arachidonylcyclopropylamide and Memory-Disorders

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.

Topics: Alzheimer Disease; Animals; Cannabinoid Receptor Agonists; Cannabinoids; Disease Models, Animal; Endocannabinoids; Memory Disorders; Microinjections; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Streptozocin

Increasing evidence shows the interaction effect of cannabinoids and sleep on cognitive functions. In the present study, we aimed to investigate the interaction effect of cannabinoids type 1 receptor (CB1r) in the CA1 hippocampal region and sleep deprivation (SD) on passive avoidance memory and depressive-like behavior in male Wistar rats. We used water box apparatus to induce total SD (TSD) for 24 h. The shuttle-box was applied to assess passive avoidance memory and locomotion apparatus was applied to assess locomotor activity. Forced swim test (FST) was used to evaluate rat's behavior. ACPA (CB1r agonist) at the doses of 0.01, 0.001 and 0.0001 μg/rat, and AM251 (CB1r antagonist) at the doses of 100, 10 and 1 ng/rat were injected intra-CA1, five minutes after training via stereotaxic surgery. Results showed SD impaired memory. ACPA at the doses of 0.01 and 0.001 μg/rat impaired memory and at all doses did not alter the effect of SD on memory. AM251 by itself did not alter memory, while at lowest dose (1 ng/rat) restored SD-induced memory deficit. Both drugs induced depressive-like behavior in a dose-dependent manner. Furthermore, both drugs decreased swimming at some doses (ACPA at 0.0001 μg/rat, AM251 at 0.001 and 0.01 ng/rat). Also, ACPA at the highest dose increased climbing of SD rats. In conclusion, we suggest CB1r may interact with the effect of SD on memory. Additionally, cannabinoids may show a dose-dependent manner in modulating mood and behavior. Interestingly, CB1r agonists and antagonists may exhibit a similar effect in some behavioral assessments.

Topics: Animals; Arachidonic Acids; Avoidance Learning; Behavior, Animal; CA1 Region, Hippocampal; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Locomotion; Male; Memory Disorders; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Sleep Deprivation; Swimming

The basolateral amygdala (BLA) is a key structure for the emotional processing and storage of memories associated with emotional events, especially fear. On the other hand, endocannabinoids and CB1 receptors play a key role in learning and memory partly through long-term synaptic depression of GABAergic synapses in the BLA. The aim of this study was to explore the effects of GABA-A receptor agonist and antagonist in the fear-related memory acquisition deficits induced by ACPA (a selective CB1 cannabinoid receptor agonist). This study used context and tone fear conditioning paradigms to assess fear-related memory in male NMRI mice. Our results showed that the pre-training intraperitoneal administration of ACPA (0.5mg/kg) or (0.1 and 0.5mg/kg) decreased the percentage of freezing time in the contextual and tone fear conditioning, respectively. This indicated an impaired context- or tone-dependent fear memory acquisition. Moreover, the pre-training intra-BLA microinjection of GABA-A receptor agonist, muscimol, at 0.05 and 0.5μg/mouse impaired context-dependent fear memory, while the same doses of GABA-A antagonist, bicuculline, impaired tone-dependent fear memory. However, a subthreshold dose of muscimol or bicuculline increased the effect of ACPA at 0.1 and 0.5 or 0.05mg/kg on context- or tone-dependent fear memory, respectively. In addition, bicuculline at the lower dose increased the ACPA response on locomotor activity compared to its respective group. Such findings highlighted an interaction between BLA GABAergic and cannabinoidergic systems during the acquisition phase of conditioned fear memories.

Topics: Amygdala; Animals; Arachidonic Acids; Bicuculline; Endocannabinoids; Fear; GABA-A Receptor Agonists; GABA-A Receptor Antagonists; Learning; Learning Disabilities; Long-Term Synaptic Depression; Male; Memory; Memory Disorders; Mice; Muscimol; Receptor, Cannabinoid, CB1; Receptors, GABA-A

Some studies have indicated a close relation between serotonergic and cannabinoidergic systems in several brain regions. Thus, the aim of current study is investigating the effect of 5-HT1 receptors of accumbens shell (Acb shell) on aversive memory deficit induced by ACPA (cannabinoid CB1 receptor agonist) using test-retest protocol of elevated plus-maze (EPM) in male Wistar rats.. Bilateral guide cannulae were implanted to allow microinjection of ACPA, CP94253 HCL (5-HT1 receptor agonist agonist) or GR127935 HCL (5-HT1 receptor antagonist).. Post-test intra-Acb shell of ACPA (0.002 μg/rat), CP94253 (0.5 and 5 ng/rat) and GR127935 (5 ng/rat) increased the percentage of open-arms time (%OAT) in the EPM task compared to the control group, indicating aversive memory deficit. Moreover, concurrent microinjection of the subthreshold dose of CP94253 and GR127935 into Acb shell did not alter open-arms exploratory behavior induced by intra-Acb shell of ACPA on the retest day.. Our data suggests that Acb shell 5-HT1 receptor does not affect aversive memory deficit induced by ACPA in the Acb shell.

Topics: Animals; Arachidonic Acids; Avoidance Learning; Behavior, Animal; Exploratory Behavior; Male; Maze Learning; Memory; Memory Disorders; Microinjections; Nucleus Accumbens; Oxadiazoles; Piperazines; Pyridines; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists

The present study investigates the effects of 5-HT4 receptors of the nucleus accumbens (NAc) shell on the impairment of emotional memory consolidation induced by cannabinoid CB1 receptor stimulation. The elevated plus maze test-retest paradigm was used to assess memory in adult male Wistar rats. Intra-NAc shell administration of ACPA (selective cannabinoid CB1 receptor agonist 0.006 µg/rat) and RS23597 (5-HT4 receptor antagonist 0.01 µg/rat), immediately after training, decreased emotional memory consolidation, suggesting a drug-induced amnesia, whereas post-training intra-NAc shell microinjections of RS67333 (5-HT4 receptor agonist 0.016 µg/rat) increased emotional memory consolidation. Interestingly, RS67333 exerted a dual effect on ACPA-induced behaviors, potentiating and restoring amnesia caused by the subthreshold and effective doses of ACPA, respectively. However, neither RS23597 nor AM251 (CB1 receptor antagonist 30, 60 and 120 ng/rat) affected emotional memory consolidation. Nonetheless, a subthreshold dose of AM251 (120 ng/rat) reversed the amnesia induced by ACPA (0.006 µg/rat) and RS23597 (0.01 µg/rat). None of the above doses altered the locomotor activity. In conclusion, our results suggest that the NAc-shell 5-HT4 receptors are involved in the modulation of ACPA-induced amnesia.

Topics: Aniline Compounds; Animals; Arachidonic Acids; Cannabinoid Receptor Antagonists; Disease Models, Animal; Dose-Response Relationship, Drug; Emotions; Male; Maze Learning; Memory Consolidation; Memory Disorders; Motor Activity; Nootropic Agents; Nucleus Accumbens; Piperidines; Pyrazoles; Random Allocation; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists

The serotonergic system has often been defined as a neuromodulator system, and is specifically involved in learning and memory via its various receptors. Serotonin is involved in many of the same processes affected by cannabinoids. The present study investigated the influence of bilateral post-training intra-prelimbic (PL) administrations of serotonergic 5-hydroxytryptamine type-3 (5-HT3) receptor agents on arachidonylcyclopropylamide (ACPA) (cannabinoid CB1 receptor agonist)-induced amnesia, using the step-through inhibitory avoidance (IA) task to assess memory in adult male Sprague-Dawley rats. The results indicated that sole intra-PL microinjection of ACPA (0.1 and 0.5 μg/rat) and 5-HT3 serotonin receptor agonist (m-Chlorophenylbiguanide hydrochloride, m-CPBG; 0.001, 0.01 and 0.1 μg/rat) impaired, whereas Y-25130 (a selective 5-HT3 serotonin receptor antagonist; 0.001 and 0.01 and 0.1 μg/rat) did not alter IA memory consolidation, by itself. Moreover, intra-PL administration of subthreshold dose of m-CPBG (0.0005 μg/rat) potentiated, while Y-25130 (0. 1 μg/rat) restored ACPA-induced memory consolidation deficit. The isobologram analysis showed that there is a synergistic effect between ACPA and m-CPBG on memory consolidation deficit. These findings suggest that 5-HT3 receptor mechanism(s), at least partly, play(s) a role in modulating the effect of ACPA on memory consolidation in the PL area.

Topics: Animals; Arachidonic Acids; Avoidance Learning; Biguanides; Bridged Bicyclo Compounds, Heterocyclic; Cannabinoid Receptor Agonists; Cerebral Cortex; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Male; Memory Disorders; Motor Activity; Oxazines; Rats; Rats, Sprague-Dawley; Reaction Time; Receptor, Cannabinoid, CB1; Receptors, Serotonin, 5-HT3; Serotonin Antagonists; Serotonin Receptor Agonists

The possible interactions between the cannabinoid and serotonin systems in the regions of the brain involved in emotional learning and memory formation have been studied by some researchers. In view of the key role of the amygdala in the acquisition and expression of fear memory, we investigated the involvement of basolateral amygdala (BLA) serotonin 5-HT4 receptors in arachidonylcyclopropylamide (ACPA; selective CB1 cannabinoid receptor agonist)-induced fear memory consolidation impairment. In our study, a context and tone fear conditioning apparatus was used for testing fear conditioning in adult male NMRI mice. The results showed that intraperitoneal administration of ACPA 0.5 or 0.05, 0.1 and 0.5mg/kg immediately after training decreased the percentage of freezing time in context or tone fear conditioning respectively, suggesting a context- or tone-dependent fear memory consolidation impairment. Post-training intra-BLA microinjections of RS67333, as 5-HT4 serotonin receptor agonist, at doses of 0.025 and 0.05 µg/mouse also impaired context or tone memory consolidation, while RS23597, as 5-HT4 serotonin receptor antagonist, did not produce a marked difference in both fear memories as compared with the control group. Moreover, a subthreshold dose of RS67333 did not alter ACPA response in both fear conditionings. Interestingly, a subthreshold dose of RS23597 potentiated or reversed ACPA response at the dose of 0.01 or 0.05 respectively. It is concluded that BLA serotonin 5-HT4 receptors are involved in tone-dependent fear memory consolidation impairment induced by CB1 activation using ACPA, suggesting a modulatory role for serotonin 5-HT4 receptor.

Topics: Acoustic Stimulation; Amygdala; Analysis of Variance; Aniline Compounds; Animals; Arachidonic Acids; Cannabinoid Receptor Modulators; Cannabinoids; Conditioning, Classical; Dose-Response Relationship, Drug; Fear; Male; Memory Disorders; Mice; Microinjections; Piperidines; Reaction Time; Serotonin; Serotonin Agents

The current study was designed to examine the involvement of cannabinoid CB1 receptors in the basolateral amygdala (BLA) in scopolamine-induced memory impairment in adult male Wistar rats. The animals were bilaterally implanted with the cannulas in the BLA and submitted to a step-through type passive avoidance task to measure the memory formation. The results showed that intraperitoneal (i.p.) administration of different doses of scopolamine (0.5-1.5mg/kg) immediately after the training phase (post-training) impaired memory consolidation. Bilateral microinjection of the cannabinoid CB1 receptor agonist, arachydonilcyclopropylamide (ACPA; 1-4ng/rat), into the BLA significantly improved scopolamine-induced memory consolidation impairment. On the other hand, co-administration of AM251, a cannabinoid CB1 receptor antagonist (0.25-1ng/rat, intra-BLA), with an ineffective dose of scopolamine (0.5mg/kg, i.p.), significantly impaired memory consolidation and mimicked the response of a higher dose of scopolamine. It is important to note that post-training intra-BLA microinjections of the same doses of ACPA or AM251 alone had no effect on memory consolidation. Moreover, the blockade of the BLA CB1 receptors by 0.3ng/rat of AM251 prevented ACPA-induced improvement of the scopolamine response. In view of the known actions of the drugs used, the present data pointed to the involvement of the BLA CB1 receptors in scopolamine-induced memory consolidation impairment. Furthermore, it seems that a functional interaction between the BLA endocannabinoid and cholinergic muscarinic systems may be critical for memory formation.

Topics: Animals; Arachidonic Acids; Avoidance Learning; Basolateral Nuclear Complex; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Disease Models, Animal; Dose-Response Relationship, Drug; Endocannabinoids; Male; Memory Consolidation; Memory Disorders; Nootropic Agents; Piperidines; Pyrazoles; Rats, Wistar; Receptor, Cannabinoid, CB1; Scopolamine

Functional interactions between cannabinoid and alpha-2 adrenergic systems in cognitive control in the medial prefrontal cortex (mPFC) seem possible. The present study evaluated the possible role of alpha-2 adrenoceptors of the prefrontal cortex on effect of arachidonylcyclopropylamide (ACPA), a cannabinoid CB1 receptor (CB1R) agonist, in adult male Wistar rats. The animals were bilaterally implanted with chronic cannulae in the mPFC, trained in a step-through task, and tested 24 h after training to measure step-through latency. Results indicate that pre-training microinjection of ACPA (0.05 and 0.5 μg/rat) and clonidine (alpha-2 adrenoceptor agonist; 1 and 2 μg/rat) reduce memory acquisition. Pre-training subthreshold dose of clonidine (0.5 µg/rat) restored memory-impairing effect of ACPA (0.05 and 0.5 µg/rat). On the other hand, pre-training administration of the alpha-2 adrenoceptor antagonist yohimbine in all doses used (0.5, 1, and 2 μg/rat) did not affect memory acquisition by itself, while a subthreshold dose of yohimbine (2 µg/rat) potentiated memory impairment induced by ACPA (0.005 µg/rat). Finally, a subthreshold dose of SKF96365 (a Ca(2+) channel blocker) blocked clonidine and yohimbine effect of memory responses induced by ACPA. In conclusion, these data indicate that mPFC alpha-2 adrenoceptors play an important role in ACPA-induced amnesia and Ca(2+) channels have a critical role this phenomenon.

Topics: Amnesia; Animals; Arachidonic Acids; Calcium Channels; Clonidine; Dose-Response Relationship, Drug; Imidazoles; Male; Memory; Memory Disorders; Prefrontal Cortex; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Receptors, Adrenergic, alpha-2; Yohimbine

The present study evaluates the roles of serotonergic receptors of the medial septum on amnesia induced by arachidonylcyclopropylamide (ACPA; as selective cannabinoid CB1 receptor agonist) in adult male Wistar rats. Cannulae were implanted in the medial septum of the brain of the rats. The animals were trained in a passive avoidance learning apparatus, and were tested 24 hours after training for step-through latency. Results indicated that post-training medial septum administration of CP94253 (5-HT1B/1D receptor agonist) and cinancerine (as 5-HT2 receptor antagonist) reduced the step-through latency showing an amnesic response, while GR127935 (5-HT1B/1D receptor antagonist) and αm5htm (as 5-HT2A/2B/2D receptor agonist) did not alter memory consolidation by themselves. On continuing the test, the results showed that CP94253 increased and GR127935 did not alter ACPA (0.02 µg/rat)-induced memory impairment, respectively. Other data indicated that αm5htm induced a modulatory effect, while cinancerine restored ACPA-induced amnesia. Using SKF-96365 (inhibitor of transient receptor potential TRPC3/6 and TRPV2 channels) demonstrated that TRPC3, TRPC3 and TRPV2 channels have a significant role, according to our results.

Topics: Animals; Arachidonic Acids; Avoidance Learning; Cinanserin; Imidazoles; Male; Memory Consolidation; Memory Disorders; Oxadiazoles; Piperazines; Pyridines; Rats; Septal Nuclei; Serotonin 5-HT1 Receptor Agonists; Serotonin 5-HT1 Receptor Antagonists; Serotonin 5-HT2 Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; TRPC Cation Channels

The critical role of cannabinoidergic and serotonergic systems of the amygdala in modulation of anxiety-like behaviors and emotional memory has already been demonstrated. The present study aimed to investigate the possible role of the basolateral amygdala (BLA) 5-HT3 and 5-HT4 serotonergic systems upon ACPA (CB1 cannabinoid receptor agonist)-induced anxiolytic-like behaviors and emotional memory impairment using the elevated plus-maze (EPM) test-retest paradigm in male mice.. bilateral guide-cannulae were implanted to allow intra-BLA microinjection of serotonergic agents.. the intraperitoneal injection of ACPA could induce anxiolytic-like behaviors and reduce the emotional memory formation. Intra-BLA injection of M-Chlorophenylbiguanide (M-Chl, a 5-HT3 serotonin receptor agonist) neither altered the anxiety-like behaviors nor the emotional memory formation by itself, while the higher dose of Y-25130 (a 5-HT3 serotonin receptor antagonist) reduced the emotional memory formation and locomotor activity but not the anxiety-like behaviors. Furthermore, injection of a higher dose of RS67333 and RS23597 (as 5-HT4 serotonin receptor agonist and antagonist, respectively) did not alter the anxiety-like behaviors, while reduced the emotional memory formation. In addition, the intra-BLA injection of M-Chl but not Y-25130 and RS67333 restored the ACPA-induced anxiolytic-like behaviors and emotional memory deficit, while a higher dose of RS67333 decreased the locomotor activity. Moreover, the intra-BLA microinjection of RS23597 could restore the ACPA-induced anxiolytic-like behaviors but not the emotional memory deficit.. based on our findings, ACPA seems to induce its anxiolytic-like behaviors and emotional memory formation deficits via activation and deactivation of the BLA 5-HT4 and 5-HT3 serotonin receptors.

Topics: Amygdala; Analysis of Variance; Animals; Anxiety Disorders; Arachidonic Acids; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Maze Learning; Memory Disorders; Mice; Microinjections; Receptor, Cannabinoid, CB1; Receptors, Serotonin, 5-HT3; Receptors, Serotonin, 5-HT4; Serotonin Agents

Interactions between cannabinoid and glutamate systems have been demonstrated in some brain areas associated with mnemonic functions. This study investigates the effects of bilateral post-training intra-nucleus accumbens (NAc) shell administrations of glutamate NMDA receptor agents on memory impairment induced by cannabinoid CB1 receptor activation during a step-through inhibitory avoidance (IA) task. Our results showed post-training administration of ACPA (CB1 receptor agonist; 3 ng/side) impairs IA memory consolidation, whereas AM251 (CB1 receptor antagonist; 0.3, 3 and 30 ng/side), NMDA (0.3, 3 and 30 ng/side), and d-AP7 (NMDA receptor antagonist; 3, 30 and 300 ng/side) were ineffective. However, co-administration of AM251 (30 ng/side) or NMDA (30 ng/side) with ACPA (3 ng/side) prevented the memory-impairing effect of ACPA. Meanwhile, co-administration of NMDA (30 ng/side) and a subthreshold dose of ACPA (0.15 ng/side) decreased memory consolidation. Moreover, post-training microinjection of AM251 (30 ng/side) or d-AP7 (300 ng/side) prevented memory impairment induced by co-administration of subthreshold doses of NMDA and ACPA. The data indicated that NMDA receptor mechanism(s), at least partly, play(s) a role in modulating the effect of ACPA on memory consolidation in the NAc shell.

Topics: 2-Amino-5-phosphonovalerate; Animals; Arachidonic Acids; Avoidance Learning; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Agonists; Glutamic Acid; Male; Memory; Memory Disorders; Motor Activity; N-Methylaspartate; Nucleus Accumbens; Piperidines; Pyrazoles; Rats, Wistar; Receptor, Cannabinoid, CB1