Involvement of alpha 7 nicotinic acetylcholine receptors in gene expression of dopamine biosynthetic enzymes in rat brain.
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.
Serova
Lidia
L
Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, New York 10595, USA.
Sabban
Esther L
EL
D000818:Animals; D004298:Dopamine / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D006136:GTP Cyclohydrolase / Q000096:biosynthesis* / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009538:Nicotine / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000502:physiology*; D013378:Substantia Nigra / Q000187:drug effects / Q000201:enzymology; D014446:Tyrosine 3-Monooxygenase / Q000096:biosynthesis* / Q000235:genetics*; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000201:enzymology; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579165:Chrna7 protein, rat; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine; D014446:Tyrosine 3-Monooxygenase; D006136:GTP Cyclohydrolase; D004298:Dopamine