Post-Weaning Treatment with Probiotic Inhibited Stress-Induced Amnesia in Adulthood Rats: The Mediation of GABAergic System and BDNF/c-Fos Signaling Pathways.

The current study aimed to examine the effect of post-weaning treatment with probiotics on memory formation under stress during the adult period in male Wistar rats. Considering GABA is a potential mediator between probiotics and the host, the present study also investigated the involvement of the GABAergic system in the probiotic response. The hippocampal and prefrontal cortical (PFC) expression levels of BDNF and c-Fos were also assessed to show whether the treatments affect the memory-related signaling pathway. Three weeks after birth, the post-weaning rats were fed with probiotic water (PW) or tap water (TW) for 2, 3, 4, or 5 weeks. Exposure to acute stress impaired memory formation in a passive avoidance learning task. Feeding the post-weaning animals with probiotic strains (3, 4, or 5 weeks) inhibited stress-induced amnesia of the adult period. Post-training intracerebroventricular (ICV) microinjection of muscimol improved stress-induced amnesia in the animals fed with TW. ICV microinjection of muscimol inhibited probiotic treatment's significant effect on the stress response in the memory task. The expression levels of BDNF and c-Fos in the PFC and the hippocampus were significantly decreased in the stress animal group. The levels of BDNF and c-Fos were increased in the PW/stress animal group. The muscimol response was compounded with the decreased levels of BDNF and c-Fos in the PFC and the hippocampus. Thus, the GABA-A receptor mechanism may mediate the inhibitory effect of this probiotic mixture on stress-induced amnesia, which may be associated with the PFC and hippocampal BDNF/c-Fos signaling changes.

Nitric oxide blockade in mediodorsal thalamus impaired nicotine/ethanol-induced memory retrieval in rats via inhibition of prefrontal cortical pCREB/CREB signaling pathway.

Reciprocal connections between the mediodorsal thalamic nucleus (MD) and the prefrontal cortex (PFC) are important for memory processes. Since the co-abuse of nicotine and ethanol affects memory formation, this study investigated the effect of nitric oxide inhibition in the MD on memory retrieval induced by co-administration of nicotine and ethanol. Subsequently, western blot analysis was used to evaluate how this change would alter the PFC pCREB/CREB signaling pathway. Male Wistar rats were bilaterally cannulated into the MD and the memory retrieval was measured by passive avoidance task. Intraperitoneal (i.p.) administration of ethanol (1 g/kg, i.p) 30 min before the test impaired memory retrieval and caused ethanol-induced amnesia. Subcutaneous (s.c.) administration of nicotine (0.05-0.2 mg/kg, s.c.) prevented ethanol-induced amnesia and improved memory retrieval. Intra-MD microinjection of a nitric oxide synthase (NOS) inhibitor, L-NAME (0.5-1 µg/rat) inhibited the improving effect of nicotine (0.2 mg/kg, s.c.) on ethanol-induced amnesia, while intra-MD microinjection of a precursor of nitric oxide, l-arginine (0.25-1 µg/rat), potentiated such effect. Noteworthy, intra-MD microinjection of the same doses of L-NAME or l-arginine by itself had no effect on memory retrieval. Furthermore, intra-MD microinjection of L-NAME (0.05, 0.1 and 0.3 µg/rat) reversed the l-arginine improving effect on nicotine response. Successful memory retrieval significantly increased the p-CREB/CREB ratio in the PFC tissue. Ethanol-induced amnesia, however, decreased this ratio in the PFC while the co-administration of nicotine and ethanol increased the PFC CREB signaling. Interestingly, the inhibitory effect of L-NAME and the potentiating effect of l-arginine on nicotine response were associated with the decrease and increase of the PFC p-CREB/CREB ratio respectively. It can be concluded that MD-PFC connections are involved in the combined effects of nicotine and ethanol on memory retrieval. The mediodorsal thalamic NO system possibly mediated this interaction via the pCREB/CREB signaling pathways in the PFC.

Corticolimbic analysis of microRNAs and protein expressions in scopolamine-induced memory loss under stress.

The aim of the present study was to assess thealterations of corticolimbic microRNAs and protein expressions in the effect of scopolamine with or without stress on passive-avoidance memory in male Wistar rats. The expressions of miR-1, miR-10 and miR-26 and also the levels of p-CREB, CREB, C-FOS and BDNF in the prefrontal cortex (PFC), the hippocampus and the amygdala were evaluated using RT-qPCR and Western blotting techniques. The data showed that the administration of a muscarinic receptor antagonist, scopolamine or the exposure to 30 min stress significantly induced memory loss. Interestingly, the injection of an ineffective dose of scopolamine (0.5 mg/kg) alongside with exposure to an ineffective time of stress (10 min) impaired memory formation, suggesting a potentiative effect of stress on scopolamine response. Our results showed that memory formation was associated with the down-regulated expression of miR-1, miR-10 and miR-26 in the PFC and the hippocampus, but not the amygdala. The relative expression increase of miR-1 and miR-10 in the PFC and the hippocampus was shown in memory loss induced by scopolamine administration or 30-min stress. The PFC level of miR-10 and also hippocampal level of miR-1 and miR-10 were significantly up-regulated, while amygdala miR-1 and miR-26 were down-regulated in scopolamine-induced memory loss under stress. Memory formation increased BDNF, C-FOS and p-CREB/CREB in the PFC, the hippocampus and the amygdala. In contrast, the PFC, hippocampal and amygdala protein expressions were significantly decreased in memory loss induced by scopolamine administration (2 mg/kg), stress exposure (for 30 min) or scopolamine (0.5 mg/kg) plus stress (10 min). One of the most significant findings to emerge from this study is that the stress exposure potentiated the amnesic effect of scopolamine may via affecting the expressions of miRs and proteins in the PFC, the hippocampus and the amygdala. It is possible to hypothesis that corticolimbic signaling pathways play a critical role in relationship between stress and Alzheimer's disease.

Contribution of the basolateral amygdala NMDA and muscarinic receptors in rat's memory retrieval.

The present study was designed to investigate the involvement of the muscarinic cholinergic receptors in the basolateral amygdala (BLA) in memory retrieval. Also, the possible relationship between the BLA muscarinic cholinergic and the NMDA receptor systems was evaluated in the inhibitory avoidance learning. Male Wistar rats were bilaterally cannulated into the BLAs and memory retrieval was measured in a step-through type inhibitory avoidance apparatus. Intra-BLA microinjection of different doses of a non-selective muscarinic receptor antagonist, scopolamine (0.5-1µg/rat, intra-BLA), 5min before the testing phase dose-dependently induced amnesia. Pre-test intra-BLA microinjection of different doses of NMDA (0.005-0.05µg/rat) reversed scopolamine-induced amnesia and improved memory retrieval. In addition, different doses of a selective NMDA receptor antagonist, D-AP5 (0.001-0.005µg/rat, intra-BLA) potentiated the response of an ineffective dose of scopolamine (0.5µg/rat) to inhibit memory retrieval. It should be considered that pre-test intra-BLA microinjection of the same doses of NMDA or D-AP5 by themselves had no effect on memory retrieval. Similar to ANOVA analysis, our cubic interpolation analysis also predicted that the activation or inactivation of the NMDA receptors by different doses of drugs can affect the scopolamine response. On the other hand, pre-test intra-BLA microinjection of D-AP5 inhibited the reversal effect of NMDA on scopolamine-induced amnesia. It can be concluded that the BLA cholinergic system, via muscarinic receptors, has a critical role in memory retrieval. Our results also suggest that a cooperative interaction between the BLA NMDA and muscarinic acetylcholine receptors modulates memory formation of inhibitory avoidance task in rats.

Role of hippocampal and prefrontal cortical signaling pathways in dextromethorphan effect on morphine-induced memory impairment in rats.

Evidence suggests that dextromethorphan (DM), an NMDA receptor antagonist, induces memory impairment. Considering that DM is widely used in cough-treating medications, and the co-abuse of DM with morphine has recently been reported, the aims of the present study was (1) to investigate whether there is a functional interaction between morphine and DM in passive avoidance learning and (2) to assess the possible role of the hippocampal and prefrontal cortical (PFC) signaling pathways in the effects of the drugs on memory formation. Our findings indicated that post-training or pre-test administration of morphine (2 and 6 mg/kg) or DM (10-30 mg/kg) impaired memory consolidation and retrieval which was associated with the attenuation of the levels of phosphorylated Ca(2+)/calmodulin-dependent protein kinase II (p-CAMKII) and cAMP responsive element-binding protein (p-CREB) in the targeted sites. Moreover, the memory impairment induced by post-training administration of morphine was reversed by pre-test administration of the same dose of morphine or DM (30 mg/kg), indicating state-dependent learning (SDL) and a cross-SDL between the drugs. It is important to note that the levels of p-CAMKII/CAMKII and p-CREB/CREB in the hippocampus and the PFC increased in drugs-induced SDL. In addition, DM administration potentiated morphine-induced SDL which was related to the enhanced levels of hippocampal and PFC CAMKII-CREB signaling pathways. It can be concluded that there is a relationship between the hippocampus and the PFC in the effect of DM and/or morphine on memory retrieval. Moreover, a cross SDL can be induced between the co-administration of DM and morphine. Interestingly, CAMKII-CREB signaling pathways also mediate the drugs-induced SDL.

µ-Opioid and N-methyl-D-aspartate receptors in the amygdala contribute to minocycline-induced potentiation of morphine analgesia in rats.

The aim of the present study was to investigate the role of the amygdala in the potentiative effect of minocycline, a semisynthetic tetracycline antibiotic, on morphine analgesia in male Wistar rats. We also examined the involvement of the amygdala µ-opioid and N-methyl-D-aspartate (NMDA) receptors in the minocycline-induced potentiation of morphine analgesia. Intraperitoneal administration of morphine (3-9 mg/kg) induced analgesia in a tail-flick test. Bilateral intra-amygdala injection of minocycline (10-20 µg/rat) enhanced the analgesic response of an ineffective dose of morphine (3 mg/kg). Injection of a higher dose of minocycline into the amygdala also induced analgesia. Moreover, bilateral intra-amygdala injection of naloxone (0.5-1.5 µg/rat) reversed minocycline-induced potentiation of morphine analgesia. Pretreatment of animals with NMDA (0.01-0.1 µg/rat, intra-amygdala) also inhibited the potentiative effect of minocycline on morphine response. Bilateral intra-amygdala injection of the same doses of naloxone or NMDA plus morphine had no effect on the tail-flick latency in the absence of minocycline. It can be concluded that the amygdala has a key role in the potentiative effect of minocycline on morphine analgesia. In addition, amygdala opioidergic and glutamatergic mechanisms may be involved, probably through µ-opioid and NMDA receptors, in the modulation of the minocycline-induced potentiation of morphine analgesia in the tail-flick test.

Basolateral amygdala GABA-A receptors mediate stress-induced memory retrieval impairment in rats.

The present study was designed to investigate the involvement of GABA-A receptors of the basolateral amygdala (BLA) in the impairing effect of acute stress on memory retrieval. The BLAs of adult male Wistar rats were bilaterally cannulated and memory retrieval was measured in a step-through type passive avoidance apparatus. Acute stress was evoked by placing the animals on an elevated platform for 10, 20 and 30 min. The results indicated that exposure to 20 and 30 min stress, but not 10 min, before memory retrieval testing (pre-test exposure to stress) decreased the step-through latency, indicating stress-induced memory retrieval impairment. Intra-BLA microinjection of a GABA-A receptor agonist, muscimol (0.005-0.02 µg/rat), 5 min before exposure to an ineffective stress (10 min exposure to stress) induced memory retrieval impairment. It is important to note that pre-test intra-BLA microinjection of the same doses of muscimol had no effect on memory retrieval in the rats unexposed to 10 min stress. The blockade of GABA-A receptors of the BLA by injecting an antagonist, bicuculline (0.4-0.5 µg/rat), 5 min before 20 min exposure to stress, prevented stress-induced memory retrieval. Pre-test intra-BLA microinjection of the same doses of bicuculline (0.4-0.5 µg/rat) in rats unexposed to 20 min stress had no effect on memory retrieval. In addition, pre-treatment with bicuculline (0.1-0.4 µg/rat, intra-BLA) reversed muscimol (0.02 µg/rat, intra-BLA)-induced potentiation on the effect of stress in passive avoidance learning. It can be concluded that pre-test exposure to stress can induce memory retrieval impairment and the BLA GABA-A receptors may be involved in stress-induced memory retrieval impairment.

Neuronal biomarkers as potential therapeutic targets for drug addiction related to sex differences in the brain: Opportunities for personalized treatment approaches.

Biological sex disparities manifest at various stages of drug addiction, including craving, substance abuse, abstinence, and relapse. These discrepancies are underpinned by notable distinctions in neurobiological substrates, encompassing brain structures, functions, and neurotransmitter systems implicated in drug addiction. Neuronal biomarkers, such as neurotransmitters, signaling proteins, and genes may be associated with the diagnosis, prognosis, and treatment outcomes in both biological sexes afflicted by drug abuse. Sex differences in the neural reward system, mainly through dopaminergic transmission during drug abuse, can be attributed to modifications in neurotransmitter systems and signaling pathways. This results in distinct patterns of neural activation and responsiveness to addictive substances in males and females. Sex hormones, the estrus/menstrual cycle, and cerebral neurochemistry contribute to the progression of psychological and physiological dependence in both male and female individuals grappling with addiction. Moreover, the alteration of sex hormone balance and neurotransmitter release plays a pivotal role in substance use disorders, subsequently modulating cognitive functions pertinent to reward, including memory formation, decision-making, and locomotor activity. Comparative investigations reveal distinctions in brain region volume, gene expression, neuronal firing, and circuitry in substance use disorders affecting individuals of both biological sexes. This review examines prevalent substance use disorders to elucidate the impact of sex hormones as therapeutic biomarkers on the mesocorticolimbic neurotransmitter systems via diverse mechanisms within the addicted brain. We underscore the imperative necessity of considering these variations to gain a deeper comprehension of addiction mechanisms and potentially discern sex-specific neuronal biomarkers for tailored therapeutic interventions.

Combination of microRNA and suicide gene for targeting Glioblastoma: Inducing apoptosis and significantly suppressing tumor growth in vivo.

Glioblastoma (GBM), a grade IV brain tumor, presents a severe challenge in treatment and eradication due to its high genetic variability and the existence of stem-like cells with self-renewal potential. Conventional therapies fall short of preventing recurrence and fail to extend the median survival of patients significantly. However, the emergence of gene therapy, which has recently obtained significant clinical outcomes, brings hope. It has the potential to be a suitable strategy for the treatment of GBM. Notably, microRNAs (miRNAs) have been noticed as critical players in the development and progress of GBM. The combined usage of hsa-miR-34a and Cytosine Deaminase (CD) suicide gene and 5-fluorocytosine (5FC) prodrug caused cytotoxicity against U87MG Glioma cells in vitro. The apoptosis and cell cycle arrest rates were measured by flow cytometry. The lentiviral vector generated overexpression of CD/miR-34a in the presence of 5FC significantly promoted apoptosis and caused cell cycle arrest in U87MG cells. The expression level of the BCL2, SOX2, and P53 genes, target genes of hsa-miR-34a, was examined by quantitative real-time PCR. The treatment led to a substantial downregulation of Bcl2 and SOX2 genes while elevating the expression levels of Caspase7 and P53 genes compared to the scrambled control. The hsa-miR-34a hindered the proliferation of GBM cancer cells and elevated apoptosis through the P53-miR-34a-Bcl2 axis. The CD suicide gene with 5FC treatment demonstrated similar results to miR-34a in the apoptosis, cell cycle, and real-time assays. The combination of CD and miR-34a produced a synergistic effect. In vivo, anti-GBM efficacy evaluation in rats bearing intracranial C6 Glioma cells revealed a remarkable induction of apoptosis and a significant inhibition of tumor growth compared with the scrambled control. The simultaneous use of CD/miR-34a with 5FC almost entirely suppressed tumor growth in rat models. The combined application of hsa-miR-34a and CD suicide gene against GBM tumors led to significant induction of apoptosis in U87MG cells and a considerable reduction in tumor growth in vivo.

The role of glutamate NMDA receptors of the mediodorsal thalamus in scopolamine-induced amnesia in rats.

The current study was designed to examine the role of glutamate NMDA receptors of the mediodorsal thalamus (MD) in scopolamine-induced memory impairment. Adult male rats were bilaterally cannulated into the MD. According to the results, intraperitoneal (i.p.) administration of scopolamine (1.5 mg/kg) immediately after the training phase (post-training) impaired memory consolidation. Bilateral microinjection of the glutamate NMDA receptors agonist, N-Methyl-D-aspartic acid (NMDA; 0.05 µg/rat), into the MD significantly improved scopolamine-induced memory consolidation impairment. Co-administration of D-AP5, a glutamate NMDA receptor antagonist (0.001-0.005 µg/rat, intra-MD) potentiated the response of an ineffective dose of scopolamine (0.5 mg/kg, i.p.) to impair memory consolidation, mimicking the response of a higher dose of scopolamine. Noteworthy, post-training intra-MD microinjections of the same doses of NMDA or D-AP5 alone had no effect on memory consolidation. Moreover, the blockade of the glutamate NMDA receptors by 0.003 ng/rat of D-AP5 prevented the improving effect of NMDA on scopolamine-induced amnesia. Thus, it can be concluded that the MD glutamatergic system may be involved in scopolamine-induced memory impairment via the NMDA receptor signaling pathway.

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.

Dorsal hippocampal cannabinoid CB1 receptors mediate the interactive effects of nicotine and ethanol on passive avoidance learning in mice.

The present study evaluated the involvement of the dorsal hippocampal cannabinoid CB1 receptors in the combined effect of ethanol and nicotine on passive avoidance learning in adult male mice. The results indicated that pre-training administration of ethanol (1 g/kg, i.p.) impaired memory retrieval. Pre-test administration of ethanol (0.5 and 1 g/kg, i.p.) or nicotine (0.5 and 0.7 mg/kg, s.c.) significantly reversed ethanol-induced amnesia, suggesting a functional interaction between ethanol and nicotine. Pre-test microinjection of a selective CB1 receptor agonist, ACPA (3 and 5 ng/mouse), plus an ineffective dose of ethanol (0.25 g/kg) or nicotine (0.3 mg/kg) improved memory retrieval, while ACPA by itself could not reverse ethanol-induced amnesia. Pre-test intra-CA1 microinjection of a selective CB1 receptor antagonist, AM251 (0.5-2 ng/mouse), did not lead to a significant change in ethanol-induced amnesia. However, pre-test intra-CA1 microinjection of AM251 prevented the ethanol (1 g/kg) or nicotine (0.7 mg/kg) response on ethanol-induced amnesia. In order to support the involvement of the dorsal hippocampal CB1 receptors in nicotine response, the scheduled mixed treatments of AM251 (0.1-1 ng/mouse), ACPA (5 ng/mouse) and nicotine (0.3 mg/kg) were used. The results indicated that AM251 reversed the response of ACPA to the interactive effects of nicotine and ethanol in passive avoidance learning. Furthermore, pre-test intra-CA1 microinjection of the same doses of ACPA or AM251 had no effect on memory retrieval. These findings show that the cannabinoid CB1 receptors of dorsal hippocampus are important in the combined effect of ethanol and nicotine on passive avoidance learning.

Does CA1 dopaminergic system play a role in cholestasis induced hypothermia?

OBJECTIVE: There is some of evidence describing that cholestasis induces hypothermia. Meanwhile, there is paucity of comprehensive data on the mechanism(s) governing this phenomenon. The present study was undertaken to determine the effect of CA1 dopaminergica system on cholestasis induced hypothermia. METHODS: Male NMRI mice weighing 25-30g, were used. Bilateral cannulae were implanted in dorsal hippocampi (CA1) for drug microinjection. Animals were randomly divided into non-operated control, sham-operated and bile duct-ligated (BDL) groups. Cholestasis was induced by means of main bile duct ligation. Body temperatures were measured before, two and four days after BDL. RESULTS: Data indicated that, two and four days post BDL, the body temperature decreases as compared to the sham-operated animals, which indicates hypothermia. Intra-CA1 injection of different doses of sulpiride (SUL; 0.25, 0.5 and 0.75µg/mouse), SCH23390 (SCH; 0.125, 025 and 0.5µg/mouse), SKF38393 (SKF; 0.25, 0.5 and 1µg/mouse) and quinpirole (QUI; 0.25, 05 and 0.75µg/mouse) exerted no effect on body temperature in non-operated and sham operated mice, by themselves. Moreover, intra-CA1 injection of SUL, QUI or SKF blocked, whereas, SCH tended to increase BDL induced hypothermia. CONCLUSIONS: The present data revealed that the CA1 dopaminergic system is possibly involved in the BDL induced impairment of thermoregulation.

Activation of ventral hippocampal CB1 receptors inhibits ketamine-induced anxiogenic-like behavior: Alteration of BDNF/c-Fos levels in the mouse hippocampus.

Considering the increasing usage of ketamine as a recreational drug with hallucinogenic properties and also scarce studies about receptor systems responsible for its effects, in the present study we aimed to investigate whether the activation of the ventral hippocampal (VH) CB1 cannabinoid receptors affects the anxiety-like behaviors induced by ketamine. Also, the levels of BDNF and c-Fos proteins in the mouse hippocampus were measured following the treatments. For this purpose, male NMRI mice were cannulated bilaterally in the VH with a stereotaxic apparatus. Anxiety properties and protein changes were measured using elevated plus-maze (EPM) and western blotting respectively. The results revealed that intraperitoneal (i.p.) administration of ketamine (5-20 mg/kg) significantly decreased the percentage of open arm time (%OAT) and open arm entry (%OAE) in the EPM with no alteration in the locomotor activity suggesting an anxiogenic-like behavior to ketamine. Furthermore, ketamine administration (10 mg/kg, i.p.) increased BDNF and c-Fos levels in the hippocampus. Interestingly, activation of the VH CB1 receptors by ACPA (0.5-4 ng/mouse) inhibited the anxiogenic-like behaviors produced by ketamine, whereas the microinjection of the same doses of ACPA into VH by itself had no effect on the EPM parameters. Hippocampal levels of BDNF and c-Fos decreased after treatment with combined ketamine with ACPA. These results suggest the therapeutic potency of cannabinoid receptor agonists for ketamine-induced anxiogenic-related responses. This effect might be at least partially mediated by the alteration of BDNF and c-Fos signaling in the hippocampus.

Neurobiochemical characteristics of arginine-rich peptides explain their potential therapeutic efficacy in neurodegenerative diseases.

Neurodegenerative diseases, including Alzheimer̕ s disease (AD), Parkinson̕ s disease (PD), Huntington̕ s disease (HD), and Amyotrophic Lateral Sclerosis (ALS) require special attention to find new potential treatment methods. This review aims to summarize the current knowledge of the relationship between the biochemical properties of arginine-rich peptides (ARPs) and their neuroprotective effects to deal with the harmful effects of risk factors. It seems that ARPs have portrayed a promising and fantastic landscape for treating neurodegeneration-associated disorders. With multimodal mechanisms of action, ARPs play various unprecedented roles, including as the novel delivery platforms for entering the central nervous system (CNS), the potent antagonists for calcium influx, the invader molecules for targeting mitochondria, and the protein stabilizers. Interestingly, these peptides inhibit the proteolytic enzymes and block protein aggregation to induce pro-survival signaling pathways. ARPs also serve as the scavengers of toxic molecules and the reducers of oxidative stress agents. They also have anti-inflammatory, antimicrobial, and anti-cancer properties. Moreover, by providing an efficient nucleic acid delivery system, ARPs can play an essential role in developing various fields, including gene vaccines, gene therapy, gene editing, and imaging. ARP agents and ARP/cargo therapeutics can be raised as an emergent class of neurotherapeutics for neurodegeneration. Part of the aim of this review is to present recent advances in treating neurodegenerative diseases using ARPs as an emerging and powerful therapeutic tool. The applications and progress of ARPs-based nucleic acid delivery systems have also been discussed to highlight their usefulness as a broad-acting class of drugs.

Pharmacological activation of mediodorsal thalamic GABA-A receptors modulates morphine/cetirizine-induced changes in the prefrontal cortical GFAP expression in a rat model of neuropathic pain.

The present study investigated the involvement of mediodorsal thalamic (MD) GABA-A receptors in cetirizine/morphine-induced anti-allodynia using a rat model of neuropathic pain. To assess the importance of the prefrontal cortex (PFC) for chronic pain processing, its expression level changes of glial fibrillary acidic protein (GFAP) were measured following drug treatments. Each animal was subjected to chronic constriction of the sciatic nerve surgery simultaneously with the MD cannulation under stereotaxic surgery. The results showed that the administration of morphine (3-5 mg/kg) or cetirizine (1-3 mg/kg) produced significant analgesia in neuropathic rats. Systemic administration of cetirizine (2.5 and 3 mg/kg) potentiated the analgesic response to a low and intolerance dose of morphine (3 mg/kg). Intra-MD microinjection of muscimol, a selective GABA-A receptor agonist (0.005-0.01 µg/rat), increased the cetirizine/morphine-induced anti-allodynia, while muscimol by itself did not affect neuropathic pain. The neuropathic pain was associated with the increased PFC expression level of GFAP, suggesting the impact of chronic pain on PFC glial management. Interestingly, the anti-allodynia was associated with a decrease in the PFC expression level of GFAP under the drugs' co-administration. Thus, cetirizine has a significant potentiating effect on morphine response in neuropathic pain via interacting with the MD GABA-A receptors. It seems that neuropathic pain affects the prefrontal cortex GFAP signaling pathway. In clinical studies, these findings can be considered to create a combination therapy with low doses of GABA-A receptor agonist plus cetirizine and morphine to manage neuropathic pain.

Shared Mechanisms of GABAergic and Opioidergic Transmission Regulate Corticolimbic Reward Systems and Cognitive Aspects of Motivational Behaviors.

The functional interplay between the corticolimbic GABAergic and opioidergic systems plays a crucial role in regulating the reward system and cognitive aspects of motivational behaviors leading to the development of addictive behaviors and disorders. This review provides a summary of the shared mechanisms of GABAergic and opioidergic transmission, which modulate the activity of dopaminergic neurons located in the ventral tegmental area (VTA), the central hub of the reward mechanisms. This review comprehensively covers the neuroanatomical and neurobiological aspects of corticolimbic inhibitory neurons that express opioid receptors, which act as modulators of corticolimbic GABAergic transmission. The presence of opioid and GABA receptors on the same neurons allows for the modulation of the activity of dopaminergic neurons in the ventral tegmental area, which plays a key role in the reward mechanisms of the brain. This colocalization of receptors and their immunochemical markers can provide a comprehensive understanding for clinicians and researchers, revealing the neuronal circuits that contribute to the reward system. Moreover, this review highlights the importance of GABAergic transmission-induced neuroplasticity under the modulation of opioid receptors. It discusses their interactive role in reinforcement learning, network oscillation, aversive behaviors, and local feedback or feedforward inhibitions in reward mechanisms. Understanding the shared mechanisms of these systems may lead to the development of new therapeutic approaches for addiction, reward-related disorders, and drug-induced cognitive impairment.

Addictive drugs modify neurogenesis, synaptogenesis and synaptic plasticity to impair memory formation through neurotransmitter imbalances and signaling dysfunction.

Drug abuse changes neurophysiological functions at multiple cellular and molecular levels in the addicted brain. Well-supported scientific evidence suggests that drugs negatively affect memory formation, decision-making and inhibition, and emotional and cognitive behaviors. The mesocorticolimbic brain regions are involved in reward-related learning and habitual drug-seeking/taking behaviors to develop physiological and psychological dependence on the drugs. This review highlights the importance of specific drug-induced chemical imbalances resulting in memory impairment through various neurotransmitter receptor-mediated signaling pathways. The mesocorticolimbic modifications in the expression levels of brain-derived neurotrophic factor (BDNF) and the cAMP-response element binding protein (CREB) impair reward-related memory formation following drug abuse. The contributions of protein kinases and microRNAs (miRNAs), along with the transcriptional and epigenetic regulation have also been considered in memory impairment underlying drug addiction. Overall, we integrate the research on various types of drug-induced memory impairment in distinguished brain regions and provide a comprehensive review with clinical implications addressing the upcoming studies.

Activation of mediodorsal thalamic dopamine receptors inhibited nicotine-induced anxiety in rats: A possible role of corticolimbic NMDA neurotransmission and BDNF expression.

The present study aimed to evaluate the functional interaction between the dopaminergic and glutamatergic systems of the mediodorsal thalamus (MD), the ventral hippocampus (VH), and the prefrontal cortex (PFC) in nicotine-induced anxiogenic-like behaviors. Brain-derived neurotrophic factor (BDNF) level changes were measured in the targeted brain areas following the drug treatments. The percentage of time spent in the open arm (% OAT) and open arm entry (% OAE) were calculated in the elevated plus maze (EPM) to measure anxiety-related behaviors in adult male Wistar rats. Systemic administration of nicotine at a dose of 0.5 mg/kg induced an anxiogenic-like response associated with decreased BDNF levels in the hippocampus and the PFC. Intra-MD microinjection of apomorphine (0.1-0.3 µg/rat) induced an anxiogenic-like response, while apomorphine inhibited nicotine-induced anxiogenic-like behaviors associated with increased hippocampal and PFC BDNF expression levels. Interestingly, the blockade of the VH or the PFC NMDA receptors via the microinjection of D-AP5 (0.3-0.5 µg/rat) into the targeted sites reversed the inhibitory effect of apomorphine (0.5 µg/rat, intra-MD) on the nicotine response and led to the decrease of BDNF levels in the hippocampus and the PFC. Also, the microinjection of a higher dose of D-AP5 (0.5 µg/rat, intra-PFC) alone produced an anxiogenic effect. These findings suggest that the functional interaction between the MD dopaminergic D1/D2-like and the VH/PFC glutamatergic NMDA receptors may be partially involved in the anxiogenic-like effects of nicotine, likely via the alteration of BDNF levels in the hippocampus and the PFC.

Memory impairment was ameliorated by corticolimbic microinjections of arachidonylcyclopropylamide (ACPA) and miRNA-regulated lentiviral particles in a streptozotocin-induced Alzheimer's rat model.

The present study aimed to investigate the effect of corticolimbic cannabinoid CB1 receptors activity on memory impairment in the intracerebroventricular (ICV)-streptozotocin (STZ) animal model of Alzheimer's like-disease. This study also assessed whether the corticolimbic overexpression of miRNA-137 or -let-7a could increase the endocannabinoids by inhibiting the monoglyceride lipase (MAGL) to ameliorate STZ response. The results showed that ICV microinjection of STZ (3 mg/kg/10 µl) impaired passive avoidance memory retrieval. The chronic microinjection of arachidonylcyclopropylamide (ACPA; 10 ng/0.5 µl), a selective cannabinoid CB1 receptor agonist, into the hippocampal CA1 region, the central amygdala (CeA) or the medial prefrontal cortex (mPFC) ameliorated the amnesic effect of ICV-STZ. Intra-CA1 or -CeA microinjection of ACPA alone did not affect memory retrieval, while its microinjection into the mPFC impaired memory formation. Based on bioinformatics analysis and verification of the MAGL gene, miRNA-137 and -let-7a were chosen to target the expression levels of MAGL in the corticolimbic regions. The chronic corticolimbic microinjection of lentiviral particles containing miRNA-137 or -let-7a ameliorated ICV-STZ-induced memory impairment. The high transfection efficiency was determined for each virus using comparing fluorescent and conventional vision. Corticolimbic overexpression of miRNA-137 or -let-7a decreased the MAGL gene expression that encodes the MAGL enzyme to increase the endocannabinoids. Thus, among the molecular mechanisms and signaling pathways involved in the pathophysiology of Alzheimer's disease (AD), it is worth mentioning the role of endocannabinoids in the corticolimbic regions. CB1 receptor agonists, miRNA-137 or -let-7a, may be potential therapeutic targets against cognitive decline in AD.