Basolateral amygdala cannabinoid CB1 receptors mediate the antinociceptive activity of harmaline in adolescent male mice.

Evidence suggests a clear role for the amygdala endocannabinoid system in pain processing. Harmaline has been also known as the main nociceptive agent extracted from the Peganum harmala plant. In this study, the role of basolateral amygdala (BLA) cannabinoid CB1 receptors in pain sensitivity of harmaline-treated mice were assessed using tail-flick and hot plate methods in adolescent male NMRI mice. Intraperitoneal administration of two higher doses of harmaline (6 and 8 mg/kg) increased tail-flick latency, suggesting an antinociceptive activity. The same result was observed for the higher dose of harmaline in the hot plate test. Intra-BLA microinjection of CB1 receptor agonist ACPA (1 and 1.5 ng/mouse) or (1.5 ng/mouse) enhanced the ineffective dose-response of harmaline on pain threshold in the tail-flick or hot plate tests, respectively. Microinjection of two higher doses of CB1 receptor antagonist AM251 (0.5 and 1 ng/mouse) attenuated the antinociceptive activity of harmaline (8 ng/mouse) in both tail-flick and hot plate tests. Meanwhile, ACPA and AM251 did not alter latency to withdraw from the noxious stimulus in both tests, by themselves. It should be noted that the analgesic dose of the drugs alone or in combination did not affect locomotor activity. The obtained results highlight that BLA CB1 receptors mediate the antinociceptive activity of harmaline.

Isobolographic analysis of the antidepressant interaction in two-drug combinations of citalopram, bupropion, and scopolamine in mice.

Depression and anxiety are psychiatric diseases that commonly occur together, and the patient burden and complexity increase when both are present. Comorbid anxiety and depression are often more resistant to common drug treatments such as antidepressants. Combination therapy is a suggested approach in treating these patients, where a decline of doses could reduce undesirable outcomes and still achieve optimal effects. We, therefore, conducted a preclinical study to assess the effect of two-drug combinations of citalopram, bupropion, and scopolamine on anxiety- and antidepressive-like behaviors in male NMRI mice and aimed to determine the nature of the interaction between components. Anxiety- or antidepressive-like activity of mice was assessed by the hole-board or forced swim test (FST), respectively. Our results revealed that citalopram (0.01-0.25 mg/kg; i.p.), bupropion (1-9 mg/kg; i.p.), or scopolamine (0.01-0.1 mg/kg; i.p.) diminished immobility time in the FST, suggesting an antidepressive-like effect. Citalopram decreased dead-dip counts in the hole-board, indicating an anxiogenic-like activity. All two-drug combinations, at inactive doses, exerted an antidepressive-like behavior. Only bupropion/scopolamine combination increased head-dip counts compared to the bupropion/saline group. Isobolographic analysis revealed an antidepressive synergy effect between citalopram plus bupropion, and an antidepressive additive impact between scopolamine plus citalopram or bupropion. It should be noted that the higher dose of each drug alone declined locomotor activity, while two-drug combinations did not affect this parameter. These results suggest a stronger antidepressive effect for citalopram/bupropion combination than other two-drug combinations.

The effect of URB597, exercise or their combination on the performance of 6-OHDA mouse model of Parkinson disease in the elevated plus maze, tail suspension test and step-down task.

Parkinson disease (PD) is a progressive neurodegenerative disorder that is often accompanied by motor and psychiatric symptoms. Various approaches have been proposed for the treatment of PD. Here, we investigated the effect of a low dose of fatty acid amide hydrolase inhibitor URB597 (as an enhancer of endocannabinoid anandamide levels), exercise or their combination on some behavior alterations in PD mice lesioned by 6-hydroxydopamine (6-OHDA). The impact of swimming exercise (5×/week for 4 weeks) and URB597 (0.1 mg/kg, 2×/week for 4 weeks) on the anxiety-related behavior (elevated plus maze; EPM), depression-related behavior (tail suspension test; TST), and passive avoidance memory (step-down task) was examined in the sham and male NMRI mouse of PD model. The results show that URB597 prevented memory deficits and elicited antidepressant- and anxiolytic-like effects but did not affect hypolocomotion in the PD mice. However, URB597 did not have a significant effect on the performance of the sham mice in the performed tests. Moreover, swimming training abolished depressive- and anxiogenic-like behaviors and increased locomotion without affecting memory deficits in the PD mice. Meanwhile, swimming decreased immobility time and increased locomotion in the sham mice. Furthermore, URB597 in association with swimming training prevented all deficits induced in the PD mice, while this combination impaired memory and produced the positive effects on depression- and anxiety-related behaviors and locomotion of the sham mice. It is concluded that although URB597 or exercise alone had positive effects on most behavioral tests, their combination improved all parameters in the PD mice.

Anodal tDCS applied to the left frontal cortex abrogates scopolamine­induced fear memory deficit via the dopaminergic system.

Evidence suggests that transcranial direct current stimulation (tDCS) modulates conditioned fear memories and has effects on cognitive flexibility via the dopaminergic system. This study examines whether modulation of scopolamine­induced fear memory deficit by anodal tDCS could be mediated by the dopaminergic system. The male NMRI mice received scopolamine, 30 min before fear conditioning, and showed impaired contextual memory retention. Mice subjected to left frontal anodal stimulation for 20 or 30 min, before fear conditioning, impaired fear memory retrieval. Anodal application for 20 min significantly decreased scopolamine response on fear retention, while the one applied for 30 min did not alter. Moreover, anodal stimulation for 30 min abolished scopolamine­induced fear memory deficit. Dopaminergic antagonists SCH23390 and sulpiride, alone or in combination, prevented the abolishment effect of anodal stimulation on scopolamine­induced fear memory deficit, whereas they did not alter the impairing effect of scopolamine at the dose of 2 mg/kg. Our data suggest that anodal stimulation for 30 min abrogates the impairing effect of scopolamine on fear memory retention. This influence could be prevented by dopaminergic antagonists, indicating the involvement of the dopaminergic system in the effect of anodal stimulation on scopolamine­induced fear memory deficit.

URB597 abrogates anxiogenic and depressive behaviors in the methamphetamine-withdrawal mice: Role of the cannabinoid receptor type 1, cannabinoid receptor type 2, and transient receptor potential vanilloid 1 channels.

BACKGROUND: Methamphetamine is an addictive stimulant that possesses toxicity in the brain when taken repeatedly or at higher doses. Methamphetamine neurotoxicity is associated with numerous forms of mental impairment, including depression and anxiety. Evidence has also demonstrated that the endocannabinoid system is involved in the regulation of anxiety and depression. AIMS: This study was designed to determine the involvement of the endocannabinoid system in anxiety- and depression-related behaviors in methamphetamine-withdrawal male NMRI mice. METHODS: The elevated plus maze and forced swim test were used to assess the level of anxiety and depression. RESULTS: We found that methamphetamine (30 mg/kg, intraperitoneal) evoked depressive- and anxiogenic-like effects at 3 days post-administration. Injection of URB597 (5-10 ng/mouse, intracerebroventricular), 10 min before the test, prevented the emotional deficits induced by methamphetamine withdrawal. Moreover, the cannabinoid receptor type 1 antagonist AM251 (1 µg/mouse) or cannabinoid receptor type 2 antagonist AM630 (5 and 10 µg/mouse) suppressed the antidepressant activity in the methamphetamine-withdrawal mice treated with URB597. The transient receptor potential vanilloid 1 antagonist capsazepine (25 µg/mouse) prevented while capsazepine (100 µg/mouse) potentiated the antidepressant efficacy in the methamphetamine-withdrawal mice treated with URB597. The higher dose of AM630 and two higher doses of capsazepine had antidepressant efficacy, by themselves. Furthermore, capsazepine (50 µg/mouse) increased locomotion in the methamphetamine-withdrawal mice treated with URB597. CONCLUSIONS: The results suggest that URB597 has a potential for preventing methamphetamine withdrawal-evoked anxiety and depression. Cannabinoid type 1 receptors, cannabinoid type 2 receptors and transient receptor potential vanilloid 1 differently affect depression-related behaviors in methamphetamine-withdrawal mice treated with URB597.

Synergistic antidepressant- and anxiolytic-like effects of harmaline along with cinanserin in acute restraint stress-treated mice.

RATIONALE: Acute restraint stress (ARS) is an experimental paradigm used for the induction of rodent models of stress-produced neuropsychiatric disorders, such as depression and anxiety. ß-carbolines and serotonin (5-HT) systems are involved in the modulation of depression and anxiety behaviors. OBJECTIVE: This study was designed to examine the effects of intracerebroventricular (i.c.v.) injection of cinanserin (5-HT2 receptor antagonist) on harmaline-induced responses on depression- and anxiety-like behaviors in the ARS mice. METHODS: For i.c.v. infusion, guide cannula was surgically implanted in the left lateral ventricle of mice. The ARS model was conducted via movement restraint at a period of 4 h. Depression- and anxiety-related behaviors were evaluated by forced swim test (FST) and elevated plus maze (EPM), respectively. RESULTS: The results displayed that the ARS mice showed depressive- and anxiety-like responses. I.p. administration of different doses of harmaline (0.31, 0.625 and 1.25 mg/kg) or i.c.v. microinjection of cinanserin (1, 2.5, and 5 µg/mouse) blocked depression- and anxiogenic-like behaviors in the ARS mice. Furthermore, co-administration of harmaline (1.25 mg/kg; i.p.) and cinanserin (5 µg/mouse; i.c.v.) prevented the depression- and anxiogenic-like effects in the ARS mice. We found a synergistic antidepressant- and anxiolytic-like effects of harmaline and cinanserin in the ARS mice. CONCLUSIONS: These results propose an interaction between harmaline and cinanserin to prevent depressive- and anxiogenic-like behaviors in the ARS mice.

Combined treatment of scopolamine and group III mGluR antagonist, CPPG, exerts antidepressant activity without affecting anxiety-related behaviors.

Clinical trials have revealed that the muscarinic receptor antagonist scopolamine produces a fast and potent antidepressant response. However, the anticholinergic adverse effects and the risk of psychosis at higher doses limit the widespread clinical use of scopolamine. Combination therapy of scopolamine and other antidepressants in treating depression has been suggested. Our experimentswere designed to examine the effects of the combining ineffective doses of scopolamine and a group III metabotropic glutamate receptor (mGluR) antagonist, CPPG, on depression- and anxiety-related behaviors in male NMRI mice. The forced swim test (FST) and the elevated plus maze (EPM) were selected to evaluate depression- and anxiety-related behaviors, respectively. Intraperitoneal (i.p.) administration of scopolamine (0.01-0.5 mg/kg) exerted profound antidepressive and anxiogenic effects. Intracerebroventricular (i.c.v.) administration of CPPG (12.5-50 nmol/mouse) elicited significant antidepressive and anxiolytic effects. Moreover, the ineffective dose of CPPG (12.5 nmol/mouse) plus ineffective doses of scopolamine (0.01 or 0.05 mg/kg) showed antidepressant-like effect while these combinations had no effect anxiety-related behaviors. It should be noted that none of the compounds altered locomotor activity. Results identify the combined administration of scopolamine and CPPG as a possible hopeful target in the future treatment of the depressive disorder.

Better antidepressant efficacy of mecamylamine in combination with L-NAME than with L-arginine.

Aff ;ective disorders, including anxiety and mood disorders, are a constellation of psychiatric diseases that aff ;ect over 10 % of the world's population. It has been proposed that drugs that change nicotinic acetylcholine receptor (nAChR) activity can affect mood- and anxiety-related behaviors. Also, neuronal nitric oxide synthase (nNOS) is closely associated with the pathophysiology of these disorders. To limit the potential adverse effects of alteration in cholinergic and nitric oxide (NO) systems, we investigated the combined efficacy of subthreshold doses of nAChR antagonist mecamylamine and NO ligands (L-arginine as agonist and l-NAME as an antagonist) on depression- and anxiety-related behaviors in male NMRI mice. Depression-related behaviors using the forced swim test (FST) and anxiety-like activity using the hole-board test were assessed. In our results, mecamylamine (3 mg/kg) showed antidepressant-like properties, and it also tended to have anxiolytic-like effects, though not significant. Concomitant treatment of subthreshold doses of mecamylamine (1 mg/kg) and l-arginine (25 mg/kg), l-NAME (1 mg/kg), or l-arginine/L-NAME were antidepressive. In contrast, l-arginine/L-NAME alone or in associated with mecamylamine showed anxiogenic-like efficacy. Isobolographic analysis exhibited an additive antidepressant effect of the combined subthreshold doses of mecamylamine and l-arginine, and a synergistic antidepressant effect of the combined subthreshold doses of mecamylamine and l-NAME. It should be noted that mecamylamine (3 mg/kg) elicited hypolocomotion. Our results suggest that mecamylamine produces a better antidepressant efficacy in combination with l-NAME than with l-arginine.

Effects of precondition α2-adrenoceptor agents on memory- and anxiety-related processes in the transient cerebral ischemic rats.

Neurological evidence for the neuroprotective function of α2-adrenoceptors in the cerebral ischemia is inconsistent. It is not examined how pretreatment with a single dose of α2-adrenoceptor agents can affect motor function and anxiety- and memory-related responses in the cerebral ischemic animals. The transient forebrain ischemia model was provided, using a bilateral common carotid arterial occlusion (two-vessel occlusion, 2VO) in male Wistar rats. The 2VO rats impaired motor functions in the Rota-rod and wire grip tests and also decreased the step-through latency and the percentage of time spent on the open arms (%OAT), the percentage of entries into the open arms (%OAE) as well as locomotion in the elevated plus maze (EPM), indicating a memory deficit and anxiety-like behavior. Intraperitoneal single administration of yohimbine (0, 0.001, 0.01, and 0.1 mg/kg) before the 2VO did not alter these parameters while the higher and middle doses of clonidine (0.01 and 0.1 mg/kg) prevented the memory deficit and hypo-locomotion and its middle dose abrogated Rota-rod dysfunction and anxiety-like response. Meanwhile, both drugs did not influence on the measured behaviors in the sham groups by themselves. Moreover, yohimbine (0.001 mg/kg) abolished the beneficial effects of clonidine (0.01 and 0.1 mg/kg) on motor function in the Rota-rod and memory retention and also at its middle dose on the %OAT and locomotion in the 2VO rats. Our findings show a neuroprotective role for clonidine in motor function and memory- and anxiety-related behaviors of 2VO rats and the importance of α2-adrenoceptors in these processes.

Cross state-dependent memory retrieval between morphine and norharmane in the mouse dorsal hippocampus.

State-dependent memory (SDM) describes a phenomenon that memory is efficiently restored only when the brain state during restoration matches the state during encoding. Some psychoactive drugs such as morphine, ethanol, and cocaine evoke SDM. The scope of this study was to investigate the cross SDM between morphine and norharmane injected into the dorsal hippocampus of male NMRI mice, and the involvement of µ-opioid receptors (MORs) in the SDM of the drugs. Bilateral cannulae were implanted into the CA1 regions (intra-CA1), and memory retrieval was measured by the step-down apparatus. Results showed that pre-test microinjection of morphine (1 µg/mouse, intra-CA1) reversed amnesia induced by pre-training administration of the same dose of morphine, indicating morphine SDM. Moreover, norharmane (10 µg/mouse) also exerted a SDM. Pre-test microinjection of naloxone (0.5 µg/mouse) abolished amnesia induced by morphine or norharmane, and impaired SDM produced by each drug. The results demonstrated the contribution of MORs in the SDM induced by morphine as well as norharmane. Pre-test administration of morphine (1 µg/mouse, intra-CA1) also inhibited amnesia induced by pre-training intra-CA1 microinjection of norharmane (10 µg/mouse) and vice versa, suggesting a cross SDM between the drugs. In conclusion, it seems that there may be a cross SDM between morphine and norharmane, and MORs have a critical role in this phenomenon.

Antinociceptive and antidepressive efficacies of the combined ineffective doses of S-ketamine and URB597.

Clinical studies have demonstrated that the NMDA receptor antagonist ketamine produces rapid antidepressant responses. There are safety concerns and adverse effects that limit the utilization of ketamine in psychiatry. Some studies have suggested combination therapy for optimal ketamine use. In this study, we evaluated the potential for combination therapy of ineffective doses of ketamine and fatty acid amide hydrolase inhibitor URB597 for the treatment of depression and pain in male NMRI mice. Intraperitoneal administration of ketamine (10 mg/kg) at the time intervals of 115, 145, and 160 min and ketamine (5 mg/kg) at the time interval of 160 min after administration increased the tail-flick latency, indicating an antinociceptive effect. The same doses of ketamine decreased immobility time in the forced swim test (FST), showing an antidepressant-like effect. Moreover, URB597 at the doses of 0.5 and 1 mg/kg induced an antinociceptive effect, while it at the dose of 1 mg/kg produced an antidepressant-like response. Furthermore, co-administration of the ineffective doses of ketamine (2.5 mg/kg) and URB597 (0.1 mg/kg) caused antinociceptive and antidepressant-like effects, while each one of them alone did not alter the performance of mice in the FST and tail-flick tests. It should be noted that none of the treatments alter animal locomotor activity compared to the control group. Therefore, the combined administration of ineffective doses of ketamine and URB597 might be an effective strategy in the therapy of depression and pain.

Additive interaction between scopolamine and nitric oxide agents on immobility in the forced swim test but not exploratory activity in the hole-board.

RATIONALE: The muscarinic cholinergic antagonist scopolamine has received an attention due to its unique antidepressant effects. However, the considerable adverse effects on nervous system limit the use of scopolamine as a psychiatric drug. OBJECTIVE: In order to overcome the limitations and increase the therapeutic effects of scopolamine, we decided to examine the effects of joint administration of sub-effective dose of scopolamine and the sub-effective dose of a nitric oxide (NO) precursor L-Arginine or a non-selective nitric oxide synthase (NOS) inhibitor L-NAME on depression- and anxiety-related behaviors in male NMRI mice. METHODS: To this aim, animal behavior was assessed in the forced swim test (FST) and hole-board apparatus. RESULTS: Scopolamine (0.05 mg/kg) significantly decreased immobility time in the FST, suggesting an antidepressant-like effect. Moreover, L-Arginine (50 mg/kg) produced an antidepressant-like response in the FST and decreased head-dip counts in the hole-board apparatus, indicating an anxiety-like effect. The same doses of scopolamine and L-Arginine decreased the locomotor activity in mice. Joint administration of sub-effective dose of scopolamine (0.01 mg/kg) with a low dose of L-Arginine (25 mg/kg) or L-NAME (1 mg/kg) induced a profound antidepressant-like effect in the FST. These drug combinations did not influence on anxiety-related behaviors. Meanwhile, L-NAME alone did not alter the performance of mice in the FST and hole-board. Isobolographic analysis revealed an additive effect for scopolamine and L-Arginine or L-NAME. CONCLUSION: Data suggests that NO agents could positively impact the therapeutic profile of scopolamine, because they might be useful for inducing antidepressant-like effect associated to scopolamine.

Ketamine-induced antidepressant like effects in mice: A possible involvement of cannabinoid system.

The purpose of this study was to explore the possible interaction between ketamine and cannabinoid system in the modulation of depression-related responses using the forced swimming test (FST), tail suspension test (TST) and open-field test (OFT) in mice. Our results revealed that intra-peritoneal (i.p.) injection of ketamine (5 and 10 mg/kg), a non-competitive NMDA antagonist, dose-dependently produced antidepressant-like effect in the FST. Moreover, i.p. administration of both CB1 and CB2 receptor drugs: ACPA (1 mg/kg; CB1 receptor agonist), AM251 (1 mg/kg; CB1 receptor antagonist), GP1a (2 mg/kg; CB2 receptor agonist) and AM630 (0.5 mg/kg; CB2 receptor antagonist) exhibited antidepressant action. Interestingly, the concomitant administration of ineffective doses of ketamine and cannabinoid receptor antagonists provoked the antidepressant-like effects as compared to control group. It should be considered, all above mentioned doses of drugs could not change locomotor activity in the OFT. It seems that possible interaction between ketamine and cannabinoid system may modulate depression-related behavior.

MLC901 during sleep deprivation rescues fear memory disruption in rats.

Several lines of evidence suggest that sleep deprivation disrupts cognitive and emotional abilities and changes the expression of distinctive categories of genes in the brain. In the present study, saline- or MLC901 (a traditional Chinese medicine)-treated male Wistar rats were first submitted to a modified water box (for 24-h sleep deprivation) and then trained in contextual and tone fear conditioning tasks with the purpose to evaluate the effect of MLC901 during sleep deprivation on fear memory retention. Hippocampal mRNA measurement was performed by reverse transcription-polymerase chain reaction (RT-PCR). We found that the exposure of rats to 24 h of sleep deprivation impaired contextual and tone fear memory retention, while administration of MLC901 (0.2, 0.4, and 0.8 mg/kg, once/12 h; i.p.) during sleep deprivation abolished memory deficits. Meanwhile, different doses of MLC901 alone had no effect on performance in both tasks. We observed that MLC901 increased the expression levels of pro-apoptotic BAD, anti-apoptotic Bcl-xL, and Tfam as an index of mitochondrial biogenesis compared to sleep-deprived rats, while MLC901 during sleep deprivation increased BAX, BAD, and Bcl-xL compared to the control group. Sleep deprivation decreased BAX and Tfam, by itself. MLC901 only decreased BAX and Tfam and increased BAD level compared to the non-sleep-deprived control group. It is suggested that MLC901 might be a therapeutic option for memory impairment during sleep deprivation.

Anxiolytic and antidepressant effects of ACPA and harmaline co-treatment.

Depression and anxiety disorders are among the most common illnesses and a close relationship between them has been found. Because the psychotropic effects and abuse liability of cannabis prevent its therapeutic application in depression and anxiety states, we decided to investigate the effects of the combination of ineffective doses of cannabinoid CB1 receptor agonist arachidonylcyclopropylamide (ACPA) and ß-carbolines on anxiety- and depression-related behaviors in male NMRI mice. Anxiety- and depression-related behaviors were assesses using elevated plus maze (EPM) and forced swim test (FST), respectively. Intraperitoneal administration of ACPA (1 mg/kg) decreased the percentage of time spent in the open-arms (%OAT) and the number of entries to the open-arms (OAE) in the EPM, indicating an anxiogenic-like effect. ACPA also decreased immobility time in the FST compared to the control group, suggesting an antidepressant-like effect. ß-carbolines including harmane (5 and 10 mg/kg), norharmane (5 mg/kg) and harmaline (2.5 and 5 mg/kg) produced an anxiogenic-like response, while the highest dose of harmane or harmaline and the middle dose of norharmane induced an antidepressant-like behavior. Furthermore, co-administration of a subthreshold dose of ACPA (0.5 mg/kg) and harmaline (1.25 mg/kg), but not harmane or norharmane (both at the dose of 2.5 mg/kg), caused anxiolytic- and antidepressant-like behaviors and decreased locomotor activity. Our findings suggest a therapeutic potential for combined ineffective doses of ACPA and harmaline on anxiety- and depression-related processes.

Co-administration of the low dose of orexin and nitrergic antagonists induces an antidepressant-like effect in mice.

It is now well-established that orexins (OXs) and their receptors are involved in the pathophysiology of depression. Considering the evidence indicating the importance of nitric oxide (NO) system in the mood modulation, this study investigated the effect of intraperitoneal (i.p.) administration of orexin 1 (OX1) receptor antagonist -SB334867- alone or in combination with NO agents on depression using the forced swimming test (FST), tail suspension test (TST) and the number of crossings in open-field test (OFT) in mice. Our results indicated that administration of SB334867 at the dose of 0.5 mg/kg decreased the immobility time in the FST without effect on locomotor activity, suggesting an antidepressant-like effect of SB334867. Moreover, l-Arginine (a NO precursor; 750 mg/kg) or L-NAME (a non-selective nitric oxide synthase (NOS) inhibitor, 10 mg/kg) administration by itself decreased the immobility time in the FST. Interestingly, co-administration of a sub-threshold dose of L-NAME, but not l-Arginine, in combination with an ineffective dose of SB334867 produced an antidepressant-like effect in the FST and TST. It should be noted, none of the drugs elicited significant effects on the locomotor activity in the OFT. Altogether, the present data propose that a combination of the sub-effective dose of OX and NO antagonists can be evaluated as an option for the clinical treatment of depression in humans.

Abolishment of fear memory-disruptive effects REM sleep deprivation by harmane.

Harmane, as a neuromodulator, implicates in the learning and memory processes. However, rapid eye movement (REM) sleep deprivation negatively affects these processes. Here, we investigated the effects of harmane (2.5 mg/kg) on the regulation of fear memory in free moving groups (FMG), large platform groups (LPG) and REM-deprived mice. We employed a flower pot technique for REM sleep deprivation and a Pavlovian fear conditioning paradigm for assessment of fear memories. FMGs received two or three pre-training intraperitoneal administrations of harmane at 12 h intervals, impaired contextual memory retention but those received three harmane administrations showed an auditory memory disruption. LPGs, with or without harmane, did not alter fear memories compared to their respective FMGs, indicating the inability of stress on fear responses of FMGs. Moreover, 12, 24 and 36 h REM sleep deprivation impaired contextual memory retrieval, while 24 and 36 h REM sleep deprivation impaired auditory fear memory retention. Furthermore, harmane only abolished contextual and auditory fear memory deficits induced by 24 h REM sleep deprivation. The data suggests a modulatory role for harmane in REM sleep deprivation response on fear memory.

The modulatory role of accumbens and hippocampus D2 receptors in anxiety and memory.

The present study investigated the role of dopamine D2 receptors (D2Rs) of the dorsal hippocampus (DH) and the nucleus accumbens (NAc) and the effect of their dopaminergic activities on anxiety-like behavior and aversive learning using a test-retest elevated plus-maze (EPM) paradigm in male Wistar rats. Guide cannulae were implanted to allow microinjection of D2R agonist quinpirole or antagonist sulpiride. The pre-test intra-NAc microinjection of quinpirole (0.0625-0.25 µg/rat) or sulpiride (0.125-0.5 µg/rat) increased the percentage of time spent in the open arms (%OAT) of EPM, suggesting an anxiolytic-like effect. However, an increase in open-arm avoidance was observed in the control rats when retested in the EPM, suggesting aversive information storage. Furthermore, a similar result was obtained in the quinpirole-treated rats. In contrast, the sulpiride-treated rats failed to demonstrate further open-arm avoidance, thus proposing an aversive learning deficit. The intra-DH microinjection of drugs alone induced an anxiolytic-like effect and learning deficit. The quinpirole (0.125 µg/rat) injected into each site had no effect on the response induced by sulpiride injected into another site. Finally, a subthreshold dose of quinpirole in both sites did not alter the %OAT; on the contrary, it preserved the aversive memory. The sulpiride induced an anxiolytic-like effect and a learning deficit. Our data suggests that the involvement of D2Rs in the interactions of DH-NAc dopaminergic system helps regulate anxiety-related behavior and EPM-associative memory.

Effects of harmane during treadmill exercise on spatial memory of restraint-stressed mice.

Chronic stress induces hippocampal-dependent memory deficits, which can be counterbalanced with prolonged exercise. On the other hand, the ß-carboline alkaloid harmane exerts potential in therapies for Alzheimer's and depression diseases and modulating neuronal responses to stress. The present study investigated the effect of chronic treatment of harmane alone or during treadmill running on spatial memory deficit in restraint-stressed mice. To examine spatial memory, adult male NMRI mice were subjected to the Y-maze. Intraperitoneal administration of harmane (0.6 mg/kg, once/ 48 h for 25 days) decreased the percentage of time in the novel arm and the number of novel arm visits, indicating a spatial memory deficit. A 9-day restraint stress (3 h/day) also produced spatial learning impairment. However, a 4-week regime of treadmill running (10 m/min for 30 min/day, 5 days/week) aggravated the stress impairing effect on spatial learning of 3-day stressed mice compared to exercise/non-stressed mice. Moreover, harmane (0.3 mg/kg) associated with exercise increased the number of novel arm visits in 9-day stressed mice compared to harmane/exercise/non-stressed or 9-day stressed group. It should be noted that none of these factors alone or in combination with each other had no effect on locomotor activity. Taken together, these data suggest that there is no interaction between harmane and exercise on spatial memory in stress condition.

Bidirectional influence of amygdala ß1-adrenoceptors blockade on cannabinoid signaling in contextual and auditory fear memory.

The basolateral amygdala (BLA) is a major target and modulator of stress and has a critical role in the neural circuitry presenting learned fear behaviors. On the other hand, both the endocannabinoid and noradrenergic systems may be involved in regulating the stress responses, fear, and anxiety. Considering the aforementioned, we have investigated the involvement of the BLA ß1-adrenoceptors in conditioned fear responses induced by ACPA, a CB1 receptor (CB1R) agonist. In adult male NMRI mice, freezing responses to context and cue were measured using a Pavlovian fear conditioning apparatus. Pre-training intra-BLA microinjection of xamoterol (0.01 and 0.02 µg/mouse), a partial ß1-adrenoceptor agonist, or atenolol (0.5 µg/mouse), a ß1-adrenoceptor antagonist, decreased freezing behavior, which suggests an impairment of contextual and auditory fear retrieval. Similar results were found with pre-training intraperitoneal administration of ACPA (0.5 mg/kg). A sub-threshold dose of xamoterol, infused into the BLA, decreased ACPA (0.005 and 0.05 mg/kg) effect on both memories, while atenolol increased ACPA response to the context at the middle dose and decreased ACPA response to the tone at the lower dose. It can be concluded that the blockade of BLA ß1-adrenoceptors differentially affects ACPA response on the contextual and auditory conditioned fear memories.