Anxiety in rats with bile duct ligation is associated with activation of JNK3 mitogen-activated protein kinase in the hippocampus.

We examine the anxiety-like behaviors in rats with bile duct ligation (BDL), as well as its relationship with the expression of JNK3 and P38 MAPKs in rat hippocampus. Male Wistar rats undergo either sham operation or BDL as a rat model of cirrhotic HE. The anxiety-like behaviors are determined using a light/dark box test two hours befor the surgery on day 1 and on days 7, 14, 21 and 28 of BDL. The gene and protein expression levels of JNK3 and p38 in the hippocampus were examined respectively with qPCR and western blotting methods on day 28 of BDL. The results revealed that anxiety was increased in the cirrhotic HE model rats during 28 days of BDL. The molecular data indicated that the gene expression of Jnk3 and protein levels of JNK3, as well as phospho-JNK3, significantly increased in the hippocampus of the cirrhotic HE model rats compared to the sham control group. However, the results revealed no significant changes in the gene expression and the protein levels of p38 as well as phospho-p38 in the hippocampus of the cirrhotic HE model rats compared to the sham control group. We conclude that the increases in the expression and activation of JNK3 MAPK in the hippocampus may underlie, at least partly, the anxiety-like behaviors in rats with cirrhotic HE.

Molecular mechanisms underlying actions of certain long noncoding RNAs in Alzheimer's disease.

Long non-coding RNAs (lncRNAs) are a group of non-protein coding RNAs that have more than 200 nucleotides. LncRNAs play an important role in the regulation of protein-coding genes at the transcriptional and post-transcriptional levels. They are found in most organs, with a high prevalence in the central nervous system. Accumulating data suggests that lncRNAs are involved in various neurodegenerative disorders, including the onset and progression of Alzheimer's disease (AD). Recent insights suggest lncRNAs, such as BACE1-AS, 51A, 17A, NDM29 and AS-UCHL1, are dysregulated in AD tissues. Furthermore, there are ongoing efforts to explore the clinical usability of lncRNAs as biomarkers in the disease. In this review, we explore the mechanisms by which aberrant expressions of the most studied lncRNAs contribute to the neuropathologies associated with AD, including amyloid ß plaques and neurofibrillary tangles. Understanding the molecular mechanisms of lncRNAs in patients with AD will reveal novel diagnosis strategies and more effective therapeutic targets.

Hepatic encephalopathy induces site-specific changes in gene expression of GluN1 subunit of NMDA receptor in rat brain.

We investigate changes in gene expression of GluN1 subunit of N-Methyl-D-Aspartate (NMDA) receptor in the prefrontal cortex (PFC), hippocampus and striatum in a rat model of hepatic encephalopathy (HE). We used male Wistar rats in which HE was induced after a common bile duct ligation (BDL). The animals were divided into three sets, and each set included three groups of control, sham operated and BDL. In the first set of animals, blood samples collected for biochemical analysis on day 21 of BDL. In the second set, changes in nociception threshold was assessed on day 21 of BDL using a hotplate test. In the third set, whole brain extracted, and the PFC, the hippocampus and the striatum in each rat were immediately dissected. We used a semi-quantitative RT-PCR method for evaluating the GluN1 gene expression. The biochemical analyses showed that plasma levels of ammonia and bilirubin in BDL rats were significantly increased compared to the sham control group on day 21 of BDL (P < 0.01). Nociception threshold was also increased in rats with BDL compared to sham group (P < 0.001). The results revealed that the GluN1 gene expression at mRNA levels in BDL group was decreased by 19 % in the PFC (P < 0.05) but increased by 82 % in the hippocampus (P < 0.01) compared to the sham control group; however, no significant change was observed in the striatum. It can be concluded that HE affects the GluN1 gene expression in rat brain with a site-specific pattern, and the PFC and hippocampus are more sensitive areas than striatum.

The Inflammation/NF-κB and BDNF/TrkB/CREB Pathways in the Cerebellum Are Implicated in the Changes in Spatial Working Memory After Both Morphine Dependence and Withdrawal in Rat.

We aimed to explore the impact of the cerebellum on the decline in spatial working memory following morphine dependence and withdrawal. Two groups of male Wistar rats received intraperitoneal injections of either saline (1 ml/kg) or morphine (10 mg/kg) twice daily for 10 days, serving as the control and dependent groups. Additionally, a withdrawal group underwent a 30-day withdrawal period after the dependence phase. Spatial working memory was assessed using a Y maze test. ELISA and western blot were used to assess protein levels in the cerebellum. On day 1, morphine impaired spatial working memory, deteriorated further after 10 days of morphine use, and nearly returned to its initial level following a 30-day withdrawal period. On day 10, significant increases in TNF-α, IL-1ß, and CXCL12 and a notable decrease in IL-10 levels were detected in the morphine-dependent group, which did not completely restore in the withdrawal group. The protein levels of CXCR4, TLR4, P2X7R, and NF-κB sharply increased in the morphine-dependent group. However, these levels almost returned to normal after withdrawal. In the morphine-dependent group, BDNF decreased, while TrkB and CREB1 increased noticeably. Nevertheless, after withdrawal, TrkB and CREB1 but not BDNF levels returned to normal. In the morphine-dependent group, both CACNA1 and KCNMA1 decreased significantly and after withdrawal, only KCNMA1 showed partial restoration, while CACNA1 did not. It can be concluded that inflammation/NF-κB and BDNF/TrkB/CREB pathways play key roles in neural adaptation within the cerebellum, contributing to the decline in spatial working memory after both morphine dependence and withdrawal.

Alpha-Pinene Decreases the Elevated Levels of Astrogliosis, Pyroptosis, and Autophagy Markers in the Hippocampus Triggered by Kainate in a Rat Model of Temporal Lobe Epilepsy.

The development and progression of temporal lobe epilepsy (TLE) are heavily influenced by inflammation, excessive activation of glial cells, and neuronal cell death. This study aimed to investigate the effects of treatment with alpha-pinene (APN) on pro-and anti-inflammatory cytokine levels, astrogliosis, pyroptosis, and autophagy markers in the hippocampus in a rat model of TLE induced by kainic acid (KA). Male Wistar rats were employed, and TLE was induced by intracerebroventricular injection of KA. APN (50 mg/kg) was intraperitoneally administered for 19 days, including two weeks before and five days after the administration of KA. After full recovery from anesthesia and KA injection, the seizure-related behavioral expressions were evaluated. On day 19, the hippocampal levels of IL-1ß, TNF-α, progranulin, IL-10, ERK1/2, phospho-ERK1/2, NF-κB, GFAP, S100-B, NLRP1, NLRP3, caspase-1, and becline-1 were examined. The results revealed that treatment with APN significantly diminished the heightened levels of IL-1ß, TNF-α, progranulin, ERK1/2, and NF-κB and reversed the reduced levels of the anti-inflammatory cytokine, IL-10, in the hippocampus caused by KA. Furthermore, administration of APN significantly reduced the levels of astrogliosis, pyroptosis, and autophagy markers in the hippocampus that were elevated by KA. It can be concluded that treatment with APN for 19 days alleviated neuroinflammation by inhibiting ERK1/2 and NF-κB signaling pathways and prevented increases in astrogliosis, pyroptosis, and autophagy markers in the hippocampus in a rat model of TLE.

ß-Adrenoceptors in the dorsal hippocampus are involved in ethanol-induced state-dependent retrieval in mice.

This study was designed to investigate the involvement of ß-adrenoceptors of the dorsal hippocampus (DH) in ethanol-induced state-dependent retrieval. We used a step-down type of inhibitory avoidance (IA) task to assess retrieval in male NMRI mice. Bilateral guide cannulae were implanted in the DH. The results showed that in the animals with pre-training injections of ethanol (1g/kg, i.p.) and pre-test saline treatment memory retrieval was impaired. Pre-test injections of ethanol (0.5 and 1g/kg, i.p.) also impaired memory retrieval in the animals that received saline before training. Ethanol (1g/kg, i.p.), when injected in both time points of pre-training and pre-test, induced state-dependent retrieval. The results also revealed that intra-DH infusions of a ß-adrenoceptor agonist salbutamol (0, 0.0025, 0.005, 0.01 and 0.02 µg/mouse) by itself had no significant effect, however, along with an ineffective dose of ethanol (0.25 g/kg) significantly improved memory retrieval. On the other hand, pre-test intra-DH infusions of different doses of a non-selective ß-adrenoceptor antagonist propranolol (0, 0.1, 0.3 and 0.5 µg/mouse) by itself had no effect on memory retrieval. But, pre-test intra-DH infusions of the same doses of propranolol (0, 0.1, 0.3 and 0.5 µg/mouse) disrupted ethanol-induced state-dependent retrieval. Interestingly, intra-DH infusions of propranolol (0.05, 0.75 and 0.1 µg/mouse) inhibited the improving effect of salbutamol on state-dependent retrieval. In conclusion, the results support the existence of a functional involvement of ß-adrenoceptors in the DH in ethanol-induced state-dependent retrieval.

Alpha-Pinene Exerts Antiseizure Effects by Preventing Oxidative Stress and Apoptosis in the Hippocampus in a Rat Model of Temporal Lobe Epilepsy Induced by Kainate.

Oxidative stress and apoptosis following seizures play pivotal roles in the consequences of repeated seizures. Beneficial effects of alpha-pinene (APN) have been reported in some experimental models of neurodegenerative diseases. However, its neuroprotective efficacy in a rat model of temporal lobe epilepsy (TLE) induced by kainic acid (KA) has remained unexplored. We aimed to explore the possible antiseizure effects of APN pretreatment and underlying molecular mechanisms in a rat model of TLE induced by KA. TLE was induced in male Wistar rats by intracerebroventricular injection of KA. APN at a dose of 50 mg/kg/day was intraperitoneally injected for 2 weeks before induction of TLE. One day after the induction of TLE, behavioral expressions of seizure were recorded and scored using Racine's scale. Furthermore, the hippocampal levels of oxidative stress markers, B-cell lymphoma 2 (Bcl2), BCL2-associated X protein (BAX), and c-Jun N-terminal kinase (JNK) protein levels were also assessed. Histopathological assessment in the hippocampus was performed with Nissl staining 5 days following induction of TLE. The results revealed that APN pretreatment alleviated epileptic seizures, diminished oxidative stress indicators, blocked the mitochondrial apoptotic pathway via decreasing BAX and raising BCL2 protein levels in the hippocampus at least partly through inhibiting JNK activity, and decreased neuronal death in the CA3 and hilus regions. These findings reveal that APN pretreatment mitigates KA-induced seizures by blocking oxidative stress and neuronal damage factors. It can be concluded that APN has a potent potential to be considered an antiseizure medication, but it needs further investigation.

Alpha-pinene moderates memory impairment induced by kainic acid via improving the BDNF/TrkB/CREB signaling pathway in rat hippocampus.

Introduction: The potential benefits of natural ingredients in the alleviation of neurodegenerative disorders are of great interest. Alpha-pinene (APN) is an essential oil belonging to monoterpenes with multiple beneficial effects. In this study, the possible improving effects of alpha-pinene on memory impairment induced by kainic acid and the underlying molecular mechanisms were examined. Methods: Memory impairment was induced by i.c.v. injection of kainic acid (KA) in male Wistar rats. Alpha-pinene (50 mg/kg/day, i.p.) was injected for 21 days, including 14 days before the KA injection and seven days afterward. Spatial working memory and inhibitory avoidance (IA) memory performance were assessed five and even days following KA injection, respectively. The hippocampal protein levels of brain-derived neurotrophic factor (BDNF), tropomyosin-like receptor kinase B (TrkB), cAMP response element binding protein (CREB), and neuronal loss in the CA1 region were also examined. Results: Results revealed that the i.c.v. injection of KA triggered memory impairment, which was notably diminished by alpha-pinene pre-and post-treatment. Histopathological evaluation revealed that alpha-pinene significantly moderated the attenuation in CA1 alive neurons induced by KA injection. Western blotting analysis confirmed that alpha-pinene pre-and post-treatment significantly reversed the KA-induced decreases in the hippocampal levels of BDNF, TrkB, phosphorylated TrkB, CREB, and phosphorylated CREB. Discussion: These findings suggest that alpha-pinene pre-and post-treatment moderate memory impairment induced by KA by restoring the BDNF/TrkB/CREB signaling pathway in the rat hippocampus.

Brain Renin-Angiotensin System: From Physiology to Pathology in Neuronal Complications Induced by SARS-CoV-2.

Angiotensin-converting enzyme 2 (ACE2), a key enzyme in the renin-angiotensin system (RAS), is expressed in various tissues and organs, including the central nervous system (CNS). The spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease-2019 (COVID-19), binds to ACE2, which raises concerns about the potential for viral infection in the CNS. There are numerous reports suggesting a link between SARS-CoV-2 infection and neurological manifestations. This study aimed to present an updated review of the role of brain RAS components, especially ACE2, in neurological complications induced by SARS-CoV-2 infection. Several routes of SARS-CoV-2 entry into the brain have been proposed. Because an anosmia condition appeared broadly in COVID-19 patients, the olfactory nerve route was suggested as an early pathway for SARS-CoV-2 entry into the brain. In addition, a hematogenous route via disintegrations in the blood-brain barrier following an increase in systemic cytokine and chemokine levels and retrograde axonal transport, especially via the vagus nerve innervating lungs, have been described. Common nonspecific neurological symptoms in COVID-19 patients are myalgia, headache, anosmia, and dysgeusia. However, more severe outcomes include cerebrovascular diseases, cognitive impairment, anxiety, encephalopathy, and stroke. Alterations in brain RAS components such as angiotensin II (Ang II) and ACE2 mediate neurological manifestations of SARS-CoV-2 infection, at least in part. Downregulation of ACE2 due to SARS-CoV-2 infection, followed by an increase in Ang II levels, leads to hyperinflammation and oxidative stress, which in turn accelerates neurodegeneration in the brain. Furthermore, ACE2 downregulation in the hypothalamus induces stress and anxiety responses by increasing corticotropin-releasing hormone. SARS-CoV-2 infection may also dysregulate the CNS neurotransmission, leading to neurological complications observed in severe cases of COVID-19. It can be concluded that the neurological manifestations of COVID-19 may be partially associated with changes in brain RAS components.

Repeated Use of Morphine Induces Anxiety by Affecting a Proinflammatory Cytokine Signaling Pathway in the Prefrontal Cortex in Rats.

We examined the role of toll-like receptors (TLRs) and proinflammatory cytokine signaling pathways in the prefrontal cortex (PFC) in anxiety-like behaviors after repeated use of morphine. Morphine (10 mg/kg) was used twice daily for 8 days to induce morphine dependence in male Wistar rats. On day 8, opioid dependence was confirmed by measuring naloxone-precipitated withdrawal signs. On days 1 and 8, anxiety-like behaviors were evaluated using a light/dark box test. Expression of TLR1 and 4, proinflammatory cytokines, and some of the downstream signaling molecules was also evaluated in the bilateral PFC at mRNA and protein levels following morphine dependence. The results revealed that morphine caused anxiolytic-like effects on day 1 while induced anxiety following 8 days of repeated injection. On day 8, a significant decrease in TLR1 expression was detected in the PFC in morphine-dependent rats, but TLR4 remained unaffected. Repeated morphine injection significantly increased IL1-ß, TNFα, and IL6 expression, but decreased IL1R and TNFR at mRNA and protein levels except for IL6R at the protein level in the PFC. The p38α mitogen-activated protein (MAP) kinase expression significantly increased but the JNK3 expression decreased in the PFC in morphine-dependent rats. Repeated injection of morphine also significantly increased the NF-κB expression in the PFC. Further, significant increases in Let-7c, mir-133b, and mir-365 were detected in the PFC in morphine-dependent rats. We conclude that TLR1 and proinflammatory cytokines signaling pathways in the PFC are associated with the anxiogenic-like effects of morphine following its chronic use in rats via a MAP kinase/NF-κB pathway.

Activation of cannabinoid CB1 receptors in the central amygdala impairs inhibitory avoidance memory consolidation via NMDA receptors.

In the present study, we investigated the influence of bilateral intra-central amygdala (intra-CeA) microinjections of N-methyl-D-aspartate (NMDA) receptor agents on amnesia induced by a cannabinoid CB1 receptor agonist, arachydonilcyclopropylamide (ACPA). This study used a step-through inhibitory (passive) avoidance task to assess memory in adult male Wistar rats. The results showed that intra-CeA administration of ACPA (2 ng/rat) immediately after training decreased inhibitory avoidance (IA) memory consolidation as evidenced by a decrease in step-through latency on the test day, which was suggestive of drug-induced amnesia. Post-training intra-CeA microinjections of NMDA (0.0001, 0.001 and 0.01 µg/rat) did not affect IA memory consolidation. However co-administration of NMDA with ACPA (2 ng/rat) prevented the impairment of IA memory consolidation that was induced by ACPA. Although post-training intra-CeA administration of the NMDA receptor antagonist, D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5; 0.01, 0.05 and 0.1 µg/rat) alone had no effect, its co-administration with an ineffective dose of ACPA (1 ng/rat) impaired IA memory consolidation. Post-training intra-CeA microinjection of an ineffective dose of D-AP5 (0.01 µg/rat) prevented an NMDA response to the impaired effect of ACPA. These results suggest that amnesia induced by intra-CeA administration of ACPA is at least partly mediated through an NMDA receptor mechanism in the Ce-A.

Differential expression of H19, BC1, MIAT1, and MALAT1 long non-coding RNAs within key brain reward regions after repeated morphine treatment.

Morphine-induced analgesic tolerance and dependence are significant limits of pain control; however, the exact molecular mechanisms underlying morphine tolerance and dependence have remained unclear. The role of long non-coding RNAs (lncRNAs) in morphine tolerance and dependence is yet to be determined. We aimed to explore the association of specific lncRNAs expression in key brain reward regions after repeated injection of morphine. Male Wistar rats received subcutaneous injections of twice-daily morphine (10 mg/kg) or saline (1 mL/kg) for eight days. On day 8 of the repeated injections, induction of morphine analgesic tolerance and dependence was confirmed through a hotplate test and a naloxone-precipitated withdrawal analysis, respectively. Expression of H19, BC1, MIAT1, and MALAT1 lncRNAs was determined from the midbrain, striatum, hypothalamus, prefrontal cortex (PFC), and hippocampus by real-time PCR on day 8 of the repeated injections. The H19 expression was significantly different between morphine-treated and control saline-treated rats in all investigated areas except for the hippocampus. The BC1 expression significantly altered in the midbrain, hypothalamus, and hippocampus, but not in the striatum and PFC after repeated morphine treatment. The MIAT1 and MALAT1 expression site-specifically altered in the midbrain, hypothalamus, and striatum; however, no significant changes were detected in their expression in the PFC and hippocampus after repeated morphine treatment. We conclude that alterations in the expression of these lncRNAs in the brain reward regions especially in the midbrain, striatum and hypothalamus may have critical roles in the development of morphine dependence and tolerance, which need to be considered in future researches.

Inhibitory avoidance memory deficit induced by scopolamine: Interaction of cholinergic and glutamatergic systems in the ventral tegmental area.

Interaction of cholinergic and glutamatergic inputs in the ventral tegmental area (VTA) influencing a learned behavior is a topic of great interest. In the present study the effect of intra-VTA administration of a nonselective muscarinic acetylcholine antagonist, scopolamine, and N-methyl-d-aspartate (NMDA) receptor agents by themselves as well as their interactions on consolidation and retrieval of inhibitory avoidance (IA) memory have been investigated. A step-through inhibitory avoidance task was used for memory assessment in male Wistar rats. The results showed that intra-VTA administration of scopolamine (1 and 2microg/rat) and NMDA receptor antagonist, MK-801 (0.75 and 1microg/rat) immediately after training, impaired consolidation of IA memory. Interestingly, co-administration of an ineffective dose of MK-801 (0.5microg/rat) with ineffective doses of scopolamine (0.25 and 0.5microg/rat) significantly decreased the consolidation process. Post-training intra-VTA injections of NMDA (0.001 and 0.01microg/rat) had no effects by itself, whereas its co-administration with scopolamine (2microg/rat) prevented the effect of the later drug. The results also showed that pre-test intra-VTA administration of scopolamine (3 and 4microg/rat) and MK-801 (1 and 2microg/rat) impaired retrieval of the IA memory. Moreover, co-administration of an ineffective dose of MK-801 (0.5microg/rat) with ineffective doses of scopolamine (1 and 2microg/rat) increasingly reduced the retrieval of the IA memory. On the contrary to its post-training treatment, pre-test administration of NMDA either alone or in combination with scopolamine caused no significant effect on retrieval of IA memory. It can be concluded that muscarinic acetylcholine and NMDA glutamate receptors in the VTA are involved in the mechanism(s) underlying consolidation and retrieval of the IA memory.

Inhibitory avoidance memory deficit induced by scopolamine: interaction with glutamatergic system in the nucleus accumbens.

The possible involvement of N-methyl-D-aspartate (NMDA) receptors of the nucleus accumbens (NAc) in amnesia induced by scopolamine was investigated. An inhibitory (passive) avoidance task was used for memory assessment in male Wistar rats. The results revealed that intra-NAc administration of a nonselective muscarinic acetylcholine antagonist, scopolamine (1 and 2 g/rat) impaired memory consolidation in the animals when tested 24 h later. Post-training intra-NAc administration of NMDA (0.005 and 0.01 g/rat) also impaired memory consolidation, whereas post-training intra-NAc administration of the NMDA receptor antagonist, MK-801 (0.5, 1 and 1.5 g/rat) did not. Intra-NAc co-administration of an ineffective dose of NMDA with ineffective doses of scopolamine (0.25 and 0.5 g/rat) after training had no significant effect on memory consolidation, but intra-NAc injections of effective doses of NMDA (0.005 and 0.01 g/rat) prevented the amnesic effect of an effective dose of scopolamine (2 g/rat). In contrast, intra-NAc co-administration of MK-801 (0.5, 1 and 1.5 g/rat) along with an effective dose of scopolamine (2 g/rat) did not prevent the effect of the latter drug. It can be concluded that NMDA receptors in the NAc are involved in the modulation of memory consolidation that was affected by scopolamine.

Mesoporous silica SBA-15 decreases hyperammonemia and affects the gene expression of mitogen-activated protein kinases in the prefrontal cortex of rats with bile duct ligation.

OBJECTIVES: We aim to examine possible ammonia lowering effects of mesoporous silica SBA-15 in rats after the common bile duct ligation (BDL). We also evaluate the effect of SBA-15 treatments during 28 days of BDL on locomotion and rearing behavior, as well as on the gene expression of Jnk3 and p38alpha (p38α) mitogen-activated protein kinases in the prefrontal cortex (PFC). MATERIALS AND METHODS: SBA-15 was prepared with the hydrothermal method from the surfactant P123 and tetraethyl orthosilicate (TEOS), and calcined at 550 ºC. Then, the product was characterized by FT-IR, XRD, SEM, and BJH-BET techniques. Male Wistar rats in sham control and a group with BDL received saline but another group with BDL received SBA-15 during 28 days of BDL. We examined all groups of rats weekly for locomotion and rearing behavior; then on day 28, we sacrificed all rats, collected the blood sample, and finally dissected the PFC from the whole brain. RESULTS: The SBA-15 treatments had no effect on locomotion but improved rearing behavior on days 7 and 14 of BDL. Biochemical analysis indicated that the SBA-15 treatments in rats with BDL significantly decreased hyperammonemia. The results also revealed that the SBA-15 treatments in rats with BDL significantly restored the decreased Jnk3 gene expression, and increased the p38α gene expression in the PFC. CONCLUSION: We conclude that SBA-15 can be used as an ammonia lowering agent in hepatic encephalopathy; however, its improving effects on locomotion and neuroinflammation, as well as signaling molecules in the brain need more investigations.

Calcium-dependent kinases in the brain have site-specific associations with locomotion and rearing impairments in rats with bile duct ligation.

We study the impairment of locomotion and rearing behavior in rats with a common bile duct ligation (BDL), and the possible involvement of the PKCγ and CamKIIα gene expression in the brain. Male Wistar rats undergo either sham operation or BDL to induce a rat model of cirrhotic hepatic encephalopathy (HE). Six groups of the animals were divided into three sets of sham-operated and BDL groups. In the first set, locomotion and rearing behavior were assessed on days 1, 7, 14, 21 and 28 of BDL. On day 28 of BDL, blood samples were collected from the second set of the animals for biochemical analysis, and the rats in the third set were used to extract the PFC, the hippocampus, and the cerebellar cortex for examining the Pkcγ and CamKIIα gene expression. The results showed that locomotion and rearing were decreased during 28 days of BDL with the most significant change on the 28th day. Biochemical analysis of the blood revealed hyperammonemia, increases in liver enzymes, and a decrease in albumin indicating liver damage and induction of cirrhotic HE. The results also showed that both of the Pkcγ and CamKIIα gene expressions were increased in the PFC but decreased in the hippocampus. However, the Pkcγ gene expression was decreased but the CamKIIα gene expression was increased in the cerebellar cortex. It can be concluded that the Ca2+-dependent kinases in different brain areas have a site-specific association with the impairment of locomotion and rearing behavior in the cirrhotic HE model rats.

The dopaminergic system plays a role in the effect of lithium on inhibitory avoidance memory in mice.

The effects of dopaminergic drugs on the inhibitory avoidance memory affected by lithium were examined in the Naval Medical Research Institute (NMRI) mice using a single-trial step-down inhibitory (passive) avoidance task. The results showed that post-training administration of lithium (10 mg/kg, i.p.) decreased the step-down latency on the test day, which was fully or partly reversed by pre-test administration of the same dose of the drug; suggesting state-dependent learning induced by lithium. Our results also showed that pre-test (i.p.) administration of the dopamine D1 receptor agonist SKF38393 and the dopamine D2 receptor agonist quinpirole by themselves and in combination with ineffective doses of lithium (0.3, 0.6 and 1.25 mg/kg) reversed the decrease of the step-down latency induced by post-training lithium. In contrast, pre-test administration of the dopamine D1 receptor antagonist SCH23390 (0.025, 0.05 and 0.1 mg/kg, i.p.) and the dopamine D2 receptor antagonist sulpiride (6.25 and 12.5 mg/kg, i.p.) alone or in combination with pre-test lithium (10 mg/kg), did not significantly alter the step-down latency on the test day, except for a higher dose of sulpiride (25 mg/kg) which by itself increased the step-down latency. Furthermore, pre-test administration of a lower dose of sulpiride (3 mg/kg) in combination with ineffective doses of lithium (03, 0.6 and 1.25 mg/kg) also reversed the decrease in the step-down latency induced by post-training lithium. In conclusion, the dopamine D1 and D2 receptor mechanism(s) may be involved, at least partly, in the effect of lithium on retrieval of the inhibitory avoidance memory influenced by the drug.

Decreased AMPA GluR2, but not GluR3, mRNA expression in rat amygdala and dorsal hippocampus following morphine-induced behavioural sensitization.

1. Repeated administration of psychostimulants and micro-opioid receptor agonists elicits a progressive enhancement of drug-induced behavioural responses, a phenomenon termed behavioural sensitization. These changes in behaviour may reflect plastic changes requiring regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptor function. 2. In the present study, rats were treated for 7 days with saline or morphine (10 mg/kg). After a washout period of either 24 h or 7 days, locomotion, oral stereotypy and state-dependent memory in a passive avoidance test were measured in the presence or absence of 6-cyano-7-nitroquinoxaline-2,3-dione disodium salt (CNQX; 3 mg/kg), an AMPA receptor antagonist. In order to evaluate the mechanism underlying the behavioural responses, quantitative real-time reverse transcription-polymerase chain reaction was used to evaluate mRNA expression of the AMPA receptor subunits GluR2 and GluR3 in the striatum, prefrontal cortex, hippocampus, hypothalamus and amygdala of animals treated repeatedly with morphine. 3. The results indicate that repeated morphine treatment followed by 7 days (but not 24 h) washout produces behavioural sensitization, as determined by locomotion, oral stereotypy and state-dependent memory. Blockade of AMPA receptors with CNQX on the test day did not alter these behavioural responses. In addition, repeated morphine treatment followed by 7 days (but not 24 h) washout decreased GluR2 mRNA expression in both the amygdala (by 50%) and hippocampus (by 35%). Repeated morphine treatment did not alter GluR3 mRNA expression in any brain area assessed. 4. These data imply that AMPA receptors are involved in the development (but not expression) phase of behavioural sensitization. The decreases in GluR2 mRNA expression in the amygdala and hippocampus may result in the formation of calcium-permeable AMPA receptors, which are believed to play an important role in behavioural sensitization.

Repeated administration of histamine improves memory retrieval of inhibitory avoidance by lithium in mice.

The influence of repeated administration of histamine on lithium-induced state dependency has been investigated. A single-trial step-down inhibitory avoidance task was used to assess memory in adult male NMRI mice. Intraperitoneal (i.p.) administration of lithium (10 mg/kg), immediately after training (post-training), impaired inhibitory avoidance memory on the test day. Pre-test administration of lithium reversed amnesia induced by the drug given after training, with the maximum response at a dose of 10 mg/kg. Repeated intracerebroventricular (i.c.v.) administration of histamine (20 microg/mouse) for 3 consecutive days followed by 5 days of no drug treatment improved memory retrieval of inhibitory avoidance by a pre-test lower dose (5 mg/kg i.p.) of lithium. In contrast, 3 days of i.c.v. injections of both the histamine H1 receptor antagonist pyrilamine (40 microg/mouse) and the histamine H2 receptor antagonist ranitidine (6.25 and 12.5 microg/mouse) prevented the improving effect of pre-test lithium (10 mg/kg i.p.) on memory retrieval. The results suggest that the repeated administration of histaminergic agents may induce a sensitization which affects the memory impairment induced by lithium.

Morphine-induced behavioral sensitization increased the mRNA expression of NMDA receptor subunits in the rat amygdala.

This study was designed to evaluate the effect of repeated morphine treatment on rat behavioral responses. In the genetic section, the mRNA expression of NMDA receptor subunits (NR1 and NR2A) was measured in certain areas of the male rat brain (striatum, prefrontal cortex, hippocampus, hypothalamus and amygdala). In the behavioral section, the effect of repeated morphine treatment on animal models such as locomotion, oral stereotypy, and state-dependent memory in a passive avoidance test was evaluated in the presence or absence of MK801 (NMDA receptor antagonist). Our results showed that chronic morphine treatment, followed by a 7-day (but not 24-hour) washout period, potentiated the effect of test doses of morphine, which is referred to as behavioral sensitization. Meanwhile, pretreatment of animals with MK801 (0.1 and 0.25 mg/kg), 30 min before a test dose of morphine (5 mg/kg), failed to attenuate the locomotion and oral stereotypy in the behavioral sensitization state. Interestingly, a higher dose of MK801 (0.25 mg/kg) decreased memory retrieval induced by morphine (2.5 mg/kg) in state-dependent memory. This effect may be due to the intrinsic motor enhancer property of higher doses of MK801, rather than the blockade of NMDA receptors. It can be concluded that MK801 does not affect morphine-induced behavioral sensitization in the expression phase. In the genetic section of the study, results of quantitative real-time RT-PCR clearly indicated that morphine sensitization increased the expression of NMDA receptor subunits mRNA in the amygdala (NR1 by 104% and NR2A by 85%), while the other areas of the brain were unaffected. Maenwhile, no change in the mRNA levels was observed in non-sensitized animals (chronic morphine treatment followed by a 24-hour washout period). In summary, the present study indicates that repeated morphine treatment followed by long-term (7-day washout) induces behavioral sensitization and causes a delayed increase in mRNA levels of NMDA receptor subunits in the rat amygdala. Meanwhile, it has previously been reported that the amygdala is involved in behavioral sensitization. Thus, it can be concluded that the increase in NMDA receptor expression is associated with morphine-induced behavioral sensitization.