Lysosomal and Dopaminergic D2 Inhibition Reversed the Effect of Morphine on Learning and Memory in Male Wistar Rats Relating Mitochondrial Biogenesis

Introduction: Opiates dependence has many side effects on body especially brain neuroplasticity leading to changes in behavior. In this study, we evaluated the effects of morphine dependence on learning and memory as well as on Peroxisome proliferator-activated receptor gamma coactivator -1 alpha (PGC-1α) protein level as a key regulator of mitochondrial biogenesis. Also, by using Chloroquine (lysosomal inhibitor) and dopaminergic system inhibitor (Sulpiride), the molecular mechanism, underling morphine addiction related to lysosome, dopamine receptors and mitochondria, has been considered in this study. Materials and Methods: Male albino Wiastar rats received morphine in their water for 21 days; during the ending 4 days, they received daily intracerebroventricular (i.c.v.) injection of Chloroquine diphosphate (50 mM). Also, i.c.v. injection of Sulpiride (0.25µg/rat) was done before behavioral test. Shuttle box apparatus was used for learning and memory evaluation. After behavioral test, the brains of rats were extracted and the level of PGC-1α protein was investigated by western blotting. Results: Results indicated that morphine oral administration has reduced learning and memory-like behavior. Pre-training i.c.v. injection of Chloroquine and Sulpiride improved learning and memory. PGC-1α protein level in rats which received Chloroquine and also in the morphine group increased and there was a more significant increase in rats which received morphine, Chloroquine and  Sulpiride altogether. Conclusion: Morphine has an adverse effect on learning and memory as it has been shown with spending more time in dark rooms of Shuttle box apparatus, which was reversed by Chloroquine (lysosomal inhibitor) and dopamine inhibitor (Sulpiride).  Increasing PGC-1α protein level may imply the important role of mitochondrial biogenesis in morphine-dependent learning changes. Overall, data suggest dopaminergic system along with lysosome and mitochondrial activity play an important role in morphine addiction status

Sleep loss and the brain vulnerability to neurodegeneration: behavioral, biochemical and neurohistopathological observations in a rat model

Background: Experimentally-induced total sleep deprivation (TSD) and chronic partial sleep restriction (CPSR) leads to the emergence of cognitive impairments. This is hypothesized to result from a consequent neuroinflammation which may also hasten the neurodegenerative processes. Neuroinflammatory markers such as tumor necrosis factor-alpha (TNFα) are thought to be potential culprits in SD-induced neurodegeneration. Methods: The effect of TSD and CPSR on memory and anxiety-related behaviors (using the Elevated Plus-Maze testretest protocol) and serum level of brain derived neurotrophic factor (BDNF) and corticosterone were assessed in male Wistar rats subjected to the modified disk-over-water (DOW)apparatus. In addition, an immunohistochemical (IHC) study was done to possibly detect the amyloid-beta (Aβ) and hyper-phosphorylated tau protein (HPτ) deposition in the dentate gyrus (DG) of the examined rats’ hippocampi. Histomorphology and neuronal numerical density assessments were done at the same level across control and experimental animals. We also studied the above parameters in rats after intraperitoneal injection of the TNFα neutralizing antibody, infliximab (IFX). Results: Rats subjected to TSD and CPSR which did not receive IFX, showed a more pronounced impairment of memory, elevated serum corticosterone and decreased BDNF levels. CPSR rats which underwent delayed brain excision following behavioral testing, showed deposition of the HPτ and revealed the least numerical density in the hippocampal DG neurons. Meanwhile, IHC study revealed no Aβ deposition in the hippocampal DG of all examined rats. Interestingly, treatment with IFX, abrogated sleep restriction-induced cognitive decline, biochemical changes and the immunohistopathology in the hippocampal DG. Conclusions: Taken together, our findings indicated that CPSR (the SD model mimicking shift work) induces not only cognitive and biochemical changes, but also pathology in the hippocampal DG. This is possibly via activation of the inflammatory mechanisms in part through TNFα-dependent pathways

State-dependent memory and its modulation by different brain areas and neurotransmitters

The state-dependent memory defines as a state that the retrieval of recently obtained information may be potential if the subject exists in a similar physiological situation as for the period of the encoding stage. Studies revealed that exogenous and endogenous compounds could induce state-dependent memory. The state-dependent memory made it probable to differentiate the effects of drugs per se on learning from the effects due to alterations in drug state during the task. Studies proposed the role of regions beyond the limbic formation and illustrated that state-dependent memory produced by various neurotransmitter systems and pharmacological compounds. Our review of the literature revealed that: (a) re-administration of drugs on the same state induce state-dependent memory; (b) many neurotransmitters induce endogenous state-dependent memory; (c) there are cross state-dependent learning and memory between some drugs; (d) some sites of the brain including the CA1 areas of the hippocampus, central nucleus of the amygdala (CeA), septum, ventral teg­mental area (VTA), and nucleus accumbens (NAC) are involved in state-dependent memory

An overview of cognitive aspects of β-carbolines

    Mind-altering drugs, especially plants, have fascinated human and always occupied man’s attention .Among the plants used by humans, those able to alter the mind and the mood have drawn special consideration. Actually, due to their amazing effects, these drugs, have occupied much of the researchers’ time and efforts towards attempts to understand their mechanism, and, hence, to understand human thoughts, behavior, cognitive aspects, sensations and etc. The fact is plants could have beneficial properties to treat mental disease and have some effects on cognitive function. Now we know that plants by originating directly from nature are not less toxic than synthetic drugs. The manner of poisoning with plants can be divided into unintentional or intentional ingestion of plant material and substance abuse. This review article deals with β-carboline, which has effect on CNS

The involvement of hippocampal CA3 TRP channels in anxiety and avoidance memory consolidation in rats tested in elevated plus maze

    In the current study, we assessed the role of transient receptor potential (TRP) channels on avoidance memory and anxiety states in CA3 area of the hippocampus. We explored the anxiety and avoidance memory states using test-retest protocol in the elevated plus maze to understand whether TRP channels can affect the above mentioned states in CA3 area. To investigate the consolidation phase of memory, the drugs were injected into the CA3 region before the test. Our data showed that the application of SKF-96365 did not alter anxiety-like behaviors but induced avoidance memory impairment. It was revealed that CA3 TRP channels could affect the avoidance memory consolidation and their role must be considered in future research

Precondition of right frontal region with anodal tDCS can restore the fear memory impairment induced by ACPA in male mice

Fear memory and learning cause behavioural patterns such as fight or flight responses, which increase survival probability, but unfit processing of fear memory and learning can lead to maladaptive behaviours and maladies such as phobias, Post-Traumatic Stress Disorder (PTSD) and anxiety disorders. The growing prevalence of these maladies shows the need to quest novel methods for their treatment. We used anodal transcranial direct current stimulation (tDCS) on the right frontal region as a precondition neuromodulator and arachidonylcyclopropylamide (ACPA), a selective CB1 cannabinoid receptor agonist, as a fear memory impairing agent to assess their effects on contextual and auditory fear conditioning (reliable model for fear studies). Right frontal anodal tDCS (0.2 mA for. 20 minutes) 24 hours before the train did not alter contextual and auditory learning and memory in short-term (24 hrs after the training phase). Moreover, intraperitoneal pre-train injection of ACPA (0.1 mg/kg) alone, decreased both contextual and auditory learning and memory in short- but not long-term. Right frontal anodal tDCS improved short-term contextual fear memory in subthreshold doses of ACPA. On the other hand, right frontal anodal tDCS in long-term improved (lower doses of ACPA) and restored (higher doses of ACPA) both fear memories. These findings showed that, aforementioned approach could cause durable learning and memory improvements. Also this combined modality could be useful for fear extinction training and maladies which inflict amnesia

The effect of crocin on total sleep-deprivation induced amnesia in male Wistar rats

Introduction: In recent years, Crocin has been used for its pharmacological functions, such as memory and learning enhancement. The aim of the present study was to assess the effect of Crocin on total sleep deprivation (TSD)-induced amnesia in male Wistar rats. Materials and Methods: The water box apparatus was used to induce sleep deprivation followed by Y- maze task as an index of learning and memory (the percentage of time in the novel arm during the retention phase was reported as an index of memory performances). The rats were divided into 12 groups, 8 rats in each group, including four control groups, four sham groups, and four TSD groups. Each group received saline and Crocin at doses of 1, 5 or 15 mg/kg twice a day. Results: The findings revealed that TSD for 24 h impaired memory function. In addition, the intra-peritoneal injection of Crocin at all doses (1, 5 and 15 mg/kg) did not change the percentage of time spent in the novel arm of Y-maze in sham of TSD, whereas it abolished the responses induced by the TSD groups. Conclusion: The findings showed a close interaction between the Crocin and SD. Based on the findings, Crocin seems to possess a modulatory effect on SD-induced amnesia

The Effect of ICV Administration of PI3K on Memory

Introduction: Brain insulin receptors (IRs) have been suggested as an important regulatory factor for cognitive functions but the involvement of IR signaling in memory deficit associated with neurodegenerative conditions is not yet explored.  Among the diverse signaling pathways of IR, PI-3 kinase and (MAP) kinase pathways in brain have been suggested for learning and memory functions. The phosphoinositide3-kinase (PI3K) complex plays important roles in virtually all cells of the body. The enzymatic activity of PI3Kto phosphorylate phosphoinositides in the membrane is mediated by a group of catalytic and regulatory subunits. Among those, the class I catalytic subunits, p110α, p110β,p110γ,and p110δ have recently drawn attention in the neuroscience field due to their specific dysregulation in diverse brain disorders. The present study was planned to investigate the effect of PI3K on memory.Materials and Methods: The animals were injected bilaterally with ICV water (control group), ICV PI3k (1,10 and 100 ng/rat) on days 1 and 3 after surgery.  The learning and memory performance was assessed two weeks after the first dose of drugs by using step-through passive avoidance paradigm (0.3 mA, 3seconds) and open field test. The results revealed that The ICV administration   of PI3K (P<0.05) altered inhibitory avoidance acquisition. PI3K at dose 1 ng/rat decreased the step- through latency during the retention test.Results: data showed that PI3K at dose of 1 ng/rat decreased the step- through latency during the retention test. In addition, the results showed that PI3K at dose 10 ng/rat increased locomotor activity. Conclusion: Finally, our data indicated that PI3K has critical role in memory consolidation and locomotor activity.

The effect of BLA GABAA receptors in anxiolytic-like effect and aversive memory deficit induced by ACPA

The roles of GABAergic receptors of the Basolateral amygdala (BLA) in the cannabinoid CB1 receptor agonist (arachydonilcyclopropylamide; ACPA)-induced anxiolytic-like effect and aversive memory deficit in adult male mice were examined in elevated plus-maze task. Results showed that pre-test intra-peritoneal injection of ACPA induced anxiolytic-like effect (at dose of 0.05 mg/kg) and aversive memory deficit (at doses of 0.025 and 0.05 mg/kg). The results revealed that Pre-test intra-BLA infusion of muscimol (GABAA receptor agonist; at doses of 0.1 and 0.2 µg/mouse) or bicuculline (GABAA receptor antagonist; at all doses) impaired and did not alter aversive memory, respectively. All previous GABA agents did not have any effects on anxiety-like behaviors. Interestingly, pretreatment with a sub-threshold dose of muscimol (0.025 µg/mouse) and bicuculline (0.025 µg/mouse) did not alter anxiolytic-like behaviors induced by ACPA, while both drugs restored ACPA-induced amnesia. Moreover, muscimol or bicuculline increased and decreased ACPA-induced locomotor activity, respectively. Finally the data may indicate that BLA GABAA receptors have critical and different roles in anxiolytic-like effect, aversive memory deficit and locomotor activity induced by ACPA

Comparison of 5-HT3 or 5-HT4 agents function into the prelimbic area on passive avoidance memory consolidation

     Growing evidence suggests that serotonin plays an important role in learning and memory and all its receptors might be implicated in this process. The present study aimed at investigating and comparing the possible involvement of 5-HT3 and 5-HT4 receptor (R) agonists/antagonists upon consolidation of inhibitory avoidance memory in the pre-limbic (PL) area. Bilateral intra-PL microinjections of m-CPBG (m-Chlorophenylbiguanide hydrochloride: a selective 5-HT3R agonist; 0.1 μg/rat), Y-25130 (a selective 5-HT3R antagonist; 0.1 μg/rat), RS67333 (a potent and highly selective 5-HT4R partial agonist; 0.5 μg/rat) and RS23597-190 (a selective 5-HT4R antagonist; 0.5 μg/rat) were performed immediately after training. The step-through inhibitory avoidance (IA) task was used to memory assessment in adult male Sprague-Dawley rats. Our data revealed that the post-training intra-PL microinjection of m-CPBG relative to saline and Y-25130 decreased inhibitory avoidance memory consolidation in the PL area. On the contrary, RS67333 increased IA memory consolidation in comparison to saline and RS23597-190. In addition, there was also a significant difference between the effects of m-CPBG and RS67333 on IA memory consolidation in the PL area. M-CPBG induced reduction of IA memory consolidation, while RS67333 increased it. However, Y-25130 compared to RS23597-190 did not show any significant difference. All above interventions did not alter locomotor activity. This study indicated that local direct agonist activation of 5-HT3Rs induced the reduction of IA memory consolidation, opposed to the local direct agonist activation of 5-HT4Rs, which mediated enhancement of IA memory consolidation. It can be proposed that 5-HT3Rs in comparison to 5-HT4Rs may be inversely involved in modulation of IA memory consolidation in the PL