Abscisic acid ameliorates motor disabilities in 6-OHDA-induced mice model of Parkinson's disease.

Parkinson's disease (PD) is characterized by a myriad of symptoms, encompassing both motor disabilities and cognitive impairments. Recent research has shown that abscisic acid (ABA) is a phytohormone found in various brain regions of several mammals and exhibits neuroprotective properties. To investigate the effects of ABA on cognitive and motor disorders, a mouse model of PD was utilized. The administration of 6-hydroxydopamine (6-OHDA) to the lateral ventricles was conducted, with ABA (10 and 15 µg/mouse, i. c.v.) being administered for one week after the 6-OHDA injection for 4 days. Motor and cognitive performance were evaluated through the use of open field, rotarod, wire grip, and shuttle box tests. The results indicated that cognitive function and motor disorders were significantly impaired in 6-OHDA-treated animals. However, in mice treated with 6-OHDA, ABA (15 µg/mouse) significantly reversed balance and muscle strength deficits. It should be noted that the administration of ABA did not significantly improve cognitive impairment or rearing in Parkinsonism mice. Therefore, the findings suggest that ABA plays a crucial role in protecting mice from motor disabilities caused by 6-OHDA.

Cross-talk between the HPA axis and addiction-related regions in stressful situations.

Addiction is a worldwide problem that has a negative impact on society by imposing significant costs on health care, public security, and the deactivation of the community economic cycle. Stress is an important risk factor in the development of addiction and relapse vulnerability. Here we review studies that have demonstrated the diverse roles of stress in addiction. Term searches were conducted manually in important reference journals as well as in the Google Scholar and PubMed databases, between 2010 and 2022. In each section of this narrative review, an effort has been made to use pertinent sources. First, we will provide an overview of changes in the Hypothalamus-Pituitary-Adrenal (HPA) axis component following stress, which impact reward-related regions including the ventral tegmental area (VTA) and nucleus accumbens (NAc). Then we will focus on internal factors altered by stress and their effects on drug addiction vulnerability. We conclude that alterations in neuro-inflammatory, neurotrophic, and neurotransmitter factors following stress pathways can impact related mechanisms on craving and relapse susceptibility.

Pharmacologic antagonism of CB1 receptors improves electrophysiological alterations in Purkinje cells exposed to 3-AP.

INTRODUCTION: Although ataxia is associated with cerebellar dysfunction, little is known about the effects of 3-AP exposure on Purkinje cell electrophysiological properties. Here, we evaluated these parameters in cerebellar vermis brain slices. METHODS: Purkinje cells were exposed to artificial cerebrospinal fluid (aCSF) (control) or to 1 mM 3-acetylpyridine (3-AP) in the recording chamber. The effects of a cannabinoid agonist (WIN; 7.5 nmol) and a cannabinoid antagonist (AM; 20 nmol) were evaluated under both conditions. RESULTS: Exposure to 3-AP induced dramatic changes in cellular excitability that likely would affect Purkinje cell output. In whole-cell current clamp recordings, 3-AP-exposed Purkinje cells demonstrated a significantly higher frequency of action potentials, a larger afterhyperpolarization (AHP), and a larger rebound of action potentials. In addition, 3-AP caused a significant decrease in the interspike interval (ISI), half-width, and first spike latency. Remarkably, the action potential frequency, AHP amplitude, rebound, ISI, action potential halfwidth, and first spike latency were no longer different from controls in 3-AP cells treated with AM. Sag percentage, on the other hand, showed no significant difference under any treatment condition, indicating that cannabinoids' actions on 3-AP-mediated Purkinje cell changes may not include effects on neuronal excitability through changes of Ih. CONCLUSIONS: These data show that cannabinoid antagonists reduce the excitability of Purkinje cells following exposure to 3-AP and suggest their potential as therapeutics in cerebellar dysfunctions.

Perspectives on Agmatine Neurotransmission in Acute and Chronic Stressrelated Conditions.

Adaptive responses to stressful stimuli in the environment are believed to restore homeostasis after stressful events. Stress activates the hypothalamic-pituitary-adrenocortical (HPA) axis, which releases glucocorticoids (GCs) into the bloodstream. Recently, agmatine, an endogenous monoamine was discovered to have the potential as a pharmacotherapy for stress. Agmatine is released in response to certain stress conditions, especially those involving GCs, and participates in establishing homeostasis disturbed by stress following GC activation. The therapeutic potential of agmatine for the management of psychological diseases involving stress and depression is promising based on a significant amount of literature. When exogenously applied, agmatine leads to reductions in levels of GCs and counteracts stress-related morphologic, synaptic, and molecular changes. However, the exact mechanism of action by which agmatine modifies the effects resulting from stress hormone secretion is not fully understood. This review aims to present the most possible mechanisms by which agmatine reduces the harmful effects of chronic and acute stress. Several studies suggest chronic stress exposure and repeated corticosteroid treatment lower agmatine levels, contributing to stress-related symptoms. Agmatine acts as an antistress agent by activating mTOR signaling, inhibiting NMDA receptors, suppressing iNOS, and maintaining bodyweight by activating α-2adrenergic receptors. Exogenous administration that restores agmatine levels may provide protection against stress-induced changes by reducing GCs release, stimulating anti-inflammatory processes, and releasing neuroprotective factors, which are not found in all therapies currently being used to treat stress-related disorders. The administration of exogenous agmatine should also be considered a therapeutic element that is capable of triggering a neural protective response that counters the effects of chronic stress. When combined with existing treatment strategies, this may have synergistic beneficial effects.

Central injection of abscisic acid attenuates mood disorders induced by subchronic stress in male mice.

Stressful life increases the risk of mental and psychological disorders and cognitive deficits. Abscisic acid (ABA) is a plant hormone that has been recently discovered in mammalians. ABA is produced in response to stressful stimuli and it can reduce anxiety-like behaviors and depression and improve cognitive function. This study was designed to evaluate the effects of microinjection of ABA on depression, anxiety, passive avoidance learning and memory deficits induced by subchronic stress. ABA (10 and 15  µ $\umu $ g/mouse, i.c.v.) was administered one week after recovery period for 4 consecutive days. A three-session forced swimming test (FST) protocol for induction of subchronic stress was administered to the mice. Exploratory, anxiety-like behavior, depression and cognitive function were assessed 24 h after the last swim stress session. The results indicated that ABA (15  µ $\umu $ g/mouse) could ameliorate anxiety and depression induced by FST. In addition, ABA had no effect on the subchronic stress-induced cognitive impairments. Taken together, the results suggest that ABA could improve anxiety and depression induced by subchronic stress.

Sex differences in the vulnerability of the hippocampus to prenatal stress.

Distressing events during pregnancy that engage activity of the body's endocrine stress response have been linked with later life cognitive deficits in offspring and associated with developmental changes in cognitive-controlling neural regions. Interestingly, prenatal stress (PS)-induced alterations have shown some sex specificity. Here, we review the literature of animal studies examining sex-specific effect of physical PS on the function and structure of the hippocampus as hippocampal impairments likely underlie PS-associated deficits in learning and memory. Furthermore, the connectivity between the hypothalamic-pituitary-adrenal (HPA) axis and the hippocampus as well as the heavy presence of glucocorticoid receptors (GRs) in the hippocampus suggests this structure plays an important role in modulation of activity within stress circuitry in a sex-specific pattern. We hope that better understanding of sex-specific, PS-related hippocampal impairment will assist in uncovering the molecular mechanisms behind sex-based risk factors in PS populations across development, and perhaps contribute to greater precision in management of cognitive disturbances in this vulnerable population.

Probable role of the hyperpolarization-activated current in the dual effects of CB1R antagonism on behaviors in a Parkinsonism mouse model.

Recent evidence from genetic and pharmacological animal models of Parkinson's disease (PD) suggests alteration in activity of hyperpolarization-activated cyclic nucleotide-gated channels (HCN) occurs following dopamine (DA) depletion. Further, based on data from our lab and others, the endocannabinoid system (ECBS) appears to be involved in PD-related processes. Therefore, we compared the motor and non-motor effects of an intracerebroventricular (i.c.v.) injection of the cannabinoid receptor type 1 (CB1R) agonist WIN 55,212-2 (WIN) and selective antagonist AM251 (AM) on motor and non-motor symptoms (NMS) of PD in a mouse model generated by an i.c.v. injection of 6-hydroxydopamine (6-OHDA). To provide further knowledge about the link between CB1R and the hyperpolarization-activated current (Ih), we conducted ex vivo investigations in the ventral tegmental area (VTA). In the current study, pharmacological antagonism of CB1R ameliorated explorative behaviors, balance, muscle strength, and passive avoidance memory deficits induced by 6-OHDA, however, anxious, and depressive-like behaviors were heightened. AM was also effective in reducing a 6-OHDA-induced TH level deficit. 6-OHDA exposure induced severe alterations in the spontaneous and evoked firing behavior of DA neurons, as evidenced by a significant increase in the mean number of spikes and a decrease in spike half-width, respectively. Interestingly, an increase in the amplitude of the sag voltage and in the amplitude of the steady state Ih current was seen. Consistent with an effect of increasing Ih, WIN exacerbated 6-OHDA-induced actions by further reducing the spike half-width and increasing the firing frequency. In addition, greater amplitudes of sEPSPs were elicited. The effects of 6-OHDA on sag voltage, Ih current amplitude, and firing frequency were reversed by administration of AM. These results suggest that ECBs might be involved in some of the 6-OHDA-induced electrophysiological alterations in VTA DA neurons in this animal model of PD. In addition, the CB1R antagonistic mechanism could be effective in modulating the devastating effects of 6-OHDA.

The cannabinoid antagonist, AM251 attenuates ataxia related deficiencies in a cerebellar ataxic model.

Aim: Disruption in cerebellar inputs, as well as dysfunction of Purkinje cells (PCs), causes a change in the timing of electrical signaling in the cerebellum resulting in disorders such as cerebellar ataxia. Although much clinical and molecular genetics research has been conducted to understand this disorder, there is no specific treatment for cerebellar ataxia. As cannabinoid type 1 receptors (CB1Rs) are highly expressed in the cerebellum and have been suggested as a therapeutic strategy, we determined whether AM251, a cannabinoid receptor antagonist, was neuroprotective of PCs in a rat cerebellar ataxic model.Materials and methods: To this end, we conducted behavioral and histological tests in the 3-acetylpyridine (3AP) rat cerebellar ataxia model, to explore whether AM251 was protective against induction of ataxia and cell death.Results: Rats with chemical degeneration of the inferior olive induced by 3AP (55 mg/kg, i.p.) clearly showed cerebellar ataxic symptoms. The locomotor activity and motor coordination of the ataxic animals were clearly disrupted compared to the control group. Further, histological analysis showed cell death and PCs degenerated with loss of cell membrane integrity associated with 3AP. Pre-treatment by AM251 improved the locomotor activity of the ataxic animals, and AM251 almost prevented PCs neuronal degeneration.Conclusion: Our data which show protection of cerebellar PCs and motor improvement in the ataxic rat model by treatment with AM251 suggests that targeting cannabinoid receptors should be considered for therapeutic intervention in cerebellar ataxia. HIGHLIGHTS:AM251 was protective against induction of ataxia and cell death.CBR antagonist typically ameliorated 3AP induced Ataxia.AM251 affected explorative and gait disturbances induced by 3AP.CBR antagonist improved impairments of anxiety-like behaviors following 3AP.

The neglected role of endocannabinoid actions at TRPC channels in ataxia.

Transient receptor potential (TRP) channels are highly expressed in cells of the cerebellum including in the dendrites and somas of Purkinje cells (PCs). Their endogenous activation promotes influx of Ca2+ and Na+, resulting in depolarization. TRP channels can be activated by endogenous endocannabinoids (eCBs) and activity of TRP channels has been shown to modulate GABA and glutamate transmission. Ataxia is caused by disruption of multiple intracellular pathways which often involve changes in Ca2+ homeostasis that can result in neural cellular dysfunction and cell death. Based on available literature, alteration of transmission of eCBs would be expected to change activity of cerebellar TRP channels. Antagonists of the endocannabinoid system (ECS) including enzymes which break eCBs down have been shown to result in reductions in postsynaptic excitatory activity mediated by TRPC channels. Further, TRPC channel antagonists could modulate both pre and postsynaptically-mediated glutamatergic and GABAergic transmission, resulting in reductions in cell death due to excitotoxicity and dysfunctions caused by abnormal inhibitory signaling. Accordingly, TRP channels, and in particular the TRPC channel, represent a potential therapeutic target for management of ataxia.

Modulation of the CB1 cannabinoid receptor has potential therapeutic utility in the 3-acetylpyridine cerebellar ataxia rat model.

Cerebellar ataxia is a neurodegenerative disorder leading to severe motor incoordination. Recently, it has been suggested that cannabinoids play a role in modulating ataxic symptoms. To understand the possible therapeutic effect of cannabinoids for the management of cerebellar ataxia, we used cannabinoid agonist/antagonists to target the cannabinoid type 1 receptor (CB1R) in the 3 acetyl pyridine (3AP) rat model of ataxia. The role of the CB1R was examined using three different doses of the CB1R agonist, WIN-55,212-2 (WIN; 0.1, 0.5, 1 mg/kg) administrated 30 min prior to 3AP (55 mg/kg, i.p.) which leads to motor impairment through destruction of the inferior olive. In some groups, the CB1R antagonist AM251 (1 mg/kg) was given in combination with WIN. Locomotor activity and motor coordination were impaired by 3AP, and the application of WIN did not ameliorate this effect. However, the abnormal gait, rearing and grooming caused by 3AP were prevented by co-administration of AM251 with WIN. While the addition of the CB1R antagonist improved some ataxic symptoms, there was no effect of AM251 on balance or locomotor activity when co-administrated with WIN. Behavioral testing indicated that not only did WIN fail to exert any protective effect on ataxic symptoms; it exacerbated ataxic symptoms, suggesting that CB1R agonists may not be the ideal therapeutic drug in this disorder. When taken together, the findings from the present study indicate that cannabinoid modulation of ataxia symptoms may not act solely through CB1Rs and other cannabinoid receptors should be considered in future studies.

Parkinson's disease related alterations in cannabinoid transmission.

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic (DAergic) neurons of the substantia nigra pars compacta (SNc) by neurodegeneration. Recent findings in animal models of PD propose tonic inhibition of the remaining DA neurons through GABA release from reactive glial cells. Movement dysfunctions could be ameliorated by promotion of activity in dormant DA cells. The endocannabinoid system (ECS) is extensively present in basal ganglia (BG) and is known as an indirect modulator of DAergic neurotransmission, thus drugs designed to target this system have shown promising therapeutic potential in PD patients. Interestingly, down/up-regulation of cannabinoid receptors (CBRs) varies across the different stages of PD, suggesting that some of the motor/ non-motor deficits may be related to changes in CBRs. Determination of the profile of changes of these receptors across the different stages of PD as well as their neural distribution within the BG could improve understanding of PD and identify pathways important in disease pathobiology. In this review, we focus on temporal and spatial alterations of CBRs during PD in the BG. At present, as inconclusive, but suggestive results have been obtained, future investigations should be conducted to extend preclinical studies examining CBRs changes within each stage in controlled clinical trials in order to determine the potential of targeting CBRs in management of PD.

Addiction and the cerebellum with a focus on actions of opioid receptors.

Increasing evidence suggests that the cerebellum could play a role in the higher cognitive processes involved in addiction as the cerebellum contains anatomical and functional pathways to circuitry controlling motivation and saliency. In addition, the cerebellum exhibits a widespread presence of receptors, including opioid receptors which are known to play a prominent role in synaptic and circuit mechanisms of plasticity associated with drug use and development of addiction to opioids and other drugs of abuse. Further, the presence of perineural nets (PNNs) in the cerebellum which contain proteins known to alter synaptic plasticity could contribute to addiction. The role the cerebellum plays in processes of addiction is likely complex, and could depend on the particular drug of abuse, the pattern of use, and the stage of the user within the addiction cycle. In this review, we discuss functional and structural modifications shown to be produced in the cerebellum by opioids that exhibit dependency-inducing properties which provide support for the conclusion that the cerebellum plays a role in addiction.