Sez6 – the sexy gene (famous autocorrect), cocaine addiction & compound X.

A layman’s explanation of my research for the non-science community 🙂

University of Melbourne lab group investigates the role of the protein, Sez6, in the enduring drug memory associated with cocaine relapse in former addicts

Drug addiction is a devastating condition that affects millions of people and their families worldwide. Drug addiction is defined as a state whereby the acquirement of drugs becomes the central priority of the addict, despite the moral, financial or personal repercussions that may result. Indeed, while the initial engagement in illicit drugs may be a choice, addiction is not- it becomes a disease. Even if an addict desires to quit, it can be an incredibly difficult process due to the enduring changes that have occurred in the brain’s reward system. Not only is drug addiction a personal burden; it is also paired with serious long-term health problems such as heart complications, anxiety, psychotic episodes and an overall increased risk of death. Additionally, drug addiction is economically destructive. In 2011, in Australia alone, a reported 132 million dollars were spent on the medical costs of illicit drug-related hospitalisation. While support groups and psychological services are available to addicts, there is currently no pharmaceutical drug treatment available to prevent cocaine relapse.

How does cocaine work in the brain?

Cocaine exerts its effect by hijacking the dopamine reward system located in the Nucleus Accumbens (NAc) of the brain. Usually, when we experience something pleasurable like good food, sex or social interaction, the neurotransmitter dopamine is released. Shortly after, tiny proteins act to quickly sweep up, break down and recycle this dopamine back into our storage systems for future use. However, cocaine hijacks this process by stopping the action of these ‘sweeping’ proteins, which leads to excess dopamine floating in our reward pathways paired with an ultra-pleasurable and longer lasting high. Consequently, cocaine rewires the reward pathway and depletes our overall dopamine storage. This means that there is less dopamine ready to fire, and so less pleasure is experienced when engaging in regular day to day activities that normally bring happiness to an individual. In turn, this creates a vicious cycle, encouraging further cocaine abuse to achieve that ‘high’ or merely to feel joy that can no longer be experienced. This lowered dopamine, along with reward centre rewiring, are responsible for the drug habits that slowly advance into addiction. When we learn something new, our brain builds new networks of brain cells called synapses. These synapses encode new memories and information. Similarly, frequent drug use that advances into addiction builds strong ‘drug memory’, and thus an increase in synapse number in the reward centres of the brain. Thus, having a better understanding of the mechanism behind this persistent ‘drug memory’ may unlock answers on how to prevent cocaine relapse.

Sez6 – new protein involved in cocaine relapse?

Presently, a lab at The University of Melbourne is investigating the role of the protein, Sez6 in cocaine relapse and ‘drug memory’. While Sez6’s mode of action is still unclear, it is involved in the creation of new synapses and binds to calcium channels to increase calcium flow into cells, which has an important role in activating ‘memory’ related pathways. Furthermore, recent preclinical studies have exhibited that blocking the area to which Sez6 usually binds on calcium channels has been effective in the treatment of cocaine relapse in mice.

The experiment: Blocking Sez6 may prevent cocaine relapse?

Given this information, The Gunnersen lab is investigating Sez6 as a potential mediator of the addiction process, and more specifically, in the persistent ‘drug memory’ responsible for relapse after long drug-free periods (abstinence). The team is exploring this through a mouse model; where mice learn to press a lever upon which they are delivered a hit of cocaine. This cocaine ‘hit’ is paired with two cues, a light flash cue and vanilla essence scent. In this way, mice form an association between the cue (light and smell) and the delivery of the cocaine reward. This model most closely resembles human drug seeking due to the strong associations addicts form with their drug abuse – such as the environment and people with whom they regularly engaged in illicit drug use. It is thought that these closely tied and enduring associations with illicit drug use are responsible for the relapse seen in former cocaine addicts, even after years of abstinence. Thus, once mice have successfully become ‘addicted’ they will have a drug free period, where they are kept in their original home cage and have no access to cocaine chambers. One mouse group will be fed regular food and the other will receive food containing a particular compound, Compound X, that inhibits Sez6 protein. In this way, Sez6 will no longer be able to bind to calcium channels and initiate calcium signalling pathways that may be responsible for enduring ‘drug memory’. Following the drug free period, both mouse groups will be reintroduced to their original cocaine chambers and their ‘lever pressing’ behaviour will be examined. If mice who received the Sez6 inhibiting drug exhibit lower pressing behaviour, and hence a lower degree of ‘cocaine relapse’ than the regular fed mice; compound X may be a promising pathway to investigate in the development of future therapeutics for human cocaine addicts. Additionally, the brains of these two mice groups will be analysed and compared for differences in the neurons of the NAc, the drug reward region of the brain. These neurons have tiny spines along their surface which reflect ‘enrichment’. When a mouse is placed in a complex environment with a variety of mazes and tasks that require ‘learning’ they will have more spines on their neurons due to ‘memories’ of the learnt task. Similarly, a drug addict presents with an increase in spine density in reward regions of the brain following regular drug abuse, representing ‘drug memories’ tied to their environment. The analysis of these brain regions will give more clues as to how neuron structure reflects addiction and relapse behaviour, and the role of Sez6 in such changes. While these are just preliminary studies, the prospect is exciting as currently no drug exists to prevent cocaine relapse. The development of such a drug will be life-changing on a personal level for cocaine addicts who struggle to kick the habit, reduce street crime, lower government costs on cocaine related-hospitalisation and increase societal well-being overall.