Smoking and Nicotine Dependence Research: Research Annual Report 2002

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.