodegeneration. In animals exposed only to nicotine the number of NADPH-diaphorase positive neurons in the CA3 area of the hippocampus and in the hilus of the dentate gyrus was higher than in controls. In contrast, KA administration lowered the number of NADPH-diaphorase positive cells in all studied hippocampal areas and in both blades of the dentate gyrus. Massive cell degeneration was observed in CA1 and CA3 areas of the hippocampus and in the hilus of the dentate gyrus after kainic acid administration. Animals exposed to kainic acid and pretreated with nicotine exhibited degeneration to a lesser extent and the number of NADPH-diaphorase positive cells was higher compared to rats, which were exposed to kainic acid only.     

Ramelteon (TAK-375) accelerates reentrainment of circadian rhythm after a phase advance of the light-dark cycle in rats

In vivo pharmacological effects of ramelteon (TAK-375), a novel, highly MT1/MT2-selective receptor agonist, were studied in rats to determine ramelteon's ability to reentrain the circadian rhythm after an abrupt phase advance. Experiments were also conducted to assess the potential cognitive side effects of ramelteon and its potential to become a drug of abuse. After an abrupt 8-h phase shift, ramelteon (0.1 and 1 mg/kg, p.o.) and melatonin (10 mg/kg, p.o.) accelerated reentrainment of running wheel activity rhythm to the new lightdark cycle. Ramelteon (3-30 mg/kg, p.o.) and melatonin (10-100 mg/kg, p.o.) did not affect learning or memory in rats tested by the water maze task and the delayed match to position task, although diazepam and triazolam impaired both of the tasks. Neither ramelteon (3-30 mg/kg, p.o.) nor melatonin (10-100 mg/kg, p.o.) demonstrated a rewarding property in the conditioned place-preference test, implying that MT1/MT2 receptor agonists have no abuse potential. In contrast, benzodiazepines and morphine showed rewarding properties in this test. The authors' results suggest that ramelteon may be useful for treatment of circadian rhythm sleep disorders without adverse effects typically associated with benzodiazepine use, such as learning and memory impairment, and drug dependence.     

Differential effects of acute progesterone administration on spatial and object memory in middle-aged and aged female C57BL/6 mice

The present study examined the effects of acute progesterone administration on hippocampal-dependent memory consolidation in ovariectomized middle-aged (16 months old) and aged (22 months old) female mice. Spatial memory was tested in a 2-day Morris water-maze task and object memory was tested using an object recognition task with 24- and 48-h delays. Immediately after water-maze training, mice received i.p. injections of vehicle, or 5.0, 10.0, or 20.0 mg/kg of water-soluble progesterone. Twenty-four hours later, retention of the platform location was tested. No overnight forgetting of the platform location was observed in middle-aged vehicle-treated mice. Acute progesterone administration had no effect on spatial memory in middle-aged mice. However, aged vehicle-treated mice demonstrated impaired memory for the platform location on Day 2 relative to Day 1. Twenty mg/kg, but not 5 or 10 mg/kg, progesterone reversed these deficits, suggesting that 20 mg/kg progesterone can improve spatial memory in aged females. In the object recognition task, mice explored two identical objects and then immediately received vehicle or progesterone injections. In middle-aged mice, 10 and 20 mg/kg progesterone enhanced object memory consolidation, relative to chance, after 24-h, but all doses were ineffective after 48-h. In aged mice, 10 mg/kg progesterone enhanced object memory consolidation, relative to chance, after 24 h, whereas both 5 and 10 mg/kg progesterone enhanced memory after 48 h. Together, these results indicate that acute progesterone differentially enhances hippocampal-dependent memory in middle-aged and aged females.