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Smoking and Nicotine
Dependence
Dr. William
Corrigall, Head  The long-range goal of the Smoking and Nicotine
Dependence Research Section is to better understand the brain mechanisms
involved in nicotine addiction and to use this knowledge to test neurochemical
targets to develop medications that can help in tobacco-use cessation.
The experimental design of our ongoing studies recognizes that nicotine,
the primary psychoactive agent in tobacco smoke, maintains voluntary
self-administration in laboratory animals. This behaviour is a core
element of addiction. Using a rat model of this self-administration
behaviour, we have previously shown that nicotine maintains self-administration
behaviour by acting on certain brain substrates. At present, our studies
have two main directions.
Neurochemistry of Nicotine Addiction
In this project, we have previously shown that
voluntary self-administration of nicotine depends on the action of the
drug in two areas: 1) neurons in the ventral tegmental area (vta) of
the midbrain that use the neurochemical dopamine as transmitter (these
neurons have been shown to be a critical pathway in drug reinforcement
processes in general) and 2) a non-dopamine system projecting to the
vta from an area in the brainstem called the pedunculopontine tegmental
nucleus (PPTg). This area may be particularly involved in nicotine addiction.
The action and reinforcement of nicotine in these brain regions is influenced
by neurochemical systems present there. These findings have been made
through micro-pharmacological manipulations of the vta and PPTg in animals
trained to self-administer nicotine.
Under the leadership of Dr. Shafiq Rahman (Research
Scientist, CAMH), our research focus has moved to examine the character-istics
of the neurochemical release of dopamine in laboratory animals during
both voluntary self-administration and experimenter-administration of
nicotine. This research relies on a technique known as in vivo microdialysis
coupled with neurochemical detection, which allows us to sample small
amounts of neurochemicals as they are released focally in the brain
reward circuits. The amount of transmitter release is then quantified
electrochemically. The unique strength of these studies is the combination
of in vivo microdialysis with nicotine self-administration, a union
that will allow us to make discoveries about brain mechanisms in nicotine-reinforced
behaviour.
In vivo microdialysis procedures allow us to
study the extracellular dopamine concentrations in the mesolimbic dopamine
system during nicotine exposure in animals trained for nicotine self-administration.
As control conditions, we are also measuring dopamine concentrations
during nicotine self-administration and food-maintained responding.
These experiments allow us to determine nicotine-specific effects on
the dopamine system, apart from the response of this brain system to
other drugs (e.g., heroin, cocaine) or behaviour motivated by natural
reinforcers (e.g., food).
Additionally, we are characterizing the dopamine
concentration during nicotine self-administration maintained on schedules
of reinforcement that require animals to do different amounts of work
to obtain their drug. In this way, we can elucidate the relationship
between the behavioural output for a drug and changes in dopamine concentration.
Similar procedures help us monitor the changes
in dopamine concentration in the mesolimbic dopamine system following
systemic administration of nicotine coupled with microinfusions of cholinergic,
GABA-ergic, glutamatergic, and opioid compounds into the VTA and the
PPTg. These compounds have been shown to modify nicotine self-administration.
Our studies in this area will explain the mode of action of these compounds
on the midbrain dopamine system.
The results of these studies will help us understand
brain mechanisms involved in nicotine addiction. In particular, the
research will uncover mechanisms within the mesolimbic dopamine system,
possibly new mechanisms that are mesolimbic-dopamine independent. Information
of this kind can support initiatives to develop medication as well as
help identify risk factors for nicotine addiction.
Drug Self-Administration in Animals/Pre-clinical
Medication Development
We are testing particularly relevant neurochemical
agents for their ability to reduce nicotine self-administration when
they are administered systemically. This year, one set of experiments
began examining agonists for GABA receptors. gaba is the brain's main
inhibitory transmitter. We have previously found that GABA agonists
delivered into the VTA or PPTg attenuated nicotine self-administration,
and did so preferentially, compared to the self-administration of cocaine.
In addition, anatomical data showed that nicotine may directly target
GABA-containing neurons in the PPTg. For these reasons, we are exploring
the efficacy of GABA agonists delivered systemically to selectively
reduce nicotine self-administration. GABA agonists are also being used
in human experimental studies of drug use, including tobacco smoking,
as a potential target for medication development.
A similar rationale gives evidence that a particular
serotonergic target may also afford a pharmacological access point to
nicotine reinforcement.
In addition, we are examining whether high-dose
nicotine replacement might be a useful smoking cessation approach. Our
animal model is a useful means to address this issue -- we can examine
the effects of sustained high-dose delivery of nicotine to the experimental
animals, and we can measure the effects of high-dose delivery on nicotine
self-administration and relapse after removal of the drug.
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