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Involvement of alpha 7 nicotinic acetylcholine receptors in gene expression of dopamine biosynthetic enzymes in rat brain.
J Pharmacol Exp Ther. 2002 Dec; 303(3):896-903.JP

Abstract

Brain dopaminergic systems are critical in mediating the physiological responses to nicotine. The effects of several concentrations of nicotine (0.08, 0.17, or 0.33 mg/kg body weight) and involvement of alpha7 nicotinic acetylcholine receptors (nAChRs) in gene expression of key enzymes in dopamine biosynthesis were evaluated in the ventral tegmental area (VTA) and substantia nigra (SN), cell bodies of the mesocorticolimbic and nigrostriatal pathways. Nicotine elicited a dose-dependent elevation of mRNA for tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine biosynthesis in VTA and SN. The VTA was more sensitive to lower concentrations of nicotine with maximal response observed with the lowest dose of nicotine. Nicotine also elevated mRNA levels of GTP cyclohydrolase I (GTPCH), rate limiting in biosynthesis of TH's essential cofactor tetrahydrobiopterin in both dopaminergic locations. The changes in TH and GTPCH mRNAs were correlated. Pretreatment with the alpha7 nAChR antagonist methyllycaconitine prevented the nicotine-induced rise in TH or GTPCH mRNA in VTA and SN. Administration of alpha7 nAChR agonist 3-[2,4-dimethoxybenzilidene]anabaseine at 1 to 10 mg/kg or (E,E-3-(cinnamylidene)anabaseine at 0.3 to 1 mg/kg increased TH mRNA in VTA and SN, but not in peripheral catecholaminergic cells. Thus, agonists of alpha7 nAChRs have therapeutic potential for increasing TH gene expression in dopaminergic regions without some of nicotine's disadvantages, such as its harmful effects on the cardiovascular system. The findings indicate that nicotine may regulate dopamine biosynthesis by alterations in gene expression of TH and its cofactor. The alpha7 nAChRs are involved in mediating these effects of nicotine.

Authors+Show Affiliations

Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York 10595, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12438507

Citation

Serova, Lidia, and Esther L. Sabban. "Involvement of Alpha 7 Nicotinic Acetylcholine Receptors in Gene Expression of Dopamine Biosynthetic Enzymes in Rat Brain." The Journal of Pharmacology and Experimental Therapeutics, vol. 303, no. 3, 2002, pp. 896-903.
Serova L, Sabban EL. Involvement of alpha 7 nicotinic acetylcholine receptors in gene expression of dopamine biosynthetic enzymes in rat brain. J Pharmacol Exp Ther. 2002;303(3):896-903.
Serova, L., & Sabban, E. L. (2002). Involvement of alpha 7 nicotinic acetylcholine receptors in gene expression of dopamine biosynthetic enzymes in rat brain. The Journal of Pharmacology and Experimental Therapeutics, 303(3), 896-903.
Serova L, Sabban EL. Involvement of Alpha 7 Nicotinic Acetylcholine Receptors in Gene Expression of Dopamine Biosynthetic Enzymes in Rat Brain. J Pharmacol Exp Ther. 2002;303(3):896-903. PubMed PMID: 12438507.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Involvement of alpha 7 nicotinic acetylcholine receptors in gene expression of dopamine biosynthetic enzymes in rat brain. AU - Serova,Lidia, AU - Sabban,Esther L, PY - 2002/11/20/pubmed PY - 2002/12/27/medline PY - 2002/11/20/entrez SP - 896 EP - 903 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 303 IS - 3 N2 - Brain dopaminergic systems are critical in mediating the physiological responses to nicotine. The effects of several concentrations of nicotine (0.08, 0.17, or 0.33 mg/kg body weight) and involvement of alpha7 nicotinic acetylcholine receptors (nAChRs) in gene expression of key enzymes in dopamine biosynthesis were evaluated in the ventral tegmental area (VTA) and substantia nigra (SN), cell bodies of the mesocorticolimbic and nigrostriatal pathways. Nicotine elicited a dose-dependent elevation of mRNA for tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine biosynthesis in VTA and SN. The VTA was more sensitive to lower concentrations of nicotine with maximal response observed with the lowest dose of nicotine. Nicotine also elevated mRNA levels of GTP cyclohydrolase I (GTPCH), rate limiting in biosynthesis of TH's essential cofactor tetrahydrobiopterin in both dopaminergic locations. The changes in TH and GTPCH mRNAs were correlated. Pretreatment with the alpha7 nAChR antagonist methyllycaconitine prevented the nicotine-induced rise in TH or GTPCH mRNA in VTA and SN. Administration of alpha7 nAChR agonist 3-[2,4-dimethoxybenzilidene]anabaseine at 1 to 10 mg/kg or (E,E-3-(cinnamylidene)anabaseine at 0.3 to 1 mg/kg increased TH mRNA in VTA and SN, but not in peripheral catecholaminergic cells. Thus, agonists of alpha7 nAChRs have therapeutic potential for increasing TH gene expression in dopaminergic regions without some of nicotine's disadvantages, such as its harmful effects on the cardiovascular system. The findings indicate that nicotine may regulate dopamine biosynthesis by alterations in gene expression of TH and its cofactor. The alpha7 nAChRs are involved in mediating these effects of nicotine. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/12438507/Involvement_of_alpha_7_nicotinic_acetylcholine_receptors_in_gene_expression_of_dopamine_biosynthetic_enzymes_in_rat_brain_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12438507 DB - PRIME DP - Unbound Medicine ER -