Impaired Passive Avoidance Learning Research Articles

Sesamin alleviates diabetes-associated behavioral deficits in rats: The role of inflammatory and neurotrophic factors

Neuroinflammation and loss of neurotrophic support have key roles in the pathophysiology of diabetes-associated behavioral deficits (DABD). Sesamin (Ses), a major lignan of sesame seed and its oil, shows anti-hyperglycemic, anti-oxidative, and neuroprotective effects. The present study was designed to assess the potential protective effects of Ses against DABD and investigate the roles of inflammatory markers and neurotrophic factors in streptozotocin (STZ)-induced diabetic rats. After confirmation of diabetes, Ses (30 mg/kg/day; P.O.) or insulin (6 IU/rat/day; S.C.) was administered to rats for eight consecutive weeks. During the eighth-week period of the study, behavioral functions of the animals were evaluated by employing standard behavioral paradigms. Moreover, inflammation status, neurotrophic factors, and histological changes were assessed in the cerebral cortex and hippocampal regions of the rats. The results of behavioral tests showed that STZ-induced diabetes increased anxiety-/depression-like behaviors, decreased locomotor/exploratory activities, and impaired passive avoidance learning and memory. These DABD were accompanied by neuroinflammation, lack of neurotrophic support, and neuronal loss in both cerebral cortex and hippocampus of the rats. Intriguingly, chronic treatment with Ses improved all the above-mentioned diabetes-related behavioral, biochemical, and histological deficits, and in some cases, it was even more effective than insulin therapy. In conclusion, the results suggest that Ses was capable of improving DABD, which might be ascribed, at least partly, to the reduction of blood glucose level, inhibition of neuroinflammation, and potentiation of neurotrophic factors.

The role of nucleus accumbens shell on acquisition and retrieval stages of morphine state dependent learning.

In the present study, the effect of transient inactivation of the shell subregion of the nucleus accumbens (NAC shell) by lidocaine on the acquisition and retrieval stages of passive avoidance learning (PAL) and memory and morphine state-dependent learning (SDL) in male wistar rats was investigated. Adult male wistar rats weighing (220-250 g) were used. Lidocaine hydrochloride was bilaterally injected into the shell area of the nucleus accumbens 5 min before of subcutaneous morphine administration. pre-training and pre-test infusion of lidocaine into the NAC shell significantly impaired PAL and memory. Furthermore, Pre-training administration of morphine (5 mg/kg, s.c.) in a step-through passive avoidance task induced state-dependent learning with impaired memory retrieval on the test day. The impairment of memory was restored after pre-test administration of the same dose of morphine. This phenomenon has been named as morphine state dependent learning (SDL). Moreover, Pre-training and pre-test inactivation of the NAC shell impaired morphine SDL. The results suggest the role of NAC shell as a common structure in the PAL and morphine SDL. It is suggested that NAC shell as a common area plays a critical role in the acquisition and retrieval stages of PAL and also morphine SDL.

Astrocyte HIF-2α supports learning in a passive avoidance paradigm under hypoxic stress.

BackgroundThe brain is extensively vascularized, useŝ20% of the body’s oxygen, and is highly sensitive to changes in oxygen. While synaptic plasticity and memory are impaired in healthy individuals by exposure to mild hypoxia, aged individuals appear to be even more sensitive. Aging is associated with progressive failure in pulmonary and cardiovascular systems, exposing the aged to both chronic and superimposed acute hypoxia. The HIF proteins, the “master regulators” of the cellular response to hypoxia, are robustly expressed in neurons and astrocytes. Astrocytes support neurons and synaptic plasticity via complex metabolic and trophic mechanisms. The activity of HIF proteins in the brain is diminished with aging, and the increased exposure to chronic and acute hypoxia with aging combined with diminished HIF activity may impair synaptic plasticity.PurposeHerein, we test the hypothesis that astrocyte HIF supports synaptic plasticity and learning upon hypoxia.Materials and MethodsAn Astrocyte-specific HIF loss-of-function model was employed, where knock-out of HIF-1α or HIF-2α in GFAP expressing cells was accomplished by cre-mediated recombination. Animals were tested for behavioral (open field and rotarod), learning (passive avoidance paradigm), and electrophysiological (long term potentiation) responses to mild hypoxic challenge.ResultsIn an astrocyte-specific HIF loss-of-function model followed by mild hypoxia, we identified that the depletion of HIF-2α resulted in an impaired passive avoidance learning performance. This was accompanied by an attenuated response to induction in long-term potentiation (LTP), suggesting that the hippocampal circuitry was perturbed upon hypoxic exposure following HIF-2α loss in astrocytes, and not due to hippocampal cell death. We investigated HIF-regulated trophic and metabolic target genes and found that they were not regulated by HIF-2α, suggesting that these specific targets may not be involved in mediating the phenotypes observed.ConclusionTogether, these results point to a role for HIF-2α in the astrocyte’s regulatory role in synaptic plasticity and learning under hypoxia and suggest that even mild, acute hypoxic challenges can impair cognitive performance in the aged population who harbor impaired HIF function.

Agmatine attenuates methamphetamine-induced passive avoidance learning and memory and CaMKII-α gene expression deteriorations in hippocampus of rat.

Methamphetamine (METH) abuse is one the most worldwide problems with wide-ranging effects on the central nervous system (CNS). Chronic METH abuse can associate with cognitive abnormalities and neurodegenerative changes in the brain. Agmatine, a cationic polyamine, has been proposed as a neuromodulator that modulates many effects of abused drugs. The aim of this study was to determine if agmatine can decrease the impairment effect of METH on memory and hippocampal CaMKII-α gene expression, a gene that plays a major role in memory. Male wistar rats (200-220 g) were allocated into 7 groups, including 5 groups of saline, METH (1, 2 mg/kg), Agmatine (5, 10 mg/kg) and 2 groups of agmatine (5, 10 mg/kg) with higher doses of METH (2 mg/kg) for 5 consecutive days (n = 8 in each group). All injections were done intraperitoneally and agmatine was administrated 10 min before METH treatment. Furthermore, Passive avoidance learning (PAL) test was assessed on the 5th day. Retention test was done 24 h after training and the rats were sacrificed immediately. Hippocampi were removed and stored at -80 °C. Finally, hippocampal CaMKII-α gene expression was measured using Quantitative Real-time PCR. Our data showed that chronic METH dose-dependently impaired PAL retrieval, as it decreased step-through latency (STL) and increased time spent in the dark compartment (TDC). While Agmatine with a higher dose (10 mg/kg) significantly decreased impairment effect of METH (2 mg/kg) on PAL and memory. Also, molecular results revealed that METH (2 mg/kg) markedly decreased hippocampal CaMKII-α gene expression while agmatine (10 mg/kg) co-adminstration prevented it. Taken together, the results propose that agmatine may provide a potential therapy for learning and memory deficits induced by METH.

Administration of muscarinic antagonists induce changes in passive avoidance learning and in synaptic transmission in the CA1 area of the hippocampus

Muscarinic acetylcholine receptors (mAChR) are known to be related to learning and memory processes. Inactivation of mAChR by cholinergic antagonists have been shown to produce amnesia in a variety of behavioral tasks. In this study, we investigated the role of M1 and M2 AChR on passive avoidance learning and plasticity of synapses formed by Schaffer collaterals in freely moving rats. Experiments were performed using Wistar male rats. Seven days before testing, a recording electrode was lowered in the CA1 region under chloral hydrate anaesthesia to record the field excitatory postsynaptic potential (fEPSP) in response to Schaffer collateral stimulation. Selective M2 receptor antagonists methoctramine and selective M1 receptors antagonist pirenzepine were intraperitoneally injected immediately after training. The effects on memory retention were examined using passive avoidance training. We measured latency of the first entry into a dark compartment of the chamber. fEPSP amplitude and slope ratio were measured before shock presentation, 90 min after the shock, and 24 hour after the shock. Methoctramine significantly impaired behavior in the passive avoidance test but pirenzepine did not induce any changes compared to control. Our results showed that pirenzepine but not methoctramine supressed the amplitude of fEPSPs. On the other hand, intracerebroventricular methoctramine administration impaired passive avoidance learning and increased the amplitude of fEPSP.

Antibodies to Glutamate Reversed the Amnesic Effects of Proinflammatory S100A9 Protein Fibrils in Aged C57Bl/6 Mice.

Chronic intranasal administration of fibrillar structures of proinflammatory S100A9 protein impaired passive avoidance learning in old C57Bl/6 mice. Combined treatment with S100A9 fibrils and antibodies to glutamate was followed by an increase in horizontal locomotor activity of animals in the open-field test and did not disturb spatial memory.

Portulaca oleracea L. prevents lipopolysaccharide-induced passive avoidance learning and memory and TNF-α impairments in hippocampus of rat

There is a growing body of evidence that neuroinflammation can impair memory. It has been indicated that Portulaca oleracea Linn. (POL), possess anti-inflammatory activity and might improve memory disruption caused by inflammation. In this study the effect of pre-treatment with the hydro-alcoholic extract of POL on memory retrieval investigated in lipopolysaccharide (LPS) treated rats. Male Wistar rats (200–220g) received either a control diet or a diet containing of POL (400mg/kg, p.o.) for 14days. Then, they received injections of either saline or LPS (1mg/kg, i.p.). In all the experimental groups, 4h following the last injection, passive avoidance learning (PAL) and memory test was performed. The retention test was done 24h after the training and then the animals were sacrificed. Hippocampal TNF-α levels measured using ELISA as one criteria of LPS-induced neuroinflammation. The results indicated that LPS significantly impaired PAL and memory and increased TNF-α levels in hippocampus tissue. Pre-treatment with POL improved memory in control rats and prevented memory and TNF-α deterioration in LPS treated rats. Taken together, the results of this study suggest that the hydro-alcoholic extract of POL may improve memory deficits in LPS treated rats, possibly via inhibition of TNF-α and anti-inflammatory activity.

Simultaneous impairment of passive avoidance learning and nociception in rats following chronic swim stress.

Background:Stress can alter response to nociception. Under certain circumstances stress enhances nociception, a phenomenon which is called stress-induced hyperalgesia (SIH). While nociception has been studied in this paradigm, possible alterations occurring in passive avoidance (PA) learning after exposing rats to this type of stress has not been studied before.Materials and Methods:In the current study, we evaluated the effect of chronic swim stress (FS) or sham swim (SS) on nociception in both spinal (tail-flick) and supraspinal (53.5°C hot-pate) levels. Furthermore, PA task was performed to see whether chronic swim stress changes PA learning or not. Mobility of rats and anxiety-like behavior were assessed using open-field test (OFT).Results:Supraspinal pain response was altered by swim stress (hot-plate test). PA learning was impaired by swim stress, rats in SS group did not show such impairments. Rats in the FS group showed increased mobility (rearing, velocity, total distant moved (TDM) and decreased anxiety-like behavior (time spent in center and grooming) compared to SS rats.Conclusions:This study demonstrated the simultaneous impairment of PA and nociception under chronic swim stress, whether this is simply a co-occurrence or not is of special interest. This finding may implicate a possible role for limbic structures, though this hypothesis should be studied by experimental lesions in different areas of rat brain to assess their possible role in the pathophysiology of SIH.

Omega-3 fatty acids prevent LPS-induced passive avoidance learning and memory and CaMKII-α gene expression impairments in hippocampus of rat

BackgroundNeuroinflammation is considered to be a major factor in several neurodegenerative diseases. Recently, the polyunsaturated fatty acid omega-3 has been shown to have anti-inflammatory effects and might play an effective role in improving memory impairment due to inflammation. In order to test this, we stimulated neuroinflammation in an animal model and induced memory dysfunction as measured by reduced retention of passive avoidance learning (PAL) and altered expression of CaMKII-α, a gene known to be crucial for memory formation. We then investigated whether treatment with dietary omega-3 prevents inflammation-induced memory dysfunction in this model. MethodsMale wistar rats (200–220g) were fed either a control diet or a diet containing omega-3 (400mg/kg, po) for 1 month prior. Rats then received injection of either saline or LPS (500μg/kg, ip) and were subjected to the PAL acquisition task. The retention test was performed 24h later, and animals were sacrificed immediately. Hippocampi were dissected and stored at −80°C. Finally, TNF-α levels and CaMKII-α gene expression were measured by ELISA and qRT-PCR, respectively. ResultsWe found that LPS treatment significantly impaired PAL and memory, increased TNF-α levels and impaired CaMKII-α gene expression. In control and LPS-injected animals, pre-treatment with omega-3 improved performance on the PAL task and increased CAMKII-α gene expression. ConclusionTaken together, these data suggest that dietary omega-3 may improve cognitive function and provide a potential therapy for memory impairment due to neuroinflammation.

Abuse potential and adverse cognitive effects of mitragynine (kratom).

Mitragynine is the major psychoactive alkaloid of the plant kratom/ketum. Kratom is widely used in Southeast Asia as a recreational drug, and increasingly appears as a pure compound or a component of 'herbal high' preparations in the Western world. While mitragynine/kratom may have analgesic, muscle relaxant and anti-inflammatory effects, its addictive properties and effects on cognitive performance are unknown. We isolated mitragynine from the plant and performed a thorough investigation of its behavioural effects in rats and mice. Here we describe an addictive profile and cognitive impairments of acute and chronic mitragynine administration, which closely resembles that of morphine. Acute mitragynine has complex effects on locomotor activity. Repeated administration induces locomotor sensitization, anxiolysis and conditioned place preference, enhances expression of dopamine transporter- and dopamine receptor-regulating factor mRNA in the mesencephalon. While there was no increase in spontaneous locomotor activity during withdrawal, animals showed hypersensitivity towards small challenging doses for up to 14 days. Severe somatic withdrawal signs developed after 12 hours, and increased level of anxiety became evident after 24 hours of withdrawal. Acute mitragynine independently impaired passive avoidance learning, memory consolidation and retrieval, possibly mediated by a disruption of cortical oscillatory activity, including the suppression of low-frequency rhythms (delta and theta) in the electrocorticogram. Chronic mitragynine administration led to impaired passive avoidance and object recognition learning. Altogether, these findings provide evidence for an addiction potential with cognitive impairments for mitragynine, which suggest its classification as a harmful drug.

Anabolic steroids differentially modulate passive avoidance learning and food intake in male and female pubertal rats: Possible role of NPY

Anabolic androgenic steroids (AAS) are a class of steroid hormones derived from testosterone, being abused by adolescents, and known to affect anxiety, learning, and memory. The neural system underlying these behaviors includes the amygdala (AMY), a forebrain region that is known to express neuropeptide Y (NPY). NPY is one of the most abundant peptides in the brain and it plays a role in the regulation of energy homeostasis, anxiety and cognitive processes. Therefore, we aimed to assess NPY modulation in the AMY and in cognitive behavioral processes after chronic exposure to AAS in pubertal rats. Female and male pubertal rats were exposed to 17α‐methyltestosterone for two weeks. Food intake and body weight were measured during AAS exposure. For general anxiety and emotional memory, we used the Elevated Plus Maze (EPM) and the Passive Avoidance Task (PAT), respectively. Using RIA, we found a significant decrease in NPY levels in females, while there was no modulation in males. AAS in females showed an increase in body weight at the first and second weeks of AAS exposure, and an increase in food intake in the second week. In males, these differences were observed in the first, but not in the second week. Anxiety was not altered in male or female animals. Females but not males, showed a significant impairment of passive avoidance learning. Taken together, our results suggest that AAS can differentially modulate emotional memory and energy metabolism, maybe through NPY‐related neural circuits. Supported by RCMI (G12RR030551), NCRR‐NIH (P20RR016470).

5,19-cyclo-9β,10ξ-androstane-3,17-dione promotes neurotrophic factor biosynthesis in 1321N1 human astrocytoma cells and improves passive avoidance learning impairment

Since neurotrophic factors are essential for neurons to form neuronal networks and maintain neuronal functions, neurotrophic factor-like substances or inducers of neurotrophic factors can be useful for the treatment of serious neuronal diseases such as Alzheimer's and Parkinson's diseases. In the present study, we examined an effect of 5,19-cyclo-9β,10ξ-androstane-3,17-dione (CAD) on neurotrophic factor synthesis in glial cells and scopolamine-induced impairment of learning in mice. 1321N1 human astrocytoma cells promoted secretion of certain neurotrophic factors in response to CAD with no cytotoxicity, which caused dramatic neurite outgrowth in rat pheochromocytoma (PC12) cells. In fact, CAD significantly enhanced nerve growth factor (NGF) secretion and its gene expression in 1321N1 cells, in a time and concentration-dependent manner. Because second messengers such as cAMP, inositol 1,4,5-trisphosphates and Ca 2+ induce NGF gene expression, we measured activities of adenylyl cyclase and phospholipase C and intracellular Ca 2+ concentration in 1321N1 cells. However, CAD changed neither second messenger levels. CAD enhanced the gene expression of proto-oncogene, c-fos that is one of the components of transcription factor (AP-1). In addition to those above, the in vivo effects of CAD were also examined. Although injection of muscarinic receptor antagonist scopolamine impaired passive avoidance learning in mice, pretreatment with CAD significantly reversed the adverse effect in a dose-dependent manner. Taking these results together, CAD has enormous therapeutic potential for serious neuronal diseases.

The Medial Amygdala Controls the Coital Access of Female Rats: A Possible Involvement of Emotional Responsiveness

Partner preference and paced mating tests were accomplished in ovariectomized female rats following bilateral radiofrequency lesions in the medial amygdala. Open field behavior and passive avoidance learning were also examined to investigate the underlying behavioral mechanism. Partner preference was determined in a chamber located between castrated and sexually active males. Airborne olfactory cues were presented to the female through small holes on the partition. The lesion diminished preference for the odor of sexually active males over that of castrated males, even after injection with a high-dose of estrogen. On the other hand, in a paced mating test the lesioned females without estrogen treatment showed a significantly shorter latency for entering the male's compartment in a two-compartment apparatus, which allowed the females, but not the males, to cross the barrier through a narrow opening at the bottom. However, an administration of estrogen and progesterone reduced the effect. The lesion had no effect on emotionality or exploratory behavior in an open field test, but it impaired passive avoidance learning capability. We suggest that a male poses an inherent threat to a female. The seemingly incompatible results of partner preference and paced mating tests can be compromised if the male is inherently aversive to the female; this emotional response can be removed by the medial amygdala lesion.

Mild hypoxia preconditioning prevents impairment of passive avoidance learning and suppression of brain NGFI-A expression induced by severe hypoxia

The aim of this work was to study effects of mild preconditioning hypobaric hypoxia (380 Torr for 2 h, repeated 3 or 6 times spaced at 24 h) on brain NGFI-A immunoreactivity and passive avoidance (PA) behavior in rats exposed to severe hypoxia (160 Torr for 3 h). Severe hypobaric hypoxia produced extensive neuronal loss in hippocampal CA1, while the preceding hypoxic preconditioning had clear protective effect on neuronal viability of vulnerable hippocampal cells. Besides, the hypoxic preconditioning prevented impairment of acquisition and retention of PA caused by severe hypoxia. The six-trial hypobaric preconditioning was more effective in protection against PA learning deficits in severe hypoxia exposed rats than the three-trial preconditioning. The preconditioning up-regulated severe hypoxia-suppressed neocortical and hippocampal expression of NGFI-A, suggesting a possible role for NGFI-A in the neuroprotective mechanisms activated by hypoxic preconditioning.

NMDA receptor subunit and CaMKII changes in rat hippocampus induced by acute MDMA treatment: a mechanism for learning impairment.

Cognitive deficits have been reported in recreational 3,4-methylenedioxymethamphetamine (MDMA, "ecstasy") users. In rats and other animal species, acute MDMA administration produces an impairment in passive avoidance and other learning tasks. Different studies have shown that this learning deficit is not strictly related to the pronounced serotonin (5-HT) depletion induced by the drug. This study was aimed at determining if acute MDMA administration induces in the rat hippocampus early molecular changes related to memory impairment in a passive avoidance task. The membrane expression of key molecules in memory consolidation, such as the NR1 and NR2B subunits of the N-methyl-D-aspartate (NMDA) receptor, Ca2+/calmodulin-dependent protein kinase II (CaMKII) and protein phosphatase 1 (PP1) was measured. Some of these studies were also performed after 5-HT depletion induced by the 5-HT synthesis inhibitor p-chlorophenylalanine (PCPA). Neurochemical studies were performed in rats treated with MDMA and killed 90 min later and also in rats subjected to passive avoidance 30 min after MDMA treatment. Western blotting was used for measuring the levels of NMDA receptor subunits, CAMKII and PP1. Enzyme activity assays were also performed. In hippocampal membrane extracts, passive avoidance training increased NMDA receptor NR1 subunit expression as well as CaMKII levels and phosphorylated CaMKII. In untrained rats, MDMA reduced NR1 and NR2B protein levels, membrane CaMKII levels and enzyme activity, and enhanced PP1 levels and activity. In trained rats, MDMA prevented the learning-specific increase in NR1 subunit expression and membrane CaMKII/pCaMKII levels. After pronounced 5-HT depletion by PCPA, MDMA impaired passive avoidance retention to a similar extent and also prevented the training-associated changes in NR1 levels and CaMKII activity. Diminished function of hippocampal CaMKII and reduced levels of synaptic NMDA receptor subunits appear to be involved in the impairment of passive avoidance learning induced in rats by acute MDMA treatment.

Endomorphins 1 and 2 induce amnesia via selective modulation of dopamine receptors in mice

The involvement of dopamine receptors in the amnesic effects of the endogenous μ-opioid receptor agonists endomorphins 1 and 2 was investigated by observing step-down type passive avoidance learning in mice. Although the dopamine D1 receptor agonist R(+)-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine-7,8-diol hydrochloride ( R(+)-SKF38393) (0.05 and 0.1 mg/kg), the dopamine D1 receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine hydrochloride ( R(+)-SCH23390) (2.5 and 5 μg/kg) or the dopamine D2 receptor agonist N-n-phenethyl- N-propylethyl-p-(3-hydroxyphenyl)-ethylamine (RU24213) (0.3 and 1 mg/kg) had no significant effects on the endomorphin-1 (10 μg)- or endomorphin-2 (10 μg)-induced decrease in step-down latency of passive avoidance learning, (−)-sulpiride (10 mg/kg), a dopamine D2 receptor antagonist, significantly reversed the decrease in step-down latency evoked by endomorphin-2 (10 μg), but not by endomorphin-1 (10 μg). Taken together, it is likely that stimulation of dopamine D2 receptors results in the endomorphin-2-but not endomorphin-1-induced impairment of passive avoidance learning.

Involvement of μ 1-opioid receptors and cholinergic neurotransmission in the endomorphins-induced impairment of passive avoidance learning in mice

The effects of naloxonazine, a μ 1-opioid receptor antagonist, and physostigmine, a cholinesterase inhibitor, on the endomorphins-induced impairment of passive avoidance learning were investigated in mice. Endomorphin-1 (10 μg) and endomorphin-2 (10 μg) significantly impaired passive avoidance learning, while naloxonazine (35 mg/kg, s.c.), a μ 1-opioid receptor antagonist, which alone failed to influence passive avoidance learning significantly inhibited the endomorphin-1 (10 μg)- but not endomorphin-2 (10 μg)-induced disturbance of such learning. A rather nonselective higher dose (50 mg/kg, s.c.) of naloxonazine almost completely antagonized the endomorphin-1 (10 μg)- and endomorphin-2 (10 μg)-induced impairment of passive avoidance learning. In contrast, physostigmine (0.025 and 0.05 mg/kg, i.p.) significantly reversed the endomorphin-1 (10 μg)- and endomorphin-2 (10 μg)-induced disturbance of passive avoidance learning, whereas physostigmine (0.025 and 0.05 mg/kg, i.p.) alone did not influence such learning. These results suggest that endomorphin-1 but not endomorphin-2 impairs learning and memory resulting from cholinergic dysfunction, and from activation of μ 1-opioid receptors.

Behavioral Effects Following Subacute Inhalation Exposure to m-Xylene or Trimethylbenzene in the Rat : A Comparative Study

Trimethylbenzene (TMB), like xylene (dimethylbenzene), is a significant constituent of some industrial solvent mixtures. In earlier studies, we found that in the rat a subacute low-level inhalation exposure to some of the TMB isomers may result in behavioral alterations detectable weeks after the exposure [Neurotoxicol Teratol 19;1997:327; Int J Occup Med Environ Health 11;1998:319]. The purpose of the present study was to compare m-xylene (XYL) and each of the TMB isomers: 1,2,3-TMB (hemimellitene — HM), 1,2,4-TMB (pseudocumene — PS), and 1,3,5-TMB (mesitylene — MES) with respect to the ability for inducing behavioral effects in the rat. The rats (10–11 animals per group) were exposed repeatedly for 4 weeks (6 h per day, 5 days per week) to XYL (XYL group), HM (HM group), PS (PS group) or MES (MES group) at 100 ppm, or sham exposed (C group) in 1.3 cu/m dynamic inhalation chambers. Starting 2 weeks after exposure the following forms of rat’s behavior were assessed: radial maze performance, spontaneous activity in an open field, learning and retention of passive and active (two-way) avoidance response, and heat-induced paw licking before and after a 2 min footshock (a test for assessment of the stress response). None of the solvent-exposed groups differed considerably from the control one with respect to the radial maze performance. Compared to control rats, the rats of the XYL, PS and MES groups, but not those of HM group, showed a significantly higher spontaneous locomotor activity in the open field, an impaired passive avoidance learning and significantly longer paw-lick latencies 24 h after footshock. Acquisition, but not retention, of the two-way active avoidance response was significantly impaired in all solvent-exposed groups. The XYL group did not differ significantly from PS, MES or HM group in any of the behavioral parameters. The above results show that a short-term exposure to any of the TMB isomers or m-xylene at concentration as low as 100 ppm may induce persistent behavioral alterations in the rat.

Serotonergic Deficits and Impaired Passive-Avoidance Learning in Rats by MDEA: A Comparison With MDMA

The serotonergic deficits induced by 3,4-methylenedioxyethamphetamine (MDEA, “eve”), were examined and compared with 3,4 methylenedioxymethamphetamine (MDMA, “ecstasy”). A single dose of MDEA (10, 20, or 40 mg/kg IP) induced a dose-related hyperthermia, but only the highest dose significantly reduced 5-HT content and 5-HT transporter density in the frontal cortex and in the hippocampus 7 days later. Long-term serotonergic deficits were much more marked when MDEA was given repeatedly (40 mg/kg IP., b.i.d., for 4 consecutive days). Single or repeated administration of MDEA induced no change on 5-HT 1A receptor density in the frontal cortex, brain stem, or hippocampus, although 3 h after both treatments plasma corticosterone levels were significantly increased. MDEA (5–20 mg/kg, IP) produced significant retention deficits in a passive-avoidance learning task. Conversely, 7 days after the repeated administration of MDEA (40 mg/kg b.i.d., for 4 consecutive days) no effect on passive-avoidance performance was observed unless rats were treated again with another dose of MDEA (20 mg/kg IP) 30 min before the training trial. The 5-HT 1A receptor antagonist, WAY 100635, prevented the impairment in retention performance induced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), but not by MDEA or MDMA, indicating that the effect of these amphetamine derivates was not mediated by 5-HT 1A receptor activation. The results suggest the risk of serotonergic dysfunction associated with MDEA abuse in humans.

Effects of oral administration of the competitive N-methyl- d-aspartate antagonist, CGP 40116, on passive avoidance, spatial learning, and neuromotor abilities in mice

The effects were investigated of the potent competitive N-methyl- d-aspartate (NMDA) receptor antagonist CGP 40116 [D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid] on the performance of mice in water maze and passive avoidance tasks, and in wire suspension, rotarod, and cage activity tests. The drug was administered per os (p.o.) in its anticonvulsant dose range. CGP 40116 dose-dependently impaired passive avoidance learning when given before, but not when given after training. The antagonist (5, 10, and 20 mg/kg, administered 4 h before each training session) dose-dependently affected water maze acquisition, and impaired retention test performance in both hidden- and visible-platform water maze tasks. In addition, the drug dose-dependently decreased swimming speed during water maze acquisition. Repeated administration of CGP 40116 (20 mg/kg, p.o.) persistently decreased cage activity and wire suspension test performance, whereas motor coordination and equilibrium on the rotarod apparatus remained unimpaired. In our administration protocol, no tolerance was found to the effects of the drug on passive avoidance learning and neuromotor abilities. The parallel effects of CGP 40116 on memory and motor performance are discussed, and it was concluded that the antagonist impairs neuromotor abilities and also induces memory impairments which cannot be entirely reduced to motor interference.