| Title & Author | Abstract | |
|---|---|---|
| 12(001) | THE ROLE OF MESOLIMBIC DOPAMINE IN NICOTINE DEPENDENCE
Target Article on Nicotine-Addiction David Balfour Department of Psychiatry University of Dundee Medical School Ninewells Hospital Dundee DD1 9SY d.j.k.balfour@dundee.ac.uk |
Abstract:
It is now widely accepted that a majority of habitual
tobacco smokers become addicted to the nicotine present in the
smoke. This brief review focuses on the evidence that nicotine
exerts on the mesolimbic dopamine (DA) system that are entirely
consistent with it having the properties of a psychostimulant drug
of abuse. Thus, the ability of nicotine to reinforce self-
administration in experimental animals depends upon its ability to
stimulate the DA-secreting neurones which project to the nucleus
accumbens. Microdialysis studies show that acute nicotine
preferentially stimulates DA overflow in the shell of the nucleus
accumbens, whereas subchronic nicotine causes sensitisation of its
stimulatory effects on DA overflow in the core of the structure.
The presentation discusses the evidence that stimulation of DA
overflow in the accumbens shell is required to elicit or, more
likely, signal the 'rewarding' properties of the drug which
reinforce self-administration. Based on the results of studies with
other psychostimulant drugs, it is possible that these effects are
mediated by the D-3 receptors that are found in relatively high
density in the subdivision of the structure. The sensitised effects
of subchronic nicotine in the core of the accumbens are thought to
mediate the transfer from 'drug-liking' to 'drug-seeking' behaviour
and, therefore, to be of fundamental importance to the development
of dependence. The nature of the receptor(s) involved remains to be
established although there is circumstantial evidence for a role of
both D-1 and D-2 receptors. Studies reported in more recent years
have suggested that increased DA overflow in the accumbens is not,
in itself, sufficient to account for the rewarding properties of
addictive drugs. The review concludes by discussing the evidence
that drugs of dependence preferentially increase DA overflow into
an extra-synaptic compartment where it gains access, by a process
of volume transmission, to extra-synaptic DA receptors located on
adjacent cells. These receptors, it is proposed, facilitate the way
in which we learn about cues associated with pleasurable stimuli
and the ways in which the may be experienced again.
Keywords: Nicotine, mesolimbic dopamine, nucleus accumbens, sensitisation, dependence. |
| 12(002) | NON-DOPAMINERGIC PATHWAYS IN NICOTINE DEPENDENCE
Target Article on Nicotine-Addiction Jacques Le Houezec PhD Scientific & Medical Advisor Pharmacia Consumer Healthcare Helsingborg Sweden jacques.lehouezec@eu.pnu.com |
Abstract:
There is strong evidence that nicotine exerts its
positive reinforcing effects through the dopaminergic reward
system. However, recent literature has shown that nicotine can
modulate other neurotransmitter systems, mainly through
pre-synaptic cholinergic receptors. This paper focuses on some of
the systems that could participate in the nicotine dependence
process.
Keywords: Nicotine dependence, GABA, noradrenaline, serotonin, non-dopaminergic pathways, nicotine withdrawal. |
| 12(003) | NICOTINE METABOLISM BY THE POLYMORPHIC CYTOCHROME
P450 2A6 (CYP2A6) ENZYME: IMPLICATIONS FOR INTERINDIVIDUAL DIFFERENCES IN SMOKING BEHAVIOUR Target Article on Nicotine-Addiction Mikael Oscarson Division of Molecular Toxicology National Institute of Environmental Medicine Karolinska Institutet SE-171 77 Stockholm Sweden mikael.oscarson@imm.ki.se |
Abstract:
Cytochrome P450 2A6 (CYP2A6) is one of the most important
enzymes in human nicotine metabolism. Genetic polymorphisms in the
CYP2A6 gene causes important interindividual variability in CYP2A6
activity and this variation can explain some of the interindividual
variability in nicotine metabolism previously reported. Here I
summarise the current knowledge about the CYP2A6 polymorphism, and
also discuss the potential importance of this polymorphism for
differences in smoking behaviour.
Keywords: Nicotine, cytochrome P450, CYP2A6, drug metabolism, genetic polymorphism, genotype, phenotype. |
| 12(004) | NICOTINIC RECEPTORS: MOLECULAR ISSUES
Target Article on Nicotine-Addiction Lucia Sivilotti Department of Pharmacology The School of Pharmacy London Lucia.Sivilotti@ulsop.ac.uk |
Abstract:
Expression of neuronal nicotinic receptors in Xenopus
oocytes has shown that several different subunit combinations are
functional, with a range of pharmacological and biophysical
properties. In the nervous system, nicotinic receptors are found on
the soma or the presynaptic terminals of neurones: the precise
molecular identification of these receptor subtypes remains a
challenge to pharmacology.
Keywords: Nicotinic receptor, autonomic ganglion, hippocampus, Xenopus oocyte. |
| 12(005) | A ROLE FOR CYP2D6 IN NICOTINE METABOLISM?
Target Article on Nicotine-Addiction Gillian Smith & Christoph Sachse Biomedical Research Centre Ninewells Hospital & Medical School Dundee DD1 9SY UK gillian.smith@icrf.icnet.uk christoph.sachse@gmx.de |
Abstract:
Nicotine is known to be metabolised to its major
metabolite cotinine by members of the cytochrome P450 monooxygenase
superfamily. Although CYP2A6 has now been identified as the
principal enzyme which catalyses this biotransformation, CYP2D6 is
also an active nicotine C-oxidase. Some 8% of the Caucasian
population have reduced or absent CYP2A6 activity; CYP2D6 may play
a significant role in nicotine metabolism in these individuals.
CYP2D6 is highly polymorphic - a number of studies linking CYP2D6
genotype to smoking behaviour have now been published. CYP2D6 may
have an important constitutive function in neurotransmitter
metabolism and CYP2D6 genotype is thought to be a critical
determinant in the success of antidepressant drug treatment.
Keywords: Nicotine, addiction, CYP2D6, cytochrome P450, genetic polymorphism, smoking behaviour. |
| 12(006) | NICOTINIC RECEPTORS IN RELATION TO NICOTINE ADDICTION
Target Article on Nicotine-Addiction Susan Wonnacott Department of Biology & Biochemistry University of Bath, Bath BA2 7AY bsssw@bath.ac.uk |
Abstract:
The first step in processing nicotine's effects on the
brain is the drug's interaction with neuronal nicotinic receptors
(nAChR). The diversity of nAChR subtypes, their various modes of
response (activation, desensitisation, prolonged inactivation), and
the complex pharmacokinetics of nicotine delivery conspire to make
this a complex issue that is difficult to unravel. The alpha4beta2
nAChR subtype has the highest affinity for nicotine and is the
primary candidate for mediating nicotine's central effects. Chronic
nicotine exposure (in both humans, animals and cell culture
systems) leads to an increase in numbers of alpha4beta2 nAChR
(upregulation), with functional implications for withdrawal.
However, there is little evidence presently that nAChR upregulation
is pertinent to the induction or maintenance of dependence.
However, the particular characteristics of the alpha7 subtype of
nAChR suggest that it may participate in long term changes in
synaptic efficacy that could be relevant to nicotine dependence.
Keywords: Nicotine, nicotinic receptors, receptor desensitisation, nicotinic receptor upregulation. |