Involvement of α7 Nicotinic Acetylcholine Receptors in Gene Expression of Dopamine Biosynthetic Enzymes in Rat Brain

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 ␣7 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 ␣7 nAChR antagonist methyllycaconitine prevented the nicotine-induced rise in TH or GTPCH mRNA in VTA and SN. Administration of ␣7 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 ␣7 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 ␣7 nAChRs are involved in mediating these effects of nicotine.Catecholaminergic systems are critical in mediating the physiological effects of nicotine. The self-administering and reinforcing properties of nicotine seem to arise from direct action on the mesocorticolimbic dopamine system. This system, with cell bodies in VTA, plays a key role in mediating the reinforcing effects of natural rewards as well as of drugs of abuse, including nicotine, through increased dopaminergic transmission in the nucleus accumbens. The nigrostriatal dopaminergic system, with cell bodies in the SN, innervates the caudate nucleus and putamen of the corpus striatum. Activation of striatal neuronal acetylcholine receptors (nAChRs) triggers release of dopamine. These receptors are also involved in mediating nicotine's effects on locomotion.

Activity-Dependent Regulation of the Dopamine Phenotype in the Adult Substantia Nigra: Prospects for Treating Parkinson's Disease

“…278 intraventricular administration of a GABA A receptor agonist (Soriano et al 1997, Yamada et al 1996; SNc TH mRNA is elevated followed systemic administration of nicotine or α-7 nicotinic acetylcholine receptor agonists (Serova & Sabban 2002); and we recently reported that the number of SNc TH+ cells in adult mice can be increased or decreased by direct brain infusions of drugs targeting SNc neuronal activity (Aumann et al 2011, Aumann et al 2008. These data are consistent with the possibility that the DA phenotype of adult SNc neurons can be gained or lost in an activity-dependent way.…”

Activation of Tyrosine Hydroxylase mRNA Translation by cAMP in Midbrain Dopaminergic Neurons

“…Some workers have shown that severe stress, chronic nicotine treatment, or reserpine treatment induces TH gene expression in midbrain, with those neurons having their cell bodies in the ventral tegmentum being more responsive than those with their cell bodies in the substantia nigra (Pasinetti et al, 1990;Ortiz et al, 1996;Serova and Sabban, 2002). However, this induction has not been observed in other studies and when observed, the effects are usually small or short-lived compared with those seen in adrenal medulla or locus coeruleus (Biguet et al, 1986;Smith et al, 1991;Melia et al, 1992).…”

Evidence for a Tetrahydrobiopterin Deficit in Schizophrenia

“…In further support of our demonstrated lack of confound status for NL use, haloperidol administration has not been shown to decrease biopterin levels in the nigrostriatal system of 6-OHDA-lesioned rats [42] . Smoking has not been assessed as a potential confound in this study; however, evidence from the literature indicates that schizophrenics are signifi cantly more likely to be smokers than controls [43,44] , and that nicotine elevates levels of GTPCH mRNA and biopterin [45][46][47] . Greater nicotine exposure for schizophrenics then would likely not account for the biopterin defi cit we have observed in our schizophrenic sample.…”