Cholinergic Receptor Modulation as a Target for Preventing Dementia in Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative condition characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) in the midbrain resulting in progressive impairment in cognitive and motor abilities. The physiological and molecular mechanisms triggering dopaminergic neuronal loss are not entirely defined. PD occurrence is associated with various genetic and environmental factors causing inflammation and mitochondrial dysfunction in the brain, leading to oxidative stress, proteinopathy, and reduced viability of dopaminergic neurons. Oxidative stress affects the conformation and function of ions, proteins, and lipids, provoking mitochondrial DNA (mtDNA) mutation and dysfunction. The disruption of protein homeostasis induces the aggregation of alpha-synuclein (α-SYN) and parkin and a deficit in proteasome degradation. Also, oxidative stress affects dopamine release by activating ATP-sensitive potassium channels. The cholinergic system is essential in modulating the striatal cells regulating cognitive and motor functions. Several muscarinic acetylcholine receptors (mAChR) and nicotinic acetylcholine receptors (nAChRs) are expressed in the striatum. The nAChRs signaling reduces neuroinflammation and facilitates neuronal survival, neurotransmitter release, and synaptic plasticity. Since there is a deficit in the nAChRs in PD, inhibiting nAChRs loss in the striatum may help prevent dopaminergic neurons loss in the striatum and its pathological consequences. The nAChRs can also stimulate other brain cells supporting cognitive and motor functions. This review discusses the cholinergic system as a therapeutic target of cotinine to prevent cognitive symptoms and transition to dementia in PD.

Characteristics and organization of discharge properties in rat hindlimb motoneurons.

The discharge properties of hindlimb motoneurons in ketamine-xylazine anesthetized rats were measured to assess contributions of persistent intrinsic currents to these characteristics and to determine their distribution in motoneuron pools. Most motoneurons (30/37) responded to ramp current injections with adapting patterns of discharge and the frequency-current (f-I) relations of nearly all motoneurons included a steep subprimary range of discharge. Despite the prevalence of adapting f-I relations, responses included indications that persistent inward currents (PICs) were activated, including increased membrane noise and prepotentials before discharge, as well as counterclockwise hysteresis and secondary ranges in f-I relations. Examination of spike thresholds and afterhyperpolarization (AHP) trajectories during repetitive discharge revealed systematic changes in threshold and trajectory within the subprimary, primary, and secondary f-I ranges. These changes in the primary and secondary ranges were qualitatively similar to those described previously for cat motoneurons. Within the subprimary range, AHP trajectories often included shallow approaches to threshold following recruitment and slope of the AHP ramp consistently increased until the subprimary range was reached. We suggest that PICs activated near recruitment contributed to these slope changes and formation of the subprimary range. Discharge characteristics were strongly correlated with motoneuron size, using input conductance as an indicator of size. Discharge adaptation, recruitment current, and frequency increased with input conductance, whereas both subprimary and primary f-I gains decreased. These results are discussed with respect to potential mechanisms and their functional implications.

Strategies for the Treatment of Parkinson's Disease: Beyond Dopamine.

Parkinson's disease (PD) is the second-leading cause of dementia and is characterized by a progressive loss of dopaminergic neurons in the substantia nigra alongside the presence of intraneuronal α-synuclein-positive inclusions. Therapies to date have been directed to the restoration of the dopaminergic system, and the prevention of dopaminergic neuronal cell death in the midbrain. This review discusses the physiological mechanisms involved in PD as well as new and prospective therapies for the disease. The current data suggest that prevention or early treatment of PD may be the most effective therapeutic strategy. New advances in the understanding of the underlying mechanisms of PD predict the development of more personalized and integral therapies in the years to come. Thus, the development of more reliable biomarkers at asymptomatic stages of the disease, and the use of genetic profiling of patients will surely permit a more effective treatment of PD.

Cotinine Enhances Fear Extinction and Astrocyte Survival by Mechanisms Involving the Nicotinic Acetylcholine Receptors Signaling.

Fear memory extinction (FE) is an important therapeutic goal for Posttraumatic stress disorder (PTSD). Cotinine facilitates FE in rodents, in part due to its inhibitory effect on the amygdala by the glutamatergic projections from the medial prefrontal cortex (mPFC). The cellular and behavioral effects of infusing cotinine into the mPFC on FE, astroglia survival, and the expression of bone morphogenetic proteins (BMP) 2 and 8, were assessed in C57BL/6 conditioned male mice. The role of the α4ß2- and α7 nicotinic acetylcholine receptors (nAChRs) on cotinine's actions were also investigated. Cotinine infused into the mPFC enhanced contextual FE and decreased BMP8 expression by a mechanism dependent on the α7nAChRs. In addition, cotinine increased BMP2 expression and prevented the loss of GFAP + astrocytes in a form independent on the α7nAChRs but dependent on the α4ß2 nAChRs. This evidence suggests that cotinine exerts its effect on FE by modulating nAChRs signaling in the brain.

Correction to: Cotinine: A Therapy for Memory Extinction in Post-traumatic Stress Disorder.

The original version of this article unfortunately contained mistake in its Funding inforation. That is, the Grant Number has an error currently read as "This work was supported by the Fondo de Ciencia y Tecnología (FONDECYT) de Chile, Grant #1150149".

Cotinine: A Therapy for Memory Extinction in Post-traumatic Stress Disorder.

Post-traumatic stress disorder (PTSD) is a mental disorder that may develop after exposure to exceptionally threatening or unescapable horrifying events. Actual therapies fail to alleviate the emotional suffering and cognitive impairment associated with this disorder, mostly because they are ineffective in treating the failure to extinguish trauma memories in a great percentage of those affected. In this review, current behavioral, cellular, and molecular evidence supporting the use of cotinine for treating PTSD are reviewed. The role of the positive modulation by cotinine of the nicotinic acetylcholine receptors (nAChRs) and their downstream effectors, the protection of astroglia, and the inhibition of microglia in the PTSD brain are also discussed.

Intranasal Cotinine Plus Krill Oil Facilitates Fear Extinction, Decreases Depressive-Like Behavior, and Increases Hippocampal Calcineurin A Levels in Mice.

Failure in fear extinction is one of the more troublesome characteristics of posttraumatic stress disorder (PTSD). Cotinine facilitates fear memory extinction and reduces depressive-like behavior when administered 24 h after fear conditioning in mice. In this study, it was investigated the behavioral and molecular effects of cotinine, and other antidepressant preparations infused intranasally. Intranasal (IN) cotinine, IN krill oil, IN cotinine plus krill oil, and oral sertraline were evaluated on depressive-like behavior and fear retention and extinction after fear conditioning in C57BL/6 mice. Since calcineurin A has been involved in facilitating fear extinction in rodents, we also investigated changes of calcineurin in the hippocampus, a region key on contextual fear extinction. Short-term treatment with cotinine formulations was superior to krill oil and oral sertraline in reducing depressive-like behavior and fear consolidation and enhancing contextual fear memory extinction in mice. IN krill oil slowed the extinction of fear. IN cotinine preparations increased the levels of calcineurin A in the hippocampus of conditioned mice. In the light of the results, the future investigation of the use of IN cotinine preparations for the extinction of contextual fear memory and treatment of treatment-resistant depression (TRD) in PTSD is discussed.

Correction to: Intranasal Cotinine Plus Krill Oil Facilitates Fear Extinction, Decreases Depressive-Like Behavior, and Increases Hippocampal Calcineurin A Levels in Mice.

The original version of this article unfortunately contained mistake in its Funding inforation.

Intranasal cotinine improves memory, and reduces depressive-like behavior, and GFAP+ cells loss induced by restraint stress in mice.

Posttraumatic stress disorder (PTSD), chronic psychological stress, and major depressive disorder have been found to be associated with a significant decrease in glial fibrillary acidic protein (GFAP) immunoreactivity in the hippocampus of rodents. Cotinine is an alkaloid that prevents memory impairment, depressive-like behavior and synaptic loss when co-administered during restraint stress, a model of PTSD and stress-induced depression, in mice. Here, we investigated the effects of post-treatment with intranasal cotinine on depressive- and anxiety-like behaviors, visual recognition memory as well as the number and morphology of GFAP+ immunoreactive cells, in the hippocampus and frontal cortex of mice subjected to prolonged restraint stress. The results revealed that in addition to the mood and cognitive impairments, restraint stress induced a significant decrease in the number and arborization of GFAP+ cells in the brain of mice. Intranasal cotinine prevented these stress-derived symptoms and the morphological abnormalities GFAP+ cells in both of these brain regions which are critical to resilience to stress. The significance of these findings for the therapy of PTSD and depression is discussed.

Post-treatment with cotinine improved memory and decreased depressive-like behavior after chemotherapy in rats.

PURPOSE: Most cancer patients treated with systemic adjuvant chemotherapy endure long-lasting side effects including decrease in concentration, forgetfulness and slower thinking, which are globally termed "chemobrain." Cotinine, the main derivative of nicotine, improved visual and spatial working memory and decreased depressive-like behavior in an animal model of chemotherapy-induced cognitive impairment. METHODS: In this study, we investigated the effect of cotinine on weight gain, locomotor activity, cognitive abilities and depressive-like behavior in rats treated with the chemotherapy mix, cyclophosphamide, methotrexate and 5-fluorouracil. Locomotor activity and depressive-like behavior were assessed using the rotarod and Porsolt's tests, respectively. Changes in cognitive abilities were determined using the novel place recognition test. RESULTS: Female rats treated with cotinine after chemotherapy, recovered weight faster, showed superior cognitive abilities and lower levels of depressive-like behavior than chemotherapy, vehicle-treated rats. CONCLUSIONS: This evidence suggests that treatment with cotinine may facilitate the recovery and diminish the cognitive consequences of chemotherapy.

Cotinine reduces depressive-like behavior, working memory deficits, and synaptic loss associated with chronic stress in mice.

Chronic stress underlies and/or exacerbates many psychiatric conditions and often results in memory impairment as well as depressive symptoms. Such afflicted individuals use tobacco more than the general population and this has been suggested as a form of self-medication. Cotinine, the predominant metabolite of nicotine, may underlie such behavior as it has been shown to ameliorate anxiety and memory loss in animal models. In this study, we sought to investigate the effects of cotinine on working memory and depressive-like behavior in mice subjected to prolonged restraint. Cotinine-treated mice displayed better performance than vehicle-treated cohorts on the working memory task, the radial arm water maze test. In addition, with or without chronic stress exposure, cotinine-treated mice engaged in fewer depressive-like behaviors as assessed using the tail suspension and Porsolt's forced swim tests. These antidepressant and nootropic effects of cotinine were associated with an increase in the synaptophysin expression, a commonly used marker of synaptic density, in the hippocampus as well as the prefrontal and entorhinal cortices of restrained mice. The beneficial effects of cotinine in preventing various consequences of chronic stress were underscored by the inhibition of the glycogen synthase kinase 3 ß in the hippocampus and prefrontal cortex. Taken together, our results show for the first time that cotinine reduces the negative effects of stress on mood, memory, and the synapse.

Cotinine reduces depressive-like behavior and hippocampal vascular endothelial growth factor downregulation after forced swim stress in mice.

Cotinine, the predominant metabolite of nicotine, appears to act as an antidepressant. We have previously shown that cotinine reduced immobile postures in Porsolt's forced swim (FS) and tail suspension tests while preserving the synaptic density in the hippocampus as well as prefrontal and entorhinal cortices of mice subjected to chronic restraint stress. In this study, we investigated the effect of daily oral cotinine (5 mg/kg) on depressive-like behavior induced by repeated, FS stress for 6 consecutive days in adult, male C57BL/6J mice. The results support our previous report that cotinine administration reduces depressive-like behavior in mice subjected or not to high salience stress. In addition, cotinine enhanced the expression of the vascular endothelial growth factor (VEGF) in the hippocampus of mice subjected to repetitive FS stress. Altogether, the results suggest that cotinine may be an effective antidepressant positively influencing mood through a mechanism involving the preservation of brain homeostasis and the expression of critical growth factors such as VEGF. (PsycINFO Database Record (c) 2014 APA, all rights reserved).

Cotinine halts the advance of Alzheimer's disease-like pathology and associated depressive-like behavior in Tg6799 mice.

Alzheimer's disease (AD) is associated with cognitive and non-cognitive symptoms for which there are currently no effective therapies. We have previously reported that cotinine, a natural product obtained from tobacco leaves, prevented memory loss and diminished amyloid-ß (Aß) plaque pathology in transgenic 6799 mice (Tg6799 mice) when treated prior to the development of the pathology. We have also shown that cotinine reduces depressive-like behavior in normal and chronically stressed C57BL/6 mice. Here, we extend our previous studies by investigating the effects of cotinine on the progression of AD-like pathology, depressive-like behavior, and the mechanisms underlying its beneficial effects in Tg6799 mice when left untreated until after a more advanced stage of the disease's development. The results show that vehicle-treated Tg6799 mice displayed an accentuated loss of working memory and an abundant Aß plaque pathology that were accompanied by higher levels of depressive-like behavior as compared to control littermates. By contrast, prolonged daily cotinine treatment to Tg6799 mice, withheld until after a mid-level progression of AD-like pathology, reduced Aß levels/plaques and depressive-like behavior. Moreover, this treatment paradigm dramatically improved working memory as compared to control littermates. The beneficial effects of cotinine were accompanied by an increase in the expression of the active form of protein kinase B and the postsynaptic density protein 95 in the hippocampi and frontal cortices of Tg6799 mice. This suggests that cotinine halts the progression of AD-like pathology while reducing depressive-like behavior by stimulating signaling pathways supporting synaptic plasticity in Tg6799 mice. The potential use of cotinine to treat cognitive and non-cognitive symptoms of AD is discussed.