Role of nicotinic acetylcholine receptor subtypes a4ß2 and a7 in nicotine-ethanol interaction and cross-tolerance: functional correlation with cerebellar nitric oxide

ECU Author/Contributor (non-ECU co-authors, if there are any, appear on document)

Najla Taslim (Creator)

Institution

East Carolina University (ECU )

Web Site: http://www.ecu.edu/lib/

Abstract: The prevalent co-abuse of alcohol and tobacco products results in higher morbidity and mortality rates than those caused by either drug alone, thus posing a serious health problem. Understanding the interactive relationship between nicotine and ethanol might lead to effective strategies for the treatment of co-addiction. This dissertation project was designed to investigate the role of two nicotinic-acetylcholine-receptor (nAChR) subtypes (i.e. a4ß2 and a7) on nicotine’s attenuation of ethanol ataxia and its functional correlation with alterations in cerebellar nitric oxide concentration. Expression levels of cerebellar a4ß2 and a7 subtypes were also determined immunohistochemically.\r\n\r\n\r\n\r\nEthanol (2g/kg\;i.p.)-induced ataxia was assessed by Rotorod in stereotaxically cannulated CD-1 male mice following the acute or repeated intracerebellar (ICB) microinfusions of a4ß2- and a7-selective agonists, RJR-2403 and PNU-282987. Acute RJR-2403 (31, 62, 125ng), and PNU-282987 (25ng, 250ng, 2.5µg), dose-dependently reduced ethanol ataxia. Pretreatment with potent a4ß2 [Dihydro-ß-erythroidine (DHßE)] and a7 [Methyllycaconitine (MLA)]-subtype–selective antagonists prevented RJR-2403 and PNU-282987’s attenuation of ethanol ataxia, respectively. Both antagonists also offset nicotine’s reduction of ethanol ataxia, confirming the contribution of a4ß2 and a7 subtype in ethanol ataxia. There was no tonic role of either subtype in ethanol ataxia. Additionally, ICB a4ß2 and a7 subtype antisense treatment data correspond with agonist-induced behavioral responses. Animals repeatedly microinfused with RJR- 2403 or PNU-282987 became tolerant to ethanol ataxia. The observed cross-tolerance was faster in onset and longer in duration with PNU-282987 than RJR-2403. Pretreatment with DHßE and MLA, prevented the development of cross-tolerance.\r\n\r\n\r\n\r\nThe cerebellar nitrite+nitrate (NOx) levels were significantly enhanced and reduced following acute/repeated RJR- 2403/PNU-282987 microinfusion and acute ethanol\r\n\r\n\r\n\r\ninjection, respectively. Pretreatment with RJR- 2403 or PNU-282987 followed by ethanol prevented the ethanol-induced decrease in NOx concentration in both acute and repeated treatment paradigms, thus correlating the decrease in NOx concentration with ataxia and elevation with attenuation of ataxia. Both a4ß2 and a7 subtypes exhibited high immunoreactivity in Purkinje, however, expression in molecular and granular cell layers was sparse. Overall, the results of the project support the role of a4ß2 and a7 subtypes in the functional interaction between nicotine and acute ethanol ataxia, with NO-cGMP signaling as a participating factor.

Additional Information

Publication

Dissertation

Language: English

Date: 2023

Subjects

Health Sciences, Pharmacology

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