Sex differences in memory performance in the object recognition test. Possible role of histamine receptors

The mnemonic performances of male and female rats were compared in an object recognition test. Females were still able to recognize a previously identified object after a 90-min between-trial interval, compared with only 60 min in the males. Because histamine (HA) involvement in memory processes has been strongly suggested, the effect of H3-HA autoreceptor antagonist thioperamide was investigated. This drug was found to produce a dose-dependent promnestic effect in both sexes, but it did not influence the time course of memory retrieval. These behavioral data were compared to the density of H1-HA, H2-HA, and H3-HA receptors in cortical membranes. The densities of H1-HA and H2-HA receptors were greater in the females, whereas that of H3-HA was substantially the same in both sexes. The behavioral effect of thioperamide was very similar in both sexes, and this agrees with a similar H3-HA receptor density; however a better memory performance might have been expected in the female after thioperamide treatment (in view of different H1-HA and H2-HA receptor density), but this was not found. Because thioperamide has also been demonstrated to influence the acetylcholine release, its possible role in regulating the cholinergic memory effect was investigated. The scopolamine-reduced visual retrieval was antagonized by thioperamide in a similar way in both sexes. In conclusion, these data have shown a better performance of the female in a visual memory test, but this behavioral difference could not be affected by an H3-HA receptor-dependent manipulation of histaminergic and cholinergic systems.     

Effects of anticholinesterase drugs tacrine and E2020, the 5-HT(3) antagonist ondansetron, and the H(3) antagonist thioperamide, in models of cognition and cholinergic function

This study presents a comparison between two inhibitors of acetylcholinesterase, tacrine and E2020 (Donepezil), the 5-HT(3) receptor antagonist ondansetron, and the H(3) receptor antagonist thioperamide, in models of cholinergic function and cognition in male, Lister hooded rats. The cognitive tests used were an operant VI20 task, the delayed match to position task (short-term memory) and the 5-choice serial reaction time task (attention). Scopolamine (SCOP) (0.075mg/kg s.c.) was utilised in both the short-term memory and attention tasks to impair performance. Both tacrine (1-30mg/kg) and E2020 (1-10mg/kg) similarly produced overt cholinomimetic signs of likely central origin (hypothermia, tremor), although tacrine produced more profound peripheral cholinomimetic signs (miosis, secretory signs) than E2020. Tacrine (30mg/kg) and E2020 (10mg/kg) reduced the number of reinforcements gained in the VI20 schedule. Similarly, both drugs attenuated the SCOP-impairment models in the short-term memory and attention tasks (1-3mg/kg). Ondansetron (10ng/kg-1mg/kg) and thioperamide (0.2-10mg/kg) failed to elicit overt cholinomimetic signs or influence the number of food reinforcements gained in the VI20 schedule. Neither ondansetron nor thioperamide attenuated the SCOP-induced impairment in either cognitive task. From the present studies, both E2020 and tacrine showed a similar behavioural profile in the models used, although E2020 was about three times more potent. Furthermore, E2020 but not tacrine appeared to show some discrimination in eliciting central and peripheral cholinomimetic signs. The failure of ondansetron and thioperamide to reverse a SCOP-induced deficit in these models is discussed.     

Interaction of nicotinic and histamine H(3) systems in the radial-arm maze repeated acquisition task

Nicotinic systems have been found in a variety of studies to play important roles in cognitive function. Nicotinic involvement in different aspects of cognitive function such as learning vs. memory may differ. We have found in rats that the spatial repeated acquisition task in the radial-arm maze is significantly improved by low doses of the nicotinic receptor antagonist mecamylamine, the atypical nicotinic receptor ligand lobeline, as well as the alpha7 nicotinic receptor agonist ARR-17779. Interestingly, nicotine in the same dose range that improves working memory in the win-shift radial maze task was not effective in improving repeated acquisition performance. Nicotinic systems interact with a variety of other neural systems. Differential involvement of these extended effects with learning vs. memory may help explain differential effects of nicotinic drugs with these cognitive functions. Histamine H(3) receptor antagonists have been shown by some studies to improve cognitive function, but others have not found this effect and some have found impairment. Nicotine stimulates the release of histamine. This effect may counter other cascading effects of nicotine in the performance of learning and memory tasks. A specific test of this hypothesis involves our study of nicotine (0.1-0.4 mg/kg) interactions with the histamine H(3) receptor antagonist thioperamide (2.5-10 mg/kg) on learning memory in the repeated acquisition test in the radial-arm maze. The highest dose of thioperamide tested caused a significant choice accuracy impairment, which was most evident during the later portions of the learning curve. The highest dose of nicotine did not change overall errors but did cause a significant impairment in learning over trials. The choice accuracy impairment induced by thioperamide was significantly attenuated by nicotine (0.4 mg/kg). The learning impairment caused by the highest dose of nicotine was significantly attenuated by thioperamide. Thioperamide also caused a slowing of response, an effect, which was attenuated by nicotine co-administration. The repeated acquisition test can help differentiate acute drug effects on learning. Nicotine and thioperamide effectively reversed each other's choice accuracy impairment even though each by itself impaired accuracy.     

Rivastigmine reverses aluminum-induced behavioral changes in rats

Aluminum, a known neurotoxin, has long been implicated in the pathogenesis of Alzheimer's disease. Its exposure is associated with impairment in the cholinergic system in the brain. In this study we investigated the behavioral effects of aluminum in rats and the possible effect of rivastigmine, a cholinesterase inhibitor, on the aluminum-induced behavioral changes. Rats were exposed to aluminum chloride (100 mg/kg/day i.p.) for 60 days before the start of behavioral tests. Rivastigmine was given in doses of 0.5, 1, 1.5 and 2.5 mg/kg i.p. 60 min before the behavioral tests. Five tests were investigated; open field test, Morris water maze, radial arm maze, passive avoidance test and rota-rod test. Results showed that aluminum exposure was associated with significant reductions in spontaneous locomotor and exploratory activities in open field test and significant impairments in learning and memory in Morris water maze, radial arm maze and passive avoidance tests. The behavioral impairments caused by aluminum were significantly improved by rivastigmine. Neither aluminum alone nor co-treatment with rivastigmine caused any significant alteration of the animals' performance in rota-rod test. The improvements in activity, learning and memory caused by rivastigmine were found to be dose-dependent, and the maximal improvement was encountered with its large dose (2.5 mg/kg). From these results we can conclude that rivastigmine can reverse behavioral deficits caused by aluminum intoxication.     

Pharmacological effects of carcinine on histaminergic neurons in the brain

1 Carcinine (beta-alanyl histamine) is an imidazole dipeptide. The present study was designed to characterize the pharmacological effects of carcinine on histaminergic activity in the brain and on certain neurobehavior. 2 Carcinine was highly selective for the histamine H3 receptor over H1 or H2 receptor (Ki (microM)=0.2939+/-0.2188 vs 3621.2+/-583.9 or 365.3+/-232.8 microM, respectively). 3 Carcinine at a dose of 20 mg kg(-1) slightly increased histidine decarboxylase (HDC) activity in the cortex (from 0.186+/-0.069 to 0.227+/-0.009 pmol mg protein(-1) min(-1)). In addition, carcinine (10, 20, and 50 mg kg(-1)) significantly decreased histamine levels in mice brain. 4 Like thioperamide, a histamine H3 receptor antagonist, carcinine (20, 50 microM) significantly increased 5-HT release from mice cortex slices, but had no apparent effect on dopamine release. 5 Carcinine (20 mg kg(-1)) significantly inhibited pentylenetetrazole-induced kindling. This inhibition was completely reversed by (R)-alpha-methylhistamine, a representative H3 receptor agonist, and alpha-fluromethylhistidine, a selective HDC inhibitor. 6 Carcinine (20 mg kg(-1)) ameliorated the learning deficit induced by scopolamine. This amelioration was reversed by (R)-alpha-methylhistamine as evaluated by the passive avoidance test in mice. 7 Like thioperamide, carcinine dose-dependently increased mice locomotor activity in the open-field test. 8 The results of this study provide first and direct evidence that carcinine, as a novel histamine H3 receptor antagonist, plays an important role in histaminergic neurons activation and might be useful in the treatment of certain diseases, such as epilepsy, and locomotor or cognitive deficit.     

Behavioral and memory improving effects of mirtazapine in rats

These experiments examined the effects of the antidepressant mirtazapine in several behavioral and memory tests. The tests were carried out on male Wistar rats weighing about 200 g. The drugs were injected 30 min before the tests. The aim of the locomotor activity test was to select a dose which had no influence on the motility of the animals and, at the same time, was active at least in one behavioral test. The chosen dose was 2.5 mg/kg. In the two-compartment exploratory test, 2.5 mg/kg of mirtazapine had a distinct anxiolytic effect after the first treatment, after 7 days the effect was weaker but still significant and it disappeared after 14 days. In the forced swimming test, the immobility time was shortened only after 14 days of administering the drug. In the maze test, mirtazapine shortened the food finding time (it improved memory) and counteracted memory loss induced by scopolamine. In the conditioned avoidance responses test (CARs), mirtazapine improved memory only after its earlier impairment by scopolamine. The authors cohclude, contrary to some published data, that after proper dose (adequate for other tests but not for the locomotor activity test), mirtazapine has a distinct memory improving activity or a memory restoring effect after scopolamine treatment.     

Histamine H3-receptor blockade in the rat nucleus basalis magnocellularis improves place recognition memory

RATIONALE: Several lines of evidence have indicated that the central histaminergic system might be involved in learning and memory OBJECTIVES: The aim of the present study was to ascertain the impact on memory processes of putative histaminergic-cholinergic interactions in the nucleus basalis magnocellularis (NBM) of the rat. METHODS: The effects of thioperamide, a histamine H3-receptor antagonist, were studied on the memory performance of rats in a two-trial, delayed, place-recognition task. The drug was injected into the NBM area 2 min prior to the first trial (1.5, 7.5, and 37.5 ng/0.5 microl; pre-acquisition treatment), within 30 s from the end of the first trial (0.3, 1.5, 7.5, and 37.5 ng/0.5 microl; post-acquisition treatment), or 2 min prior to the second trial (1.5, 7.5, and 37.5 ng/0.5 microl; pre-retrieval treatment). RESULTS: Post-acquisition intra-NBM injections of 1.5 ng and 7.5 ng, but not of 0.3 ng and 37.5 ng thioperamide, significantly enhanced memory retention in treated rats. The histamine H(3)-receptor blocker exerted pro-cognitive effects only when administered post-acquisition, since both pre-acquisition and pre-retrieval treatments were ineffective. The post-acquisition effect of the drug was time dependent and disappeared when the drug was injected 90 min after the end of the first trial. The U-shaped dose-response relationship and the time dependency of the effect of thioperamide indicated that the drug acts on mechanisms involved in memory consolidation. CONCLUSIONS: The present findings demonstrate that the pro-cognitive effect of thioperamide is probably due to the modulation of post-acquisition memory processes through an action on the cholinergic basal forebrain. Our results indicate also that H3-antagonists may provide a useful approach for improving spatial recognition memory.     

Histamine H3 receptor agonist- and antagonist-evoked vacuous chewing movements in 6-OHDA-lesioned rats occurs in an absence of change in microdialysate dopamine levels

In rats lesioned neonatally with 6-hydroxydopamine (6-OHDA), repeated treatment with SKF 38393 (1-phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol), a dopamine D(1)/D(5) receptor agonist, produces robust stereotyped and locomotor activities. The gradual induction of dopamine D(1) receptor supersensitivity is known as a priming phenomenon, and this process is thought to underlie not only the appearance of vacuous chewing movements in humans with tardive dyskinesia, but also the onset of motor dyskinesias in L-dihydroxyphenylalanine (L-DOPA)-treated Parkinson's disease patients. The object of the present study was to determine the possible influence of the histaminergic system on dopamine D(1) agonist-induced activities. We found that neither imetit (5.0 mg/kg i.p.), a histamine H(3) receptor agonist, nor thioperamide (5.0 mg/kg i.p.), a histamine H(3) receptor antagonist/inverse agonist, altered the numbers of vacuous chewing movements in non-primed-lesioned rats. However, in dopamine D(1) agonist-primed rats, thioperamide alone produced a vacuous chewing movements response (i.e., P < 0.05 vs SKF 38393, 1.0 mg/kg i.p.), but did not modify the SKF 38393 effect. Notably, both imetit and thioperamide-induced catalepsy in both non-primed and primed 6-OHDA-lesioned rats, comparable in magnitude to the effect of the dopamine D(1)/D(5) receptor antagonist SCH 23390 (7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 0.5 mg/kg i.p.). Furthermore, in primed animals both imetit and thioperamide intensified SCH 23390-evoked catalepsy. In vivo microdialysis established that neither imetit nor thioperamide altered extraneuronal levels of dopamine and its metabolites in the striatum of 6-OHDA-lesioned rats. On the basis of the present study, we believe that histaminergic systems may augment dyskinesias induced by dopamine receptor agonists, independent of direct actions on dopaminergic neurons.     

Anxiolytic-like effect of saiboku-to, an oriental herbal medicine, on histaminergics-induced anxiety in mice

Effect of saiboku-to, an oriental herbal medicine, on anxiety in mice was investigated using a light/dark test. Anxiogenic- and anxiolytic-like effects were evaluated on the basis of shortened and prolonged time spent in the light zone of the test. Subacute administration (once a day for 7 days) of saiboku-to (0.5-2.0 g/kg, p.o.) induced anxiolytic-like effect. To assess the effect of saiboku-to on brain histaminergic system in a state of anxiety, Compound 48/80 (1.0 microg/2 microl, i.c.v.), a non-neuronal mast cell histamine releaser, or thioperamide (10.0 mg/kg, i.p.), a neuronal histamine releaser possessing the inhibitory effect of histamine H(3) autoreceptors, induced decrease in the time spent in the light zone by co-injection with cimetidine (10.0 microg/2 microl, i.c.v.), a H(2) inhibitor, suggesting anxiety-like effect. These histaminergics-induced experimental anxieties were inhibited by pre-treatment with subacute administration of saiboku-to, as well as single treatment with diazepam. The results suggest that saiboku-to exhibits anxiolytic-like effect closely related to histaminergic system in the brain.     

组胺H1受体阻断剂对大鼠八臂迷宫空间记忆的影响

目的：研究和阐明组胺H1受体阻断剂对大鼠空间记忆的作用机制。方法：采用八臂迷宫学习的程序研究大鼠的空间记忆。结果：在学习过程中,腹腔内注射第一代组胺H1受体阻断剂苯海拉明（5mg/kg)或美吡拉明（20mg/kg)显著性地引起空间记忆障碍,苯海拉明（5,10mg/kg)、美吡拉敏（50mg/kg)则浓度依赖性且显著性地引起空间记忆再生过程的障碍。相反,新型组胺H1受体阻断剂依匹斯汀（50mg/kg)对大鼠的学习和记忆再生过程均无明显作用。他克林（1mg/kg)可改善苯海拉明（10mg/kg)、美吡拉敏（50mg/kg)所致的记忆障碍。结论：中枢组胺H1受体参与了调节大鼠空间记忆的作用,而且其作用主要与组胺神经及胆碱能神经相关。     

Effects of repeated electroconvulsive seizures on spontaneous alternation behavior and locomotor activity in rats

Epileptic patients are at a significantly higher risk for impairments of cognitive function and behavioral abnormalities. In this study, we investigated the effect of repeated electroconvulsive shock (ECS)-induced seizures on the spontaneous alternation behavior in a Y-maze test and the locomotor activity in an open-field test, and examined the effects of anti-epileptic drugs in rats. ECS was administered for seven consecutive days and the Y-maze and open-field tests were performed 24 h after the last ECS administration. The repeated electroconvulsive seizures significantly impaired the spontaneous alternation and increased the locomotor activity. Moreover, these behavioral changes induced by the seven administrations of ECS persisted for at least 28 d. The inhibition of the ECS-induced seizures through the daily pretreatment of the phenytoin (120 mg/kg, intraperitoneally (i.p.)), phenobarbital (60 mg/kg, i.p.) and valproate (400 mg/kg, i.p.) abolished the locomotor hyperactivity in the open-field test. The impaired spontaneous alternation behavior in the Y-maze test was also significantly suppressed by the treatment with phenytoin and valproate. However, phenobarbital injection produced no significant ameliorating effect in the Y-maze test. These results suggest that the inhibition of ECS-induced seizures through phenytoin and valproate injections suppress the development of impairment of spontaneous alternation and the locomotor hyperactivity.     

Effects of vinpocetine in scopolamine-induced learning and memory impairments

Scopolamine-induced memory dysfunctions are related to reduced cholinergic transmission. In our experiments scopolamine (3.0 mg/kg i.p.) inhibited acquisition and induced retrograde amnesia in a one-trial step- through passive avoidance task in mice. We have studied the effect of vinpocetine (Cavinton^R), in the amnesic states mentioned above compared to that of vincamine, nicergoline (Sermion^R), and papaverine, to assess its activity on learning and memory processes impaired by scopolamine. Vinpocetine decreased the disrupting effect of scopolamine on acquisition and prevented and restituted the memory loss with 21.0 and 7.0 mg/kg i.p. peak effect dose, respectively. It facilitated the recall of memory traces damaged by scopolamine. Vincamine (3.5–63.7 mg/kg i.p.) showed a favorable effect in two of the four tests (reversal of amnesia and recall). Nicergoline (5–40 mg/kg i.p.) exerted moderate activity, and papaverine (10–40 mg/kg i.p.) was ineffective in the situations tested. Our findings indicate that vinpocetine directly or indirectly influences the cholinergic system, which may explain its previously reported beneficial effect in electroconvulsive shock- and hypoxia-induced experimental amnesic states, and its therapeutic activity in human mental and cognitive disorders.     

Effects of acute and repeated oral exposure to the organophosphate insecticide chlorpyrifos on open-field activity in chicks

The effects of the organophosphate insecticide chlorpyrifos on 5min open-field activity were examined in a 7-15 days old chick model. Chlorpyrifos was acutely administered taking into account cholinesterase inhibition and determination of the acute (24h) median lethal dose (LD50). The oral LD50 value of chlorpyrifos in chicks was 18.14mg/kg, with cholinergic toxicosis observed on intoxicated chicks. Chlorpyrifos at the dose rates of 5,10 and 20mg/kg orally produced within 2h signs of cholinergic toxicosis in the chicks and significantly inhibited plasma (40-70%), whole brain (43-69%) and liver (31-46%) cholinesterase activities in a dose-dependent manner. Chlorpyrifos at 2 and 4mg/kg, orally did not produce overt signs of cholinergic toxicosis, but decreased (30, 60 and 90min after dosing) the general locomotor activity of the chicks as seen by a significant increase in the latency to move from the central square of the open-field arena, decreases in the numbers of lines crossed and vocalization score. Repeated daily chlorpyrifos treatments (2 and 4mg/kg, orally) for seven consecutive days also caused hypoactivity in chicks in the open-field behavioral paradigm. Only the high dose of chlorpyrifos (4mg/kg, orally) given repeatedly for 7 days caused significant cholinesterase inhibition in the whole brain (37%) and the liver (22%). In conclusion, chlorpyrifos at single or short-term repeated doses-induced behavioral changes in 7-15 days old chicks, in a model that could be used for further neurobehavioral studies involving subtle effects of organophosphates on chicks.     

Effect of 5-HT5A antagonists in animal models of schizophrenia, anxiety and depression

The few available data on the pharmacological effect of 5-HT5A receptors suggest that antagonists may have anxiolytic, antidepressant and antipsychotic activity. The aim of our study was to verify these suggestions in relevant animal models. Two 5-HT5A antagonist ligands, SB-699551-A (N-[2-(dimethylamino)ethyl]-N-[[4'-[[(2-phenylethyl)amino]methyl][1,1'-biphenyl]-4-yl]methyl]cyclopentanepropanamide dihydrochloride) (3-60 mg/kg, intraperitoneally) and A-843277 (N-(2,6-dimethoxybenzyl)-N'[4-(4-fluorophenyl)thiazol-2-yl]guanidine) (3-30 mg/kg, intraperitoneally), were examined in the open-field test, in a foot-shock-induced ultrasonic vocalization test, in the forced swim test (FST) and in the amphetamine-induced and phencyclidine-induced hyperlocomotion tests to examine their effect on general behavioural patterns, and their anxiolytic-like, antidepressant-like and antipsychotic-like properties, respectively. In the open-field test, SB-699551-A induced sedation and A-843277 induced writhing. In the ultrasonic vocalization test, SB-699551-A reduced vocalizations, whereas A-843277 was ineffective. In the FST, SB-699551-A was ineffective and A-843277 reduced immobility, but only at the highest dose. In the amphetamine-induced and phencyclidine-induced hyperlocomotion test, both compounds were ineffective. SB-699551-A showed an anxiolytic-like property in the ultrasonic vocalization test; however, this compound has a sedative effect. A-843277 showed an antidepressant-like property in the FST, but its immobility-reducing effect may also be a consequence of abdominal irritation. Consequently, further investigations are required to define the therapeutic potential of 5-HT5A receptor ligands in anxiety, depression and schizophrenia models.     

The determination of the optimal dose of milnacipran in the olfactory bulbectomized rat model of depression

Olfactory bulbectomy (OB) is associated with a variety of behavioral abnormalities such as hyperactivity in the "open-field" test. Previous studies have shown that chronic administration of antidepressants can reverse this behavioral deficit. The activity of milnacipran (20, 30, and 40 mg/kg, PO bid) administered in two equally divided doses twice daily was assessed in the olfactory bulbectomized rat model of depression. It was found that chronic treatment with milnacipran at the doses of 30 and 40 mg/kg, but not 20 mg/kg, attenuated the lesion-induced hyperactivity of the OB rat in the "open-field" test following 14 days of treatment. In the step-through passive avoidance test, administration of milnacipran at doses of 20, 30, and 40 mg/kg had no effect on the performance deficit associated with olfactory bulbectomy. Olfactory bulbectomy reduced the concentration of noradrenaline (NA) in the frontal cortex. However, chronic milnacipran treatment did not significantly alter this deficit. It is concluded that milnacipran, when administered chronically at doses of 30 and 40 mg/kg, are effective at reversing the "open-field" deficit associated with olfactory bulbectomy, and that a dose of 30 mg/kg is an optimal dose.     

Influence of acute or chronic calcium channel antagonists on the acquisition and consolidation of memory and nicotine-induced cognitive effects in mice

Nicotinic cholinergic receptors (nAChRs) form a heterogeneous family of ligand-gated ion channels found in the nervous system. The main objective of our research was to investigate the interaction between cholinergic nicotinic system and calcium homeostasis in cognitive processes using the modified elevated plus maze memory model in mice. The time each mouse took to move from the open arm to either of the enclosed arms on the retention trial (transfer latency, TL2) was used as an index of memory. Our results showed that a single injection of nicotine (0.035 and 0.175 mg/kg) shortened TL2 values, improving memory-related processes. Similarly, L-type calcium channel antagonists (CCAs), i.e., flunarizine, verapamil, amlodipine, nimodipine, nifedipine, and nicardipine (at the range of dose 5–20 mg/kg) administered before or after training, decreased TL2 value improving memory acquisition and/or consolidation. Interestingly, at the subthresold doses, flunarizine, nicardipine, amlodipine, verapamil, and bupropion, a nAChR antagonist, significantly reversed the nicotine improvement of memory acquisition, while flunarizine, verapamil, and bupropion attenuated the improvement of memory consolidation provoked by an acute injection of nicotine (0.035 mg/kg, s.c.). After subchronic administration (14 days, i.p.) of verapamil and amlodipine, two CCAs with the highest affinity for nAChRs, only verapamil (5 mg/kg) impaired memory acquisition and consolidation while both verapamil and amlodipine, at the subthresold, ineffective dose (2.5 mg/kg), significantly reversed the improvement of memory provoked by an acute injection of nicotine (0.035 mg/kg, s.c.). Our findings can be useful to better understand the interaction between cholinergic nicotinic receptors and calcium-related mechanisms in memory-related processes.     

Rodent antinociception following acute treatment with different histamine receptor agonists and antagonists

The effects of different histamine receptor agonists and antagonists on the nociceptive threshold were investigated in mice by two different kinds of noxious stimuli: thermal (hot plate) and chemical (acetic acid-induced abdominal writhing). Intracerebroventricular (icv) injection of the histamine H(1) receptor agonist, HTMT (6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl) heptanecarboxamide) (50 microg/mouse), produced a hypernociception in the hot plate and writhing tests. Conversely, intraperitoneal (ip) injection of dexchlorpheniramine (30 and 40 mg/kg) and diphenhydramine (20 and 40 mg/kg) increased the pain threshold in both tests. The histamine H(2) receptor agonist, dimaprit (50 and 100 microg/mouse icv), or antagonist, ranitidine (50 and 100 microg/mouse icv), raised the pain threshold in both hot plate and writhing tests. In the mouse hot plate test, the histamine H(3) receptor agonist, imetit (50 mg/kg ip), reduced the pain threshold, while the histamine H(3) receptor antagonist, thioperamide (10 and 20 mg/kg ip), produced an antinociception. The hypernociceptive effects of HTMT and imetit were antagonized by dexchlorpheniramine (20 mg/kg ip) and thioperamide (5 mg/kg ip), respectively. The results suggest that histaminergic mechanisms may be involved in the modulation of nociceptive stimuli.     

Effects of the H<Subscript>3</Subscript> antagonist,thioperamide, on behavioral alterations induced by systemic MK-801 administration in rats

Rationale  Recent studies have raised the possibility that antagonists of H₃ histamine receptors possess cognitive-enhancing and antipsychotic properties. However, little work has assessed these compounds in classic animal models of schizophrenia. Objectives  The purpose of this study was to determine if a prototypical H₃ antagonist, thioperamide, could alter behavioral deficits caused by the N-methyl-d-aspartate (NMDA) receptor antagonist, MK-801, in adult male rats. MK-801 was chosen to be studied since it produces a state of NMDA receptor hypofunction in rats that may be analogous to the one hypothesized to occur in schizophrenia. Methods  The interaction between thioperamide and MK-801 was measured in three behavioral tests: locomotor activity, prepulse inhibition (PPI), and delayed spatial alternation. In each test, rats received a subcutaneous injection of saline or thioperamide (3.0 and 10 mg/kg) followed 20 min later by a subcutaneous injection of saline or MK-801 (0.05, 0.10, and 0.30 mg/kg). Results  Locomotor activity was significantly elevated by MK-801 in a dose-dependent manner. Thioperamide pretreatment alone did not alter locomotor activity; however, its impact on MK-801 was dose-dependent. Each thioperamide dose enhanced the effects of two lower doses of MK-801 but reduced the effect of a higher MK-801 dose. Clear deficits in PPI and delayed spatial alternation were produced by MK-801 treatment, but neither impairment was significantly modified by thioperamide pretreatment. Conclusions  H₃ receptors modulate responses to NMDA antagonists in behaviorally specific and dose-dependent ways.     

Effects of histamine and cholinergic systems on memory retention of passive avoidance learning in rats

In the present study, the effects of the histamine and cholinergic systems on memory retention in adult male rats were investigated. Post-training intracerebroventricular injections were carried out in all the experiments. Cholinoceptor agonist, acetylcholine (1-10 microg/rat) or nicotine (1-10 microg/rat), increased, while a cholinoceptor antagonist, scopolamine (5-20 microg/rat), decreased memory retention. The response to acetylcholine was attenuated by scopolamine. Administration of histamine (5-20 microg/rat) reduced, but the histamine H(1) receptor antagonist, pyrilamine (10-50 microg/rat), and the histamine H(2) receptor antagonist, cimetidine (1-50 microg/rat), increased memory retention in rats. The histamine receptor antagonists attenuated the response to histamine. Histamine reduced the acetylcholine- or nicotine-induced enhancement. The histamine receptor antagonists enhanced the nicotine- or acetylcholine-induced response. Histamine potentiated the inhibitory effect induced by scopolamine. It is concluded that histaminergic and cholinergic systems have opposing effects on memory retention. Also, the histaminergic system elicits an interaction with the cholinergic system in memory retention.     

Effect of rivastigmine on scopolamine-induced memory impairment in rats

The effect of rivastigmine on memory impairments induced in rats by scopolamine (0.5 mg/kg) was assessed in the Morris water maze and passive avoidance tests and compared with that of tacrine (2.5-17.7 mg/kg). Rivastigmine, (0.5-2.5 mg/kg) inhibited cholinesterase in the cortex and hippocampus by 21-60% and antagonised the deficits in working and reference memory. Tacrine (12.5 and 17.7 mg/kg) produced significantly less inhibition of cholinesterase in the hippocampus but more in the striatum than rivastigmine (0.75 and 1.5 mg/kg) and only antagonised the deficit in reference memory. Rivastigmine (1.5 and 2.5 mg/kg) or tacrine (12.5 mg/kg), injected immediately after completion of the acquisition trial in the passive avoidance test, antagonised the deficit induced by scopolamine (1 mg/kg) in memory retention. The inability of higher doses of the cholinesterase inhibitors to antagonise memory deficits induced by scopolamine may be related to excessive cholinergic stimulation in the central nervous system.