Smoking and Nicotine Dependence: Research Annual Report 2003

Section Head: Dr. Paul Fletcher (acting)

The main focus of our research in the Smoking and Nicotine Dependence Research Section is to better understand the neurochemical basis or mechanisms underlying nicotine dependence.

A limiting factor in finding therapies to prevent smoking is that underlying mechanisms involved in nicotine addiction, such as the positive reinforcing effects of nicotine, still remain unclear. Our research gives us valuable information about the brain mechanisms involved in nicotine addiction; this work should help us identify drug targets and thus help the search for more effective therapeutic agents for smoking cessation.
Previous studies in our laboratory have shown that nicotine is the primary rewarding compound in tobacco smoke. The study of nicotine dependence, like that of other drug dependence, profits from animal models, which allow us to examine the biochemical and behavioural consequences of acute and chronic drug treatment at a depth not possible with human studies.

Under the leadership of Dr. Shafiq Rahman (Research Scientist, CAMH), we continue to explore the mechanisms that mediate the positive reinforcing effects of nicotine in the brain. We use both conventional (qualitative) and quantitative (no-net-flux) in vivo microdialysis techniques in behaving animals to measure dopamine (brain chemical for reward) release in rat brain reward circuits. We have used both microdialysis methods in the nucleus accumbens (NAc) or ventral tegmental area (VTA) after acute and subchronic (pretreatment or pre-exposure regimen) and chronic nicotine treatment.

Nicotine Receptors in the Nucleus Accumbens

Nicotine is thought to exert its rewarding effects by activating dopamine neurotransmission in the mesocorticolimbic dopamine system, which is an integral part of the brain reward system. We have shown that acute and repeated nicotine exposure stimulates the release of dopamine in the NAc, a feature shared by other drugs of abuse, such as amphetamine and cocaine. Nicotine exerts these effects by attaching to and activating specific sites called receptor proteins and, more specifically, a type of receptor called neuronal nicotinic acetylcholine receptor.

Neuronal nicotinic acetylcholine receptors have several subtypes. We have determined that stimulatory effects of nicotine in the brain reward system are mediated by the high- and low-affinity nicotinic acetylcholine receptors. We have also found that low-affinity nicotinic receptors have a special role in modulating brain dopamine function in the NAc after repeated exposure to nicotine.

Nicotine and Release-Controlling Dopamine Autoreceptors

We are also investigating the role of dopamine autoreceptors in the NAc and VTA that control the release of dopamine.

In the NAc, we have found that dopamine autoreceptor subsensitivity may not contribute directly to the sensitization of dopamine releasibility. Additional studies on the role of dopamine autoreceptors in the VTA suggest that dopamine autoreceptor subsensitivity in this area is essential in nicotine-induced sensitization of dopamine release. The regulation of release-controlling dopamine autoreceptors is associated with sensitization and/or adaptive changes that are important for the development of nicotine addiction.

Chronic Nicotine Self-Administration

We have also started to use no-net-flux (quantitative) microdialysis to examine changes in dopamine transmission in the NAc after chronic nicotine self-administration. Recent advances in microdialysis methods show that quantitative methods are useful not only in determining the true extra-cellular concentration of dopamine but also in testing for potential changes in dopamine transmission. Moreover, changes in tissue dopamine transmitter content are not necessarily paralleled by corresponding changes at the synaptic level of the reward centre.

We hope to determine whether chronic voluntary nicotine self-administration alters or influences the functional integrity of the dopamine system in the NAc (i.e., dopamine release, uptake, synthesis and metabolism). We are measuring extracellular dopamine levels and in vivo extraction fraction.

Typically, extracellular dopamine levels represent dopamine release in the NAc, and dopamine extraction fractions reflect the uptake process or clearance of a known dopamine concentration. For example, a known dopamine concentration is given through microdialysis probe into the NAc, which is measured after a time interval (dopamine in-dopamine out is equal to extraction fraction).

Our results indicate that chronic nicotine self-administration significantly reduces basal dopamine levels, which is likely due to chronic intermittent exposure to the pharmacological effects of nicotine. More importantly, chronic nicotine self-administration creates a neuroadaptive change in the brain that alters the dopamine transporter and increases uptake in the NAc.

Smoking and Nicotine Dependence: Research Annual Report 2003

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