Dissociation of the effects of ethanol on memory, anxiety, and motor behavior in mice tested in the plus-maze discriminative avoidance task

Rationale Several studies have shown the amnestic effects of ethanol (ETOH). However, while memory tasks in rodents can be markedly influenced by anxiety-like behavior and motor function, ETOH induces anxiolysis and different effects on locomotion, depending on the dose. Objective Verify the effects of ETOH in mice tested in the plus-maze discriminative avoidance task (PMDAT) concomitantly evaluating memory, anxiety-like behavior, and motor behavior. Methods ETOH acutely or repeatedly treated mice were submitted to the training session in a modified elevated plus-maze with two open and two enclosed arms, aversive stimuli in one of the enclosed arms, and tested 24 h later without aversive stimuli. Learning/memory, locomotion, and anxiety-related behavior were evaluated by aversive arm exploration, number of entries in all the arms and open arms exploration, respectively. Results Acute ETOH: (1) either increased (1.2–1.8 g/kg) or decreased (3.0 g/kg) locomotion; (2) decreased anxiety levels (1.2–3.0 g/kg); and (3) induced learning deficits (1.2–3.0 g/kg) and memory deficits (0.3–3.0 g/kg). After repeated treatment, sensitization and tolerance to hyperlocomotion and anxiolysis induced by 1.8 g/kg ETOH were observed, respectively, and tolerance to the amnestic effect of 0.6 (but not 1.8) g/kg ETOH occurred. Conclusion Neither the anxiolytic nor the locomotor effects of ETOH seem to be related to its amnestic effect in the PMDAT. Additionally, data give support to the effectiveness of the PMDAT in simultaneously evaluating learning, memory, anxiety-like behavior, and motor activity by different parameters. Possible relationships between the behavioral alterations found are discussed.     

Utility of an elevated plus-maze for the evaluation of memory in mice: effects of nootropics,scopolamine and electroconvulsive shock

An elevated plus-maze consisting of two open and two enclosed arms was employed for an evaluation of memory in mice. Mice in the plus-maze escaped from the open arm to the enclosed arm because mice apparently dislike open and high spaces. The time it took for the mice to move from the open arm to the enclosed arm (transfer latency) was recorded. The transfer latency after the 2nd day was significantly shorter than that on the 1st day when it was recorded at a rate of one trial a day for 5 days. The transfer latency on the 2nd day was significantly prolonged in the mice administered electroconvulsive shock (300 V, 1 s) or scopolamine (20 µg, ICV) immediately after the first trial compared to the transfer latency in the control group. The prolongation of transfer latency in the mice administered an electroconvulsive shock was reversed by pretreatment with aniracetam (20 mg/kg, PO), but not tacrine and physostigmine. The prolongation of transfer latency in the mice administered scopolamine was reversed by pretreatment with aniracetam (10 and 20 mg/kg, PO) tacrine (1 and 3 mg/kg, PO), or physostigmine (0.025–0.2 mg/kg, IP). These results suggest that transfer latency may be one of the parameters of learning and memory.     

Amphetamine-induced anxiety-related behavior in animal models

The purpose of this study was to examine the anxiety-related effects of acute and repeated amphetamine administration using the elevated plus maze (EPM) and light/dark box tests in mice. D-amphetamine (2 mg/kg ip, 30 min after injection) had a significant anxiogenic effect only in the EPM test, as shown by specific decreases in the percentage of time spent in the open arms as well as in the percentage of open arm entries. Tolerance to this anxiogenic action developed after 8 days of daily d-amphetamine administration (2 mg/kg, ip). An anxiolytic effect was observed after the ninth injection, i.e. there were specific increases in the percentage of time spent in the open arms and in the percentage of open arm entries. L-type voltage-dependent calcium channel antagonists: nimodipine (5, 10 and 20 mg/kg, ip), flunarizine (5, 10 and 20 mg/kg, ip), verapamil (5, 10 and 20 mg/kg, ip), and diltiazem (5, 10 and 20 mg/kg, ip) were also injected prior to an acute low dose of d-amphetamine or to each injection of subchronic d-amphetamine. Our results revealed that calcium channel blockers dose-dependently attenuated both an anxiogenic effect of d-amphetamine and the development of tolerance to this effect. Our results suggest that neural calcium-dependent mechanisms are involved in the anxiety-related responses to acute and subchronic amphetamine injection that may lead to addiction relapse in human users.     

TAK—147逆转东莨菪碱诱发的大鼠空间记忆障碍

目的:研究和阐明TAK-147对东莨菪碱诱发的大鼠空间记忆损伤的作用.方法:采用Morris水迷宫的程序研究大鼠的空间记忆,利用开场实验方法测定动物自发活动量.结果:在水迷宫的学习过程中,腹腔内注射东莨菪碱(0.4mg/kg,ip)明显延长大鼠上台的潜伏期,而腹腔内注射TAK-147或donepezil(多奈哌齐)能剂量依赖性地改善东莨菪碱诱发的记忆损伤,两药在0.1-1.0mg/kg的剂量时具有显著性差异.在记忆的再生过程中,腹腔内注射东莨菪碱(1.5mg/kg,ip)引起空间记忆再生过程的障碍分别被TAK-147(0.1,0.3和1.0mg/kg)、多奈哌齐(0.3和1.0mg/kg)以及他克林(3和5mg/kg)显著性改善.TAK-147的作用比多奈哌齐略强却明显强于他克林.此外,在开场实验中,TAK-147和多奈哌齐与生理盐水和东莨菪碱相比,对大鼠运动量未产生明显改变.结论:TAK-147在空间认知功能上起重要的作用,进一步证明TAK-147能够成为一个治疗阿尔采默病的理想的胆碱酯酶抑制药.     

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.     

Effects of psychostimulant withdrawal on latent inhibition of conditioned active avoidance and prepulse inhibition of the acoustic startle response

RATIONALE: Chronic intermittent administration of amphetamine and cocaine can precipitate psychotic episodes in humans and produce persistent behavioral changes (i.e. increased locomotion, stereotypy) in the rat. The psychostimulant sensitization model of psychosis holds that the repeated administration of drugs such as amphetamine and cocaine induces long-lasting neuroadaptations and behavioral outcomes in animals that parallel aspects of the schizophrenic condition. OBJECTIVES: In the present study, we attempted to validate this model further by examining the effects of short-term withdrawal from repeated administration of cocaine and amphetamine on performance in two animal behavioral models of cognitive deficits found in schizophrenia: latent inhibition and prepulse inhibition. Reductions in both of these behavioral phenomena have been reported in schizophrenic patients and in acutely amphetamine-treated rats. METHODS: Animals were tested after 4 days of withdrawal from 5 days of daily systemic 20 mg/kg cocaine or 1.5 mg/kg amphetamine injections for either latent inhibition of two-way active avoidance acquisition or prepulse inhibition of an acoustic startle response. RESULTS: Our results indicate that, rather than reducing the expression of these behaviors, withdrawal from either cocaine or amphetamine enhanced the expression of latent inhibition of the active avoidance response while having no effect on prepulse inhibition of acoustic startle. CONCLUSIONS: These data indicate that although the sensitized response to amphetamine and cocaine administration may model some aspects of schizophrenic psychosis, behaviors exhibited by sensitized animals in the absence of an acute drug challenge are not consistent with models of the positive symptoms of schizophrenia.     

Ganglioside GM1 attenuates scopolamine-induced amnesia in rats and mice

 Some experimental evidence suggests that the beneficial effects of monosialoganglioside GM1 on learning and memory could be related to an improving effect in central cholinergic function. The present study investigates the effects of GM1 on the memory impairment induced by scopolamine in rats or mice tested in passive (PA) and discriminative avoidance (DA) tasks, respectively. Wistar EPM-1 male rats and Swiss EPM-M1 male mice were treated daily IP with 50 mg/kg GM1 or saline for 7 or 14 days, respectively. Twenty-four hours after the last injection, GM1-treated animals received 1 mg/kg scopolamine (GM1-SCO) and saline-treated animals received 1 mg/kg scopolamine (SAL-SCO) or saline (SAL-SAL) IP. Twenty minutes later, the animals were submitted to PA or DA conditioning, and tests were performed 24 h later. The latency in entering the dark chamber of the PA apparatus (LD) presented by SAL-SCO rats was significantly decreased when compared to that presented by SAL-SAL animals. GM1-SCO animals showed an increased LD when compared to SAL-SCO animals and were not significantly different from SAL-SAL rats. GM1-SCO and SAL-SAL (but not SAL-SCO) mice spent significantly less time in the aversive enclosed arm of the discriminative avoidance apparatus when compared to the time spent in the non-aversive enclosed arm. The results are consistent with the interpretation that GM1 attenuates scopolamine-induced amnesia. Although not eliminating the participation of other transmitter systems, the present study indicates a possible role of central cholinergic transmission in the action of this compound on learning and memory. Received: 21 October 1997 / Final version: 8 June 1998     

Combined effects of acute stress and amphetamine on serial memory retrieval pattern in mice

Introduction  This study investigated the dose–effect of amphetamine on contextual serial (contextual serial discrimination (CSD)) and serial (serial discrimination (SD)) memory in acutely stressed versus nonstressed C57 Bl/6 Jico mice. Materials and methods  Memory was first evaluated in nonstress condition. Mice learned two consecutive discriminations (D1 and D2) in a four-hole board involving either distinct (CSD) or identical (SD) internal contextual cues. All mice received i.p. injections of vehicle before acquisition and vehicle or amphetamine 20 min before the memory retrieval phase occurring 24 h after acquisition. Results  Results showed that: (1) vehicle group expressed in both tasks a similar memory retrieval pattern, D2 being better retrieved than D1; (2) 2 mg/kg amphetamine significantly enhanced D1 but not D2 performance in both tasks, whereas 4 mg/kg amphetamine enhanced D2 but not D1 retrieval. Thus, amphetamine more specifically modulates serial order memory retrieval in a context-independent manner. In a further step, we studied the effect of an acute stress (electric foot shocks 5 min before retrieval) specifically on D1 performance of the CSD task in 2 mg/kg amphetamine-treated mice. Immediately after testing, blood was sampled to measure plasma corticosterone levels. Results showed that acute stress significantly improved D1 performance in vehicles but blocked the memory-enhancing effect of 2 mg/kg amphetamine, as compared to the nonstress condition. However, statistical analysis failed to evidence a significant interaction between treatments and conditions (stress vs nonstress) on corticosterone levels, contrary to another vigilance-enhancing drug, modafinil (Béracochéa, Psychopharmacology 196:1–13, 2008).     

Selective 5-HT1A antagonists WAY 100635 and NAD-299 attenuate the impairment of passive avoidance caused by scopolamine in the rat.

Systemic administration of the muscarinic-receptor antagonists atropine and scopolamine produces cognitive deficits in humans, nonhuman primates and rodents. In humans, these deficits resemble symptoms of dementia seen in Alzheimer's disease. The passive avoidance (PA) task has been one of the most frequently used animal models for studying cholinergic mechanisms in learning and memory. The present study examined the ability of two selective 5-HT(1A) receptor antagonists WAY 100635 and NAD-299 (robalzotan) and two acetylcholinesterase (AChE) inhibitors tacrine and donepezil to attenuate the impairment of PA retention caused by the nonselective muscarinic receptor antagonist scopolamine in the rat. Although demonstrating differences in their temporal kinetics, both WAY 100635 and NAD-299 attenuated the impairment of PA caused by scopolamine (0.3 mg/kg s.c.). Donepezil did not block the PA deficit caused by the 0.3 mg/kg dose of scopolamine, but it prevented the inhibitory effects of the 0.2 mg/kg dose of scopolamine. In contrast, tacrine was effective vs both the 0.2 and 0.3 mg/kg doses of scopolamine. These results indicate that (1). a functional 5-HT(1A) receptor antagonism can attenuate the anterograde amnesia produced by muscarinic-receptor blockade, and (2). the AChE inhibitors tacrine and donepezil differ in their ability to modify muscarinic-receptor-mediated function in vivo. These results suggest that 5-HT(1A) receptor antagonists may have a potential in the treatment of cognitive symptoms in psychopathologies characterized by reduced ACh transmission such as Alzheimer's disease.     

Cholinergic influence on memory stages: A study on scopolamine amnesic mice

Objectives:

The study was planned to determine cholinergic influence on different stages of memory - acquisition, consolidation and recall in scopolamine-induced amnesia (memory impairment) in mice.

Materials and Methods:

To study acquision, consolidation and recall stages of memory, we administered scopolamine (0.75, 1.5 and 3 mg/kg ip) 30 minutes and five minutes prior to first trial acquisition and consolidation and 30 minutes prior to second trial recall of passive avoidance (PA) test, respectively, in separate groups. Tacrine (5 mg/kg po) and rivastigmine (5 mg/kg po) were administered one hour prior to first trial in separate groups which received scopolamine (3 mg/kg ip) 30 minutes and five minutes prior to first trial where as the control group received vehicle only.

Results:

In the control group, there was a significant (P < 0.01) increase in transfer latency time (TLT) in the second trial compared to first indicating successful learning. In scopolamine treated groups, administering scopolamine 30 minutes or five minutes prior to first trial did not show any significant (P > 0.05) change in TLT whereas mice treated with scopolamine 30 minutes prior to second trial showed significant (P < 0.01) increase in TLT in second trial as compared to the first. Both tacrine and rivastigmine administration in scopolamine treated mice showed significant (P < 0.05-0.01) increase in TLT in second trial as compared to first trial while the rivastigmine treated group showed greater percentage retention compared to tacrine treated group.

Conclusion:

Results show that acquisition and consolidation are more susceptible to the scopolamine effects than recall. Thus, it may be concluded that cholinergic influence is more on acquisition and consolidation as compared to recall.     

Radial maze as a tool for assessing the effect of drugs on the working memory of rats

The effect of physostigmine (0.2 mg/kg), scopolamine (0.1 mg/kg), d,l-amphetamine (1 mg/kg), apomorphine (0.05 mg/kg), and piracetam (100 mg/kg) on working memory was examined in 12 rats that were highly overtrained in the radial maze. In experiment 1, drugs administered 10 min before the trial did not worsen performance of rats in the 12-arm maze. In experiment 2, insertion of a 5-min delay between the sixth and seventh choices increased the number of errors over choices 7–12. Performance was unaffected by pretreatment with physostigmine or apomorphine, but was significantly impaired by scopolamine, amphetamine, and piracetam. In experiment 3, performed in a 24-arm maze, the number of errors and trial duration increased, but performance was not decreased by amphetamine or piracetam. It is concluded that the uninterrupted radial maze task is relatively resistant to pharmacological disruption, but that scopolamine, amphetamine, and piracetam enhance the effect of stimuli interfering with the storage of spatial information over delays.     

Models of memory dysfunction? A comparison of the effects of scopolamine and lorazepam on memory,psychomotor performance and mood

The effects on memory, psychomotor functions and mood of intramuscular scopolamine (0.3 mg, 0.6 mg) were compared with those of oral lorazepam (2 mg) and placebo. Thirty-six volunteers took part in a doubleblind, independent groups design. Subjects completed a battery of tests 1 and 3 h after drug administration. Both doses of scopolamine produced levels of sedation comparable to that produced by lorazepam. The time course of effects of scopolamine and lorazepam differed but the pattern of psychomotor impairments and amnestic effects produced was very similar. In terms of mood, lorazepam had an anxiolytic effect whereas scopolamine increased ratings of anxiety. Levels of sedation, indexed by either subjective ratings or motor retardation (tapping speed), were related more to psychomotor performance than to performance on memory tasks. The results suggest that benzodiazepines and scopolamine have similar amnestic and sedative effects and as such may not offer distinct models of memory dysfunction.     

Tacrine-scopolamine interactions on state-dependent retrieval

Abstract Objectives. This study examined the effects of tacrine on scopolamine-induced state-dependence. Methods. Rats were trained to complete an FR10 schedule of lever presses for milk reward within 120 s after the onset of an operant session and were subsequently tested for the retrieval of the response in either the same or a different, pharmacologically defined, state. Results. In rats trained with 2.5 mg/kg scopolamine, the pre-test administration of 10 mg/kg tacrine prevented scopolamine from enabling the retrieval that otherwise occurred when animals were both trained and tested with scopolamine. However, retrieval of the response was also hampered in animals that were trained with tacrine-scopolamine co-administration and tested with saline, and vice versa, indicating that the co-administration of tacrine and scopolamine did not induce the saline-associated, presumably normal state. At ≥2.5 mg/kg doses, tacrine itself induced state-dependence with both tacrine-to-saline and saline-to-tacrine state changes. Conclusion. The findings indicate that tacrine is unable to normalize the particular mnesic state induced by scopolamine. The data may elucidate tacrine's limited therapeutic efficacy insofar as scopolamine's mnesic actions both model human pathology and are due to scopolamine producing state-dependence. Electronic Publication     

Comparison of acute and chronic treatment of various serotonergic agents with those of diazepam and idazoxan in the rat elevated X-maze

The aim of this study was to use the elevated X-maze to compare acute and chronic treatments of a 5-HT_1A partial agonist, ipsapirone, a 5-HT₂ antagonist, ritanserin, and a 5-HT₃ antagonist, ondansetron, with those of established anxiolytic (diazepam) and anxiogenic (idazoxan) compounds. Acute diazepam (5 mg/kg IP) produced a significant increase in the percentage open:total entries and time and time spent in the end of the open arms (anxiolytic profile) on the elevated X-maze. Chronic treatment with diazepam (5 mg/kg IP twice daily for 14 days) still produced an anxiolytic profile which was not apparent 24 h after cessation of chronic treatment (withdrawal). In contrast, idazoxan given both acutely (0.25 mg/kg IP) and chronically (0.8 mg/kg/h at a flow rate of 5.5 µl/h for 14 days, via osmotic minipumps) resulted in a significant decrease in the percentage open:total entries and time and time spent in the end of the open arms (anxiogenic profile). Acute administration of ipsapirone had no effect on any of the behavioural parameters at doses of 0.01 and 1 mg/kg IP, while 0.1 mg/kg IP produced a significant anxiogenic profile. Chronic treatment with ipsapirone (0.01, 0.1 and 1 mg/kg IP twice daily for 14 days) had no significant effect on rat behaviour on the X-maze but 24 h after ending treatment, ipsapirone at the highest dose used (1 mg/kg) produced a significant anxiogenic profile which was absent when the animals were tested 7 days after cessation of treatment. Ritanserin (0.05 and 0.25 mg/kg IP) had no effect acutely on any of the parameters measured but chronic treatment (0.25 mg/kg IP, twice daily for 14 days) produced a significant anxiolytic effect which was still present 24 h but not 7 days after cessation of treatment. Acute ondansetron (0.01, 0.1 and 1 mg/kg IP) had no effect while chronic ondansetron (0.01 mg/kg IP, twice daily for 14 days) produced a significant anxiolytic profile which was not a result of handling during the chronic dosing schedule, an effect was not measureable 24 h after treatment ended. The results demonstrate that the X-maze can detect anxiolytic activity in non-benzodiazepine drugs, as ritanserin and ondansetron showed anxiolytic profiles but only after chronic treatment. In contrast, the X-maze failed to detect any anxiolytic activity with the 5-HT_1A partial agonist ipsapirone after either acute or chronic treatment.     

Combined action of thioperamide plus scopolamine, diphenhydramine, or methysergide on memory in mice.

The aim of the present experiments was to test the role played by the interaction of the selective H3 receptor antagonist, thioperamide, with the cholinergic, histaminergic, and serotonergic systems in modifying memory. The behavioral tests used (open-field and passive-avoidance repetition) were selected on the basis of the action displayed by thioperamide in these behavioral situations. Posttrial administration of thioperamide (5 mg/kg) resulted in an improvement in memory consolidation, as tested in the repetition of the open-field test, but repeated posttrial administration of thioperamide (2 or 5 mg/kg) had no effect in the repetition of passive avoidance test. Scopolamine (2 mg/kg) caused a deterioration in the memory processes in both tests: this effect was blocked by 2 mg/kg of thioperamide, which was itself ineffective in the test. These results may suggest that both the improvement in memory due to thioperamide and its antagonism of the amnestic effects of scopolamine are determined by activation of central cholinergic systems, due to thioperamide inhibition of H3 heteroreceptors. Diphenhydramine (2 or 10 mg/kg) was itself ineffective in the tests, but counteracted the memory improvement caused by thioperamide in the repetition of the open-field test. The effect of diphenhydramine is discussed in terms of interactions between histaminergic and cholinergic systems. Methysergide counteracted the effect of thioperamide in the open-field test only at a high dosage (50 mg/kg). The possible implication of serotonergic systems on the effects of the methysergide-thioperamide interaction in the memory process is discussed.     

Dose-related anxiogenic effect of glycine in the elevated plus maze and in electrodermal activity

We investigated effect of glycine on anxiety at different doses using electrodermal activity and an elevated-plus maze. A single dose of glycine was injected intraperitoneally into three different groups of mice at 250 mg/kg, 750 mg/kg, and 1250 mg/kg. The anxiety scores with the elevated-plus maze, consisting of two open arms and two enclosed arms, were measured 30 minutes after injection. Then skin conductance level was measured. Glycine significantly decreased the times spent on the open arms in middle-dose and high-dose groups compared with the control group. The skin conductance level was statistically lower in high dose group than control groups. Conclusion; glycine at a dose of 750 mg/kg induced a nearly maximal anxiogenic effect because a higher dose was not more effective.     

Effects of nicotine on memory impairment induced by blockade of muscarinic,nicotinic and dopamine D2 receptors in rats

Scopolamine dose-dependently inhibits passive avoidance latency and decreases spontaneous alternation in the Y-maze, suggesting effects on long-term and short-term memory, respectively. Chlorisondamine (10 mg/kg), a compound which produces a long-lasting central nicotinic receptor blockade, did not affect short-term and long-term memory performance. In normal rats, nicotine at the doses of 0.3, 1.0, and 3.0 mg/kg administered once had a facilitating effect on short-term memory; a higher dose (3.0 mg/kg) did not show a more pronounced effect than a lower one (0.3 mg/kg). Nicotine, by activating the nicotinic acetylcholine receptors, attenuated the impairment of short-term memory induced by muscarinic or dopamine D2 receptor blockade. On long-term memory, a single dose of nicotine (0.3, 1.0, 3.0 mg/kg) did not affect memory performance, but improved it after chronic (10 consecutive days, 0.3 mg/kg) administration. The antiamnesic effect of nicotine administered once was observed in scopolamine-, scopolamine+chlorisondamine- or sulpiride-treated rats. These results suggest that the antiamnesic effect of nicotine can result from an action at nicotinic receptors subtypes not blocked by chlorisondamine or at nonnicotinic receptors.     

Behavioral effects of serotonergic and dopaminergic drugs in cats following chronic amphetamine administration

Chronic administration of amphetamine to cats (twice daily, in doses increasing from 5 to 15 mg/kg over a 10-day period) elicited a number of behaviors e.g. limb flicking, abortive grooming, and excessive head shaking, which were originally proposed as an animal behavioral model for studying the actions of hallucinogens that depress central serotonergic neurotransmission. This drug treatment produced large decreases (approximately 50%) in central nervous system serotonin (5HT) and its major metabolite, 5-hydroxyindoleacetic acid, and even larger decreases (approximately 90%) in the levels of dopamine (DA) and norepinephrine. Administration of the 5HT precursors L-tryptophan (25 mg/kg i.p.) or L-5-hydroxytryptophan (12.5 mg/kg i.p), a direct-acting 5HT agonist (quipazine, 1 mg/kg i.p.) or a monoamine oxidase inhibitor (tranylcypromine, 4 mg/kg i.p.) produced no significant changes in these behaviors in cats treated chronically with amphetamine. Administration of a 5HT reuptake blocker (fluoxetine, 5 mg/kg i.p.) produced a small, but significant, decrease in the frequency of occurencence of these behaviors in amphetamine-treated cats. L-Dihydroxyphenylalanine (L-DOPA, 20 mg/kg i.p.) greatly potentiated these behaviors in cats chronically treated with amphetamine, but L-DOPA was totally ineffective in eliciting these behaviors in naive animals. The behavioral effects of apomorphine (2 mg/kg i.p.) were also significantly potentiated by chronic amphetamine pretreatment. The amino acid precursor of DA, L-tyrosine (25 mg/kg i.p.), and a DA reuptake blocker, bupropion (5 mg/kg i.p.) were without significant effect on these behaviors in amphetamine-treated cats. The data suggest that these cat behaviors are elicited by an action at central DA receptors and that these receptors become supersensitive following chronic amphetamine administration. Furthermore, there may be a qualitative change in DA receptors, since L-DOPA is very effective in potentiating these behaviors in cats treated chronically with amphetamine, but is totally ineffective in naive cats.     

Hypericum perforatum extract demonstrates antioxidant properties against elevated rat brain oxidative status induced by amnestic dose of scopolamine

This study was designed to investigate if the impairment of learning and memory induced by acute administration of scopolamine (1.4 mg/kg ip) in rats is associated with altered brain oxidative stress status. The passive avoidance paradigm was used to assess retrieval memory of rats after scopolamine treatment. Following retrieval testing, biochemical assessments of malondialdehyde (MDA), glutathione peroxidase (GSHPx), glutathione (GSH), and superoxide dismutase (SOD) levels/activities as oxidative stress indices were performed. This study also investigated the effect of acute administration of Hypericum perforatum extract (4.0, 8.0, 12.0, and 25.0 mg/kg ip), containing flavonoids with documented antioxidant activity, on brain oxidative status of nai;ve rats treated with amnestic dose of scopolamine. Results showed that administration of 1.4 mg/kg of scopolamine impaired retrieval memory of rats and that such amnesia was associated with elevated MDA and reduced GSH brain levels. In nai;ve rats, which have not been exposed to conditioned fear, scopolamine administration also increased MDA and reduced GSH levels, although with an increase in brain GSHPx activity. Pretreatment of the animals with Hypericum extract (4, 8, and 12 mg/kg) resulted in an antioxidant effect through altering brain MDA, GSHPx, and/or GSH level/activity. Since oxidative stress is implicated in the pathophysiology of dementia, the findings of this study may substantiate the value of scopolamine-induced amnesia in rats as a valid animal model to screen for drugs with potential therapeutic benefit in dementia. Exposure of animals to conditioned fear may be suggested to impair the balance between the rate of lipid peroxidation and the activation of GSHPx as a compensatory antioxidant protective mechanism. It is also concluded that low doses of Hypericum extract, demonstrating antioxidant activity, may be of value for demented patients exhibiting elevated brain oxidative status. Since depression commonly coexists with dementia, Hypericum extract as a drug with documented antidepressant action may also be a better alternative than several other antidepressant medications that have not been evaluated to test their effect on brain oxidative status during amnesia.     

The neurosteroid pregnenolone sulfate reduces learning deficits induced by scopolamine and has promnestic effects in mice performing an appetitive learning task

The effects of the neurosteroid pregnenolone sulfate (PS) on learning as well as on scopolamine-induced learning deficits were studied in Swiss mice using an appetitively reinforced Go-No Go visual discrimination task. Subcutaneous (SC) administration of scopolamine (0.3–3 mg/kg) after the first session of training dose-dependently impairs learning during the following sessions in this task. Moreover, intracerebroventricular (ICV) administration of PS (0.01–10 nmol) dose-dependently blocks learning deficits induced by scopolamine (3 mg/kg), with the most potent effects at the dose of 0.5 nmol PS. In addition to antagonizing the amnestic effects of scopolamine, PS (0.5 nmol ICV) has a memory-enhancing effect, when administered alone after the first training session. Scopolamine (3 mg/kg SC) also produced substantial deficits on retrieval performance in the Go-No Go visual discrimination task, and caused motor disturbances, when administered 15 min before testing. PS (0.5 nmol ICV) also reduced scopolamine-induced deficits on retrieval but had no effect on scopolamine-induced motor impairments in the traction reflex test. Such a rapid effect of PS on memory processes may be mediated via NMDA and/or GABA_A receptors.