Addiction

Tobacco smoking is the single greatest cause of preventable ill health and death in Australia especially within regional and rural Australia. The number of smokers hospitalised or killed by smoking is greater than that caused by alcohol and all other illicit drugs combined. Recent public health initiatives targeting smoking have been successful in reducing the incidence of smoking in younger age groups, however smoking amongst older, unemployed or disadvantaged groups has remained relatively stable.

Stopping smoking has immediate health benefits but quitting is not easy. Less than 3% of smokers successfully quit each year, with multiple quit attempts required before any lasting abstinence is achieved. To assist with the quit process, approximately 30% of smokers will resort to the use of popular anti-smoking treatments. Through blocking the immediate symptoms of cravings and withdrawal, such treatments facilitate quitting during the first weeks of abstinence. However, such gains in the short-term do not necessarily persist into the long-term: at best anti-smoking treatments can double the chance of quitting 6 months later, at worst they confer no advantage over placebo. It may be that through blocking the experience of cravings, the smoker never learns the necessary inhibitory control to overcome or resist triggers of relapse in the absence of a pharmacological aid.

This project uses an animal model of nicotine addiction, to determine what undermines the long-term effectiveness of anti-smoking treatments and whether the more strategic use of anti-smoking treatments promotes better long-term smoking cessation outcomes. 

The symptoms of withdrawal and cravings are due to nicotine-induced changes in the brain. Of the 4000 chemicals present in tobacco smoke, nicotine is primarily responsible for the addictive properties of cigarettes. Upon inhalation, nicotine rapidly enters the blood stream, crosses the blood-brain barrier and binds to nicotinic acetylcholine receptors (nAChRs). Nicotine receptors are widely distributed throughout the brain, including within the midbrain dopamine system, which is critical for reward-related processes. The ventral tegmental area (VTA) and nucleus accumbens (NAc) are key components of this system. Nicotine binds to nAChRs on dopamine neurons in the VTA that project to the NAc. The ensuing dopamine release in the NAc mediates the rewarding effects of smoking.

Chronic smoking changes this circuitry, allowing smoking to be maintained by other factors. For example, nicotine-related cues hijack this circuitry through activation of the basolateral amygdala (BLA), which is strongly interconnected with the NAc. Through these connections, smoking-related cues themselves begin to trigger dopamine release in the NAc, further driving smoking behaviour. Nicotinic activation of other brain areas can also modulate dopamine release in the NAc and may be important in prompting relapse. One such area is the medial prefrontal cortex (mPFC), which directly projects to both the NAc and the VTA. Via these projections, the mPFC regulates dopaminergic regulation of adaptive and maladaptive behaviours. In the rat, the mPFC contains anatomically and functionally distinct sub-regions: the more dorsal prelimbic cortex (PrL) is critical to promoting relapse of drug-seeking, whereas the more ventral infralimbic cortex (IL) has been implicated in inhibitory control of behaviour, including inhibition of drug-seeking across abstinence. The IL also plays a critical role in resisting relapse: suppression of activity of the IL results in relapse of cocaine seeking, whereas activation of this region strengthens resistance to cocaine-induced relapse. These results suggest that maintenance of abstinence and resistance to relapse relies on the integrity and strength of inhibitory circuits that specifically involve the IL.

The habenula is another brain region that has recently emerged as an important component of the inhibitory circuits that mediates withdrawal and cravings in nicotine addiction. The habenula shares connections with both the IL and VTA, and importantly, is rich in expression of nicotine receptors. Direct or indirect input from the habenula to the VTA acts to dampen the excitation of dopamine neurons following nicotine exposure, normalising NAc dopamine levels. However, when nicotine is abruptly removed (as in a quit attempt), the habenula continues to exert this suppressive influence. In the absence of the direct effects of nicotine on the VTA, this hyperactivity of the habenula is manifested as the aversive state of withdrawal. It is not clear whether this hyperactivity of the habenula is reactivated following exposure to nicotine-associated cues or how it might be influenced by anti-smoking treatments.

Aim: To determine the effect of common anti-smoking treatments on abstinence, relapse and underlying neural circuits.

Hypothesis: Exposure to nicotine-related cues and experience of cravings is necessary for development of inhibitory neural circuits that prevent relapse. Through blunting the experience of cravings (short-term gain), pharmacotherapies inhibit the development of these circuits, thus reducing their effectiveness in preventing relapse in the long-term (long-term pain).