Neuroactive effects of cotinine on the hippocampus: Behavioral and biochemical parameters

Aguiar, R.B. de; Parfitt, Gustavo M.; Jaboinski, J.; Barros, Daniela M.

doi:10.1016/j.neuropharm.2013.03.032

Cited by 19 publications

(12 citation statements)

References 51 publications

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“…As a PAM, cotinine will not have agonistic effect over the receptors but will enhance its activation by agonists (Oddo, 2012). This idea explains recent evidence that both the improvement of sensorimotor desensitization (Vainio et al, 2000; Wildeboer-Andrud et al, 2014) and fear extinction induced by cotinine (de Aguiar et al, 2013) depended on the activation of α7 and α4β2nAChRs subtypes. In addition, previous evidence suggests that cotinine, by stimulating the α4β2nAChRs and/or α6β2nAChRs, may evoke the release of DA in a calcium-dependent manner in the striatum (Dwoskin et al, 1999).…”

Section: Discussionmentioning

confidence: 72%

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

Patel

Grizzell

Holmes

et al. 2014

Front. Aging Neurosci.

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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-β (Aβ) 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 Aβ 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 Aβ 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.

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Section: Discussionmentioning

confidence: 72%

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

Patel

Grizzell

Holmes

et al. 2014

Front. Aging Neurosci.

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“…Furthermore, COT was able to reduce the MDA formation provoked by 6-OHDA autoxidation in rat brain mitochondria preparations [ 104 ]. However, conflicting results were obtained by Aguiar et al [ 105 ], which showed that COT increased lipid peroxidation but also increased antioxidant capacity in rat hippocampus. Nevertheless, the authors suggested that this increase in oxidative stress by COT depends upon the dose and did not cause the corresponding cognitive impairments.…”

Section: Resultsmentioning

confidence: 99%

Cotinine and 6-Hydroxy-L-Nicotine Reverses Memory Deficits and Reduces Oxidative Stress in Aβ25-35-Induced Rat Model of Alzheimer’s Disease

et al. 2020

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The nicotinic derivatives, cotinine (COT), and 6-hydroxy-L-nicotine (6HLN), showed promising cognitive-improving effects without exhibiting the nicotine’s side-effects. Here, we investigated the impact of COT and 6HLN on memory impairment and the oxidative stress in the Aβ25-35-induced rat model of Alzheimer’s disease (AD). COT and 6HLN were chronically administered to Aβ25-35-treated rats, and their memory performances were assessed using in vivo tasks (Y-maze, novel object recognition, and radial arm maze). By using in silico tools, we attempted to associate the behavioral outcomes with the calculated binding potential of these nicotinic compounds in the allosteric sites of α7 and α4β2 subtypes of the nicotinic acetylcholine receptors (nAChRs). The oxidative status and acetylcholinesterase (AChE) activity were determined from the hippocampal tissues. RT-qPCR assessed bdnf, arc, and il-1β mRNA levels. Our data revealed that COT and 6HLN could bind to α7 and α4β2 nAChRs with similar or even higher affinity than nicotine. Consequently, the treatment exhibited a pro-cognitive, antioxidant, and anti-AChE profile in the Aβ25-35-induced rat model of AD. Finally, RT-qPCR analysis revealed that COT and 6HLN positively modulated the bdnf, arc, and il-1β genes expression. Therefore, these nicotinic derivatives that act on the cholinergic system might represent a promising choice to ameliorate AD conditions.

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“…Epidemiological studies indicate a high prevalence of tobacco use in PTSD patients, and tobacco use has been proposed as a form of self-medication to improve neuropsychiatric symptoms in PTSD ( Leonard et al, 2001 ). In rodent fear conditioning models of PTSD, cotinine administration, either systemically or locally into the hippocampus and medial prefrontal cortex, reduced the retention of fear memory and facilitated extinction of fear memory ( Zeitlin et al, 2012 ; Aguiar et al, 2013 ; Alvarez-Ricartes et al, 2018 ; Oliveros-Matus et al, 2020 ). Interestingly, the effects of cotinine in the hippocampus were shared by nicotinic antagonists, such as mecamylamine, dihydro-β-erythroidine, and methyllycaconitine, suggesting that inhibition of nAChRs may underlie cotinine’s effects in hippocampus ( Aguiar et al, 2013 ).…”

Section: Effects Of Cotinine On Neuropsychiatric Symptomsmentioning

confidence: 99%

“…In rodent fear conditioning models of PTSD, cotinine administration, either systemically or locally into the hippocampus and medial prefrontal cortex, reduced the retention of fear memory and facilitated extinction of fear memory ( Zeitlin et al, 2012 ; Aguiar et al, 2013 ; Alvarez-Ricartes et al, 2018 ; Oliveros-Matus et al, 2020 ). Interestingly, the effects of cotinine in the hippocampus were shared by nicotinic antagonists, such as mecamylamine, dihydro-β-erythroidine, and methyllycaconitine, suggesting that inhibition of nAChRs may underlie cotinine’s effects in hippocampus ( Aguiar et al, 2013 ). Co-administration of methyllycaconitine but not dihydro-β-erythroidine, with cotinine into the medial prefrontal cortex abolished the effect of cotinine on extinction of fear conditioning, suggesting an involvement of α7 nAChRs-, but not α4β2 ∗ nAChRs-mediated mechanisms within the medial prefrontal cortex ( Oliveros-Matus et al, 2020 ).…”

Section: Effects Of Cotinine On Neuropsychiatric Symptomsmentioning

confidence: 99%

Cotinine: Pharmacologically Active Metabolite of Nicotine and Neural Mechanisms for Its Actions

Tan

Vrana

Ding

2021

Front. Behav. Neurosci.

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Tobacco use disorder continues to be a leading public health issue and cause of premature death in the United States. Nicotine is considered as the major tobacco alkaloid causing addiction through its actions on nicotinic acetylcholine receptors (nAChRs). Current pharmacotherapies targeting nicotine’s effects produce only modest effectiveness in promoting cessation, highlighting the critical need for a better understanding of mechanisms of nicotine addiction to inform future treatments. There is growing interest in identifying potential contributions of non-nicotine components to tobacco reinforcement. Cotinine is a minor alkaloid, but the major metabolite of nicotine that can act as a weak agonist of nAChRs. Accumulating evidence indicates that cotinine produces diverse effects and may contribute to effects of nicotine. In this review, we summarize findings implicating cotinine as a neuroactive metabolite of nicotine and discuss available evidence regarding potential mechanisms underlying its effects. Preclinical findings reveal that cotinine crosses the blood brain barrier and interacts with both nAChRs and non-nAChRs in the nervous system, and produces neuropharmacological and behavioral effects. Clinical studies suggest that cotinine is psychoactive in humans. However, reviewing evidence regarding mechanisms underlying effects of cotinine provides a mixed picture with a lack of consensus. Therefore, more research is warranted in order to provide better insight into the actions of cotinine and its contribution to tobacco addiction.

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Neuroactive effects of cotinine on the hippocampus: Behavioral and biochemical parameters

Cited by 19 publications

References 51 publications

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

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

Cotinine and 6-Hydroxy-L-Nicotine Reverses Memory Deficits and Reduces Oxidative Stress in Aβ25-35-Induced Rat Model of Alzheimer’s Disease

Cotinine: Pharmacologically Active Metabolite of Nicotine and Neural Mechanisms for Its Actions

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