Evidence for the involvement of central serotonergic mechanisms in cholinergic tremor induced by tacrine in Balb/c mice

Mehta, Hina; Haobam, Reena; Rajamma, Usha; Mohanakumar, Kochupurackal P.

doi:10.1016/j.bbr.2005.05.002

Cited by 12 publications

(15 citation statements)

References 46 publications

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“…GABAergic enhanced tone is then associated with a diminished cholinergic activity in the tegmental nuclei, and the observed reduction of REM sleep after DOI administration is consistent with this figure [Wilson and Argyropoulos, 2005;Monti and Jantos, 2006]. In his experiment, Mehta et al [2005] reported that the administration of tacrine (a potent cholinesterase inhibitor) was associated with tremors in animals: after that, the serotonin's tone, but not the dopamine's or the norepinephrine's ones, was enhanced in a number of sites in the animals' brains, one of which was the raphe nuclei. He also reported that the administration of HTR2A/2C antagonists and HTR2C antagonist alone were able to decrease the tacrine induced tremors in animals of a quantity as large as 83% and 20% respectively.…”

Section: Htr2c Agonist-antagonist Challengessupporting

confidence: 74%

“…In fact, it has been demonstrated that HTR2C is crucial to the serotonergic inhibiting action toward the dopaminergic system [Trent and Tepper, 1991;De Deurwaerdere and Spampinato, 1999;Di Giovanni et al, 1999;, probably via GABAergic interneurons in the striatum and in the SN, and glutamatergic neurons in the subthalamic nucleus [Rick et al, 1995;Eberle-Wang et al, 1996;Fox et al, 1998]. Moreover, an increased serotonergic tone has been claimed to cause oral dyskinesia via HTR2C activity [Meltzer and Nash, 1991;Melamed et al, 1996], this may be related to the cholinergic activation of striatum via HTR2C [Mehta et al, 2005;Bonsi et al, 2007]. There are some conflicting findings that reported a major role played by HTR3 receptors at the inhibition of…”

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confidence: 94%

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Focus on HTR2C: A possible suggestion for genetic studies of complex disorders

Drago

Serretti

2009

American J of Med Genetics Pt B

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HTR2C is one of the most relevant and investigated serotonin receptors. Its role in important brain structures such as the midbrain, the lateral septal complex, the hypothalamus, the olfactory bulb, the pons, the choroid plexus, the nucleus pallidus, the striatum and the amygdala, the nucleus accumbens and the anterior cingulated gyrus candidate it as a promising target for genetic association studies. The biological relevance of these brain structures is reviewed by way of the focus on HTR2C activity, with a special attention paid to psychiatric disorders. Evidence from the genetic association studies that dealt with HTR2C is reviewed and discussed alongside the findings derived from the neuronatmic investigations. The reasons for the discrepancies between these two sets of reports are discussed. As a result, HTR2C is shown to play a pivotal role in many different psychiatric behaviors or psychiatric related disrupted molecular balances, nevertheless, genetic association studies brought inconsistent results so far. The most replicated association involve the feeding behavior and antipsychotic induced side effects, both weight gain and motor related: Cys23Ser (rs6318) and -759C/T (rs3813929) report the most consistent results. The lack of association found in other independent studies dampens the clinical impact of these reports. Here, we report a possible explanation for discrepant findings that is poorly or not at all usually considered, that is that HTR2C may exert different or even opposite activities in the brain depending on the structure analyzed and that mRNA editing activity may compensate possible genetically controlled functional effects. The incomplete coverage of the HTR2C variants is proposed as the best cost-benefit ratio bias to fix. The evidence of brain area specific HTR2C mRNA editing opens a debate about how the brain can differently modulate stress events, and process antidepressant treatments, in different brain areas. The mRNA editing activity on HTR2C may play a major role for the negative association results.

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Section: Htr2c Agonist-antagonist Challengessupporting

confidence: 74%

mentioning

confidence: 94%

Focus on HTR2C: A possible suggestion for genetic studies of complex disorders

Drago

Serretti

2009

American J of Med Genetics Pt B

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“…It has been shown that while mianserin -a 5-HT (2A/2C) antagonist -attenuated the tacrine-induced motor dysfunction, a combined treatment with atropine (a muscarinic antagonist) and mianserin completely blocked the response [20] . The tremor caused by tacrine treatment is therefore at least in part mediated by a central serotonergic mechanism.…”

Section: Discussionmentioning

confidence: 99%

Comparison Studies of Tacrine and Bis(7)-Tacrine on the Suppression of Scopolamine-Induced Behavioral Changes and Inhibition of Acetylcholinesterase in Mice

Pan

Xiang

et al. 2009

Pharmacology

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Effects of the cholinesterase inhibitors tacrine and bis(7)- tacrine (0.25–20 μmol/kg, s.c.) on locomotor activity and passive-avoidance response were investigated in mice treated with scopolamine (SCP, 1 or 5 μmol/kg, i.p.), using an open-field test and step-through task with a 24-hour retention interval. Drugs were given 30 min prior to the first session. During the acquisition session, SCP treatment increased the locomotor activity (10–16%). Tacrine, but not bis(7)-tacrine, cotreatment significantly reduced the locomotor activity by 23 or 27%, when compared with the SCP-treated control mice. In the step-through task, tacrine or bis(7)-tacrine coadministration dose-dependently attenuated the increase in the number of footshocks (by 50 or 58%) in SCP-treated mice. The lowest dose of tacrine and bis(7)-tacrine for prolonging the retention latency (up to 500%) in SCP-treated mice was 5 and 1 μmol/kg, respectively. Tacrine and bis(7)-tacrine inhibited brain acetylcholinesterase (AChE) activity 15 min (but not 30 min) after the drug administration in mice. At the same dose of 20 μmol/kg, the bis(7)-tacrine-induced AChE inhibition in serum was 14-fold higher than that of tacrine. The results indicated that bis(7)-tacrine was less potent than tacrine in causing motor dysfunction. However, bis(7)-tacrine was more potent than tacrine in the cognitive enhancement of SCP-induced memory loss and in AChE inhibition.

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“…Two mice from each virus group were sacrificed on days 1, 2, and 3. A 2-mm mouse brain section taken at the injection site was homogenized in viral growth medium sufficient to make a 10% (wt/vol) homogenate (23), approximately 1 ml. The titers of the resulting 10% homogenates are shown for each mouse in Fig.…”

Section: Experimental Outlinementioning

confidence: 99%

“…The whole brain was removed, washed with PBS to remove blood, and frozen at Ϫ20°C for 1 to 2 h. A 2-mmthick coronal brain section containing the injection site was isolated using a mouse coronal acrylic brain matrix (Roboz Surgical Instrument Co. Inc., Gaithersburg, MD). A 10% (wt/vol) homogenate of brain tissue was made in medium 199V (23). Brains were Dounce homogenized in Tenbroeck tissue grinder glass 2-ml tubes (Kontes Glass Company, Vineland, NJ).…”

Section: Cells and Virusesmentioning

confidence: 99%

Ultrastructural Analysis of ICP34.5 ⁻ Herpes Simplex Virus 1 Replication in Mouse Brain Cells In Vivo

Mehta

Müller

Markovitz

2010

J Virol

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Replication-competent forms of herpes simplex virus 1 (HSV-1) defective in the viral neurovirulence factor infected cell protein 34.5 (ICP34.5) are under investigation for use in the therapeutic treatment of cancer. In mouse models, intratumoral injection of ICP34.5-defective oncolytic HSVs (oHSVs) has resulted in the infection and lysis of tumor cells, an associated decrease in tumor size, and increased survival times. The ability of these oHSVs to infect and lyse cells is frequently characterized as exclusive to or selective for tumor cells. However, the extent to which ICP34.5-deficient HSV-1 replicates in and may be neurotoxic to normal brain cell types in vivo is poorly understood. Here we report that HSV-1 defective in ICP34.5 expression is capable of establishing a productive infection in at least one normal mouse brain cell type. We show that ␥34.5 deletion viruses replicate productively in and induce cellular damage in infected ependymal cells. Further evaluation of the effects of oHSVs on normal brain cells in animal models is needed to enhance our understanding of the risks associated with the use of current and future oHSVs in the brains of clinical trial subjects and to provide information that can be used to create improved oHSVs for future use.Several types of replication-competent neuroattenuated herpes simplex viruses (HSVs) are currently being evaluated in clinical cancer trials for safety and therapeutic activity (32), as well as for vaccine development (20). A critical safety concern associated with the clinical use of these oncolytic HSVs (oHSVs) is their ability to enter, replicate in, and spread to a wide range of cell types in different regions of the nervous system. One potential complication resulting from invasion of the central nervous system by HSV is herpes simplex encephalitis (HSE), an infection that causes lifelong neurological damage or death. A limited number of genes have been demonstrated to contribute to the virus's ability to trigger HSE. The viral gene ␥34.5 encodes the neurovirulence protein infected cell protein 34.5 (ICP34.5) (29). Viruses lacking the ␥34.5 gene (e.g., R3616 and 1716) were found to be 5 logs less neurovirulent than wild-type strains of 19,36), as quantified by the intracranial LD 50 , i.e., the lethal dose in 50% of mice inoculated intracerebroventricularly with the virus. The basis for this neuroattenuation was initially reported to be the inability of the ␥34.5 deletion viruses to infect or replicate in brain cells (4). Subsequent immunohistochemical studies on infected brain tissue of intracerebroventricularly inoculated mice suggested that ␥34.5 deletion viruses retained the ability to infect a wide range of brain cell types and to replicate in and, by day 7, destroy ependymal cells (ECs) (16,21).To create a more neuroattenuated and thus safer virus, the virus G207 was constructed from the ␥34.5 deletion virus R3616 by insertional mutagenesis of the U L 39 gene (25). The U L 39 gene encodes the large subunit of the viral ribonucleotide reductase (vR...

show abstract

Evidence for the involvement of central serotonergic mechanisms in cholinergic tremor induced by tacrine in Balb/c mice

Cited by 12 publications

References 46 publications

Focus on HTR2C: A possible suggestion for genetic studies of complex disorders

Focus on HTR2C: A possible suggestion for genetic studies of complex disorders

Comparison Studies of Tacrine and Bis(7)-Tacrine on the Suppression of Scopolamine-Induced Behavioral Changes and Inhibition of Acetylcholinesterase in Mice

Ultrastructural Analysis of ICP34.5 ⁻ Herpes Simplex Virus 1 Replication in Mouse Brain Cells In Vivo

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Evidence for the involvement of central serotonergic mechanisms in cholinergic tremor induced by tacrine in Balb/c mice

Cited by 12 publications

References 46 publications

Focus on HTR2C: A possible suggestion for genetic studies of complex disorders

Focus on HTR2C: A possible suggestion for genetic studies of complex disorders

Comparison Studies of Tacrine and Bis(7)-Tacrine on the Suppression of Scopolamine-Induced Behavioral Changes and Inhibition of Acetylcholinesterase in Mice

Ultrastructural Analysis of ICP34.5 − Herpes Simplex Virus 1 Replication in Mouse Brain Cells In Vivo

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Ultrastructural Analysis of ICP34.5 ⁻ Herpes Simplex Virus 1 Replication in Mouse Brain Cells In Vivo