Repeated pre-exposure to morphine inhibited the amnesic effect of ethanol on spatial memory: Involvement of CaMKII and BDNF.

Evidence has suggested that addiction and memory systems are related, but the signaling cascades underlying this interaction have not been completelyealed yet. The importance of calcium-calmodulin-dependent protein kinase II (CaMKII) and brain-derived neurotrophic factor (BDNF) in the memory processes and also in drug addiction has been previously established. In this present investigation, we examined the effects of repeated morphine pretreatment on impairment of spatial learning and memory acquisition induced by systemic ethanol administration in adult male rats. Also, we assessed how these drug exposures influence the expression level of CaMKII and BDNF in the hippocampus and amygdala. Animals were trained by a single training session of 8 trials, and a probe test containing a 60-s free-swim without a platform was administered 24 h later. Before training trials, rats were treated with a once-daily subcutaneous morphine injection for 3 days followed by a 5-day washout period. The results showed that pre-training ethanol (1 g/kg) impaired spatial learning and memory acquisition and down-regulated the mRNA expression of CaMKII and BDNF. The amnesic effect of ethanol was suppressed in morphine- (15 mg/kg/day) pretreated animals. Furthermore, the mRNA expression level of CaMKII and BDNF increased significantly following ethanol administration in morphine-pretreated rats. Conversely, this improvement in spatial memory acquisition was prevented by daily subcutaneous administration of naloxone (2 mg/kg) 15 min prior to morphine administration. Our findings suggest that sub-chronic morphine treatment reverses ethanol-induced spatial memory impairment, which could be explained by modulating CaMKII and BDNF mRNA expressions in the hippocampus and amygdala.

Modulation of autophagy by melatonin via sirtuins in stroke: From mechanisms to therapies.

Sirtuins perform an important effect on the neural cell fate following stroke. Several mechanisms that have been correlated with stroke are oxidative stress, apoptosis, necrosis and autophagy. Autophagy is usually regarded as unitary of the neural cell survival mechanisms. Recently, the importance of the sirtuins effect on autophagy by antioxidant agents for stroke treatment mentioned in various studies. One of these agents is melatonin. Melatonin can modulate autophagy by changing on sirtuin pathways. Melatonin and its metabolites adjust various sirtuins pathways related to apoptosis, proliferation, metastases, autophagy and inflammation in case of stroke. In this review, we will discuss about the modulation of autophagy by melatonin via sirtuins in stroke.

Neurological manifestations of coronavirus infections, before and after COVID-19: a review of animal studies.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus, which was first identified in December 2019 in China, has resulted in a yet ongoing viral pandemic. Coronaviridae could potentially cause several disorders in a wide range of hosts such as birds and mammals. Although infections caused by this family of viruses are predominantly limited to the respiratory tract, Betacoronaviruses are potentially able to invade the central nervous system (CNS) as well as many other organs, thereby inducing neurological damage ranging from mild to lethal in both animals and humans. Over the past two decades, three novel CoVs, SARS-CoV-1, MERS-CoV, and SARS-CoV-2, emerging from animal reservoirs have exhibited neurotropic properties causing severe and even fatal neurological diseases. The pathobiology of these neuroinvasive viruses has yet to be fully known. Both clinical features of the previous CoV epidemics (SARS-CoV-1 and MERS-CoV) and lessons from animal models used in studying neurotropic CoVs, especially SARS and MERS, constitute beneficial tools in comprehending the exact mechanisms of virus implantation and in illustrating pathogenesis and virus dissemination pathways in the CNS. Here, we review the animal research which assessed CNS infections with previous more studied neurotropic CoVs to demonstrate how experimental studies with appliable animal models can provide scientists with a roadmap in the CNS impacts of SARS-CoV-2. Indeed, animal studies can finally help us discover the underlying mechanisms of damage to the nervous system in COVID-19 patients and find novel therapeutic agents in order to reduce mortality and morbidity associated with neurological complications of SARS-CoV-2 infection.

The effect of microinjection of CART 55-102 into the nucleus accumbens shell on morphine-induced conditioned place preference in rats: Involvement of the NMDA receptor.

The addictive properties of opioids may be mediated to some extent by cocaine-and amphetamine-regulated transcript (CART) in the reward pathway. Moreover, some claims CART interacts with the glutamate system. Here, we evaluated whether intra-nucleus accumbens (NAc) shell infusions of CART induces Conditioned Place Preference (CPP) or Conditioned Place Aversion (CPA) and affects morphine reward. We also measured NR1 subunit expressions of the N-methyl-d-aspartate (NMDA) receptor in various parts of the reward pathway (NAc, prefrontal cortex and hippocampus) after conditioning tests. Animals with bilateral intra-NAc shell cannulas were place-conditioned with several doses of subcutaneous morphine prior to intra-NAc shell infusions of artificial cerebrospinal fluid (aCSF). Immunohistochemistry (IHC) showed a dose-dependent increase in the NR1 expression in all examined parts. When rats were conditioned with intra-NAc shell infusions of CART, CPP and CPA induced with 2.5 and 5 µg/side respectively and IHC showed NR1elevation with 2.5 and reduction with 5 µg/side in all areas. Sub-rewarding dose of CART administration (1.25 µg/side) prior to sub-rewarding dose of morphine (2.5 mg/kg) induced CPP and NR1 increased in all examined tissues in IHC. However, infusion of an aversive dose of CART (5 µg/side) prior to the rewarding dose of morphine (5 mg/kg) produced neither CPP nor CPA and NR1 in the NAc and hippocampus decreased significantly. It seems that the rewarding or aversive effects of intra-NAc shell CART and its facilitating or inhibiting effects on morphine reward are dose-dependent. Additionally, NMDA may be closely involved in the affective properties of opioids and CART in the reward pathway.

Evaluation of the CART peptide expression in morphine sensitization in male rats.

The importance of Cocaine- and amphetamine-regulated transcript (CART) peptide in reinforcing effects of addictive drugs specially alcohol and psychostimulants has been stablished. Involvement of CART peptide in rewarding effects of opioids in brain has recently been reported. Here we have studied the expression of CART mRNA and peptide in the reward pathway in morphine-induced sensitization phenomenon and also evaluated the peptide level fluctuations in CSF and plasma. Male Wistar rats received 7-day morphine injection (20mg/kg) and then after a 7-day washout period, a challenge dose of 10mg/kg morphine was administered and locomotor activity and oral stereotypical behaviors were recorded. Besides, the expression level of CART mRNA and peptide in four important areas of the mesocorticolimbic reward pathway including nucleus accumbens, striatum, prefrontal cortex, and hippocampus were measured by real-time PCR and western blotting, respectively. The level of the peptide in CSF and plasma was measured by Elisa method. The expression level of CART mRNA and protein in brain regions and also the peptide level in CSF and plasma were significantly down-regulated after 7-day morphine administration. These reduced levels returned to nearly normal rates after 7-day wash-out period. Administration of morphine challenge dose led to significant upregulation of CART gene expression (both mRNA and peptide) in the brain, and elevation of peptide level in CSF and plasma in morphine-sensitized rats. It can be concluded that CART is released in the framework of reward pathway and may serve as an important neurotransmitter in the process of morphine dependence and sensitization.

Recovery from ketamine-induced amnesia by blockade of GABA-A receptor in the medial prefrontal cortex of mice.

Ketamine and other noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists are known to induce deficits in learning and cognitive performance sensitive to prefrontal cortex (PFC) functions. The interaction of a glutamatergic and GABAergic systems is essential for many cognitive behaviors. In order to understand the effect of γ-aminobutyric acid (GABA)/glutamate interactions on learning and memory, we investigated the effects of intra medial prefrontal cortex (mPFC) injections of GABAergic agents on ketamine-induced amnesia using a one-trial passive avoidance task in mice. Pre-training systemic administration of ketamine (5, 10 and 15mg/kg, i.p.) dose-dependently decreased the memory acquisition of a one-trial passive avoidance task. Pre-training intra-mPFC injection of muscimol, GABAA receptor agonist (0.05, 0.1 and 0.2µg/mouse) and baclofen GABAB receptor agonist (0.05, 0.1, 0.5 and 1µg/mouse), impaired memory acquisition. However, co-pretreatment of different doses of muscimol and baclofen with a lower dose of ketamine (5mg/kg), which did not induce amnesia by itself, caused inhibition of memory formation. Our data showed that sole pre-training administration of bicuculline, GABA-A receptor antagonist and phaclofen GABA-B receptor antagonist into the mPFC, did not affect memory acquisition. In addition, the amnesia induced by pre-training ketamine (15mg/kg) was significantly decreased by the pretreatment of bicuculline (0.005, 0.1 and 0.5µg/mouse). It can be concluded that GABAergic system of the mPFC is involved in the ketamine-induced impairment of memory acquisition.

Evaluation of CART peptide level in rat plasma and CSF: Possible role as a biomarker in opioid addiction.

It has been shown previously that cocaine- and amphetamine-regulated transcript (CART) peptide has a modulatory role and homeostatic regulatory effect in motivation to and reward of the drugs of abuse specially psychostimulants. Recent data also showed that in addition to psychostimulants, CART is critically involved in the different stages of opioid addiction. Here we have evaluated the fluctuations in the level of CART peptide in plasma and CSF in different phases of opioid addiction to find out whether CART can serve as a suitable marker in opioid addiction studies. Male rats were randomly distributed in groups of control, acute low-dose (10mg/kg) morphine, acute high-dose morphine (80mg/kg), chronic escalating doses of morphine, withdrawal syndrome precipitated by administration of naloxone (1mg/kg), and abstinent after long-term drug-free maintenance of addicted animals. The level of CART peptide in CSF and plasma samples was measured by enzyme immunoassay. CART peptide concentration in the CSF and plasma was significantly elevated in acute high-dose morphine and withdrawal state animals and down-regulated in addicted rats. In abstinent group, CART peptide level was up-regulated in plasma but not in CSF samples. As the observed results are in agreement with data regarding the CART mRNA and protein expression in the brain reward pathway in opioid addiction phases, it may be suggested that evaluation of CART peptide level in CSF or plasma could be a suitable marker which reflects the rises and falls of the peptide concentration in brain in the development of opioid addiction.

The influence of dopaminergic system in medial prefrontal cortex on ketamine-induced amnesia in passive avoidance task in mice.

Dopaminergic modulations of glutamate receptors are essential for the prefrontal cortical (PFC) behavioral and cognitive functions. In order to understand the effect of dopamine/glutamate interactions on learning and memory, we investigated the effects of intra medial prefrontal cortex (mPFC) injections of dopaminergic agents on ketamine-induced amnesia by using a one-trial passive avoidance task in mice. Pre-training administration of ketamine (5, 10 and 15mg/kg, i.p.) dose-dependently decreased the memory acquisition of a one-trial passive avoidance task. Pre-training intra-mPFC administration of SKF 38393, D1 receptor agonist and quinpirol D2 receptor agonist, alone did not affect memory acquisition. However, amnesia induced by pre-training ketamine (15mg/kg) significantly decreased by pretreatment of SKF 38393 (2 and 4µg/mouse) and quinpirol (0.3, 1 and 3µg/mouse). Pre-training administration of SCH 23390, D1 receptor antagonist (0.75 and 1µg/mouse, intra-mPFC), and sulpiride D2 receptor antagonist (3µg/mouse, intra-mPFC) impaired memory acquisition. In addition, co-pretreatment of different doses of SCH 23390 and sulpiride with lower dose of ketamine (5mg/kg), which did not induce amnesia by itself, caused inhibition of memory formation. It may be concluded that dopaminergic system of medial prefrontal cortex is involved in the ketamine-induced impairment of memory acquisition.

Effect of honey on peridural fibrosis formation after laminectomy in rats: a novel experimental study.

Despite progress in surgical techniques, some patients still face postoperative recurrence of pain. Recently, more attention has been focused on peridural fibrosis (PF), which may be responsible for recurrent pain after laminectomy or discectomy. Honey has been shown to exert anti-inflammatory effects on exposed tissues besides its well-known antibacterial properties. The aim of this study were to investigate the effects of honey on the prevention of postlaminectomy fibrosis formation in a rat model. A controlled blinded study was performed in 45 male adult white Sprague-Dawley rats that underwent laminectomy at the L5-L6 levels. They were divided into 3 groups (A, B, and C) of 15 rats each. Group A (sham) underwent laminectomy and group B was treated with normal saline at the laminectomy site. Rats in group C received 0.1 mL honey at the laminectomy site. All rats were killed 4 weeks after laminectomy. PF was found in 5 rats (33%) of control groups A and B, and in 2 rats (10%) in honey-treated laminectomy group C. The difference was not statistically significant. Wound healing was not affected, and there was no cerebrospinal fluid leakage. Although honey appears to be safe, it cannot cause a significant reduction of PF formation after lumbar laminectomy in rats.