| Summary: | Tobacco use is not only a major health concern worldwide but also a grotesque economic burden
on the smoker as well as the health care system. The most well-known and most researched
constituent of tobacco products is nicotine. There are a variety of products on the market that
ensure nicotine intake, including cigarettes, cigars, pipe tobacco and smokeless tobacco.
Once absorbed by the body, nicotine undergoes phase I metabolism by cytochrome P450 (CYP)
2A6 (humans) or CYP2B1 (rat) to cotinine, the major metabolite. Since nicotine is a blood flow
marker, its transport across the blood-brain barrier (BBB) has been well documented. However,
data on the BBB penetration of nicotine and cotinine in animals subject to chronic nicotine
exposure are limited. This gap in literature was identified and subsequently the focus of our first
objective. Our data indicate that neither nicotine or cotinine uptake by the BBB is altered after
chronic nicotine exposure in rat.
Nicotine exerts its effect by binding to nicotinic cholinergic receptors (nAChRs) on dopaminergic
neurons in the striatum and the ventral tegmental area (VTA). The addictive property of nicotine is
attributed to its effects on the mesocorticolimbic system, which serves a fundamental role in the
acquisition of behaviours. Smoking not only plays a role in addiction but also in Parkinson's disease
(PD), where epidemiological studies have shown that smokers have a lower incidence of PD as
opposed to non-smokers. Dopamine (DA) is one of the major neurotransmitters that plays a critical
role in addiction and PD. Centrally, the biosynthesis of DA occurs intraneuronally through the ratelimiting
enzyme, tyrosine hydroxylase (TH). DA undergoes metabolism by monoamine oxidase
(MAO) intraneuronally. DA, that is not metabolized by MAO, is subsequently transported into the
storage vesicles. After stimulation of nAChRs, DA is released into the synaptic cleft after
membrane depolarization. Released DA stimulates post-synaptic dopaminergic receptors, is
metabolized by catecholamine-0-methyl-transferase or transporter back into the pre-synaptic
neuron by DA transporter (DAT).
Little is known about the effects of whole cigarette smoke on the dopaminergic system. Therefore,
our second objective of this study was to determine the effect of whole cigarette smoke extract
(nicotine-containing and nicotine-free smoke extract), nicotine and cotinine on TH and DAT
expression in undifferentiated pheochromocytoma cells. Our third objective was closely developed
from our second. After investigating the effect in vitro, we determined the effect in vivo in rats after
28 day exposure of whole cigarette smoke extract (nicotine-containing and nicotine-free smoke
extract), nicotine and cotinine on TH and DAT regulation. Both the in vitro and in vivo TH as well
as the in vivo DAT regulation data implicated nicotine to be responsible for TH and DAT
upregulation.
It is known that nicotine releases DA from rat striatal synaptosomes. We therefore aimed to
determine whether a component of tobacco leaf extracts which is a MAO-A and MAO-B inhibitor,
2,3,6-trimethyl-I,4-naphthoquinone (TMN) release DA from rat striatal synaptosomes. We found
that TMN releases DA from synaptosomes, to a greater extent when compared to nicotine.
Our data conclude that cotinine does cross the BBB and that both nicotine and cotinine transport
do not vary after chronic nicotine exposure. We also found that nicotine, as the major constituent
of tobacco smoke, is responsible for increased DA synthesis and DA transport back into the
presynaptic neuron. TMN, is not only a MAO-A and MAO-B inhibitor but experiments from our
laboratory indicate that in striatal synaptosomes, TMN releases DA to a greater extent than
nicotine. === Thesis (Ph.D. (Pharmaceutical Chemistry))--North-West University, Potchefstroom Campus, 2005.
|
|---|
