researchers identify pathway that may protect against cocaine addiction

A study by researchers  gives insight into changes in the reward circuitry of the brain that may provide resistance against cocaine addiction. Scientists found that strengthening signalling along a neural pathway that runs through the nucleus accumbens — a region of the brain involved in motivation, pleasure, and addiction — can reduce cocaine-seeking behaviour in mice.

Research suggests that about 1 in 5 people who use cocaine will become addicted, but it remains unclear why certain people are more vulnerable to drug addiction than others.

A key step in understanding addiction and advancing treatment is to identify the differences in brain connectivity between subjects that compulsively take cocaine and those who do not. 

Until now, most efforts have focused on finding traits associated with vulnerability to develop compulsive cocaine use. However, identifying mechanisms that promote resilience may prove to have more therapeutic value.

In the study, mice were conditioned to receive an intravenous dose of cocaine each time they poked their nose into a hole in their enclosure. Cocaine was then made unavailable for periods of time during the day. Some of the mice would stop seeking the drug once it was removed while others would obsessively continue to poke the hole in an effort to obtain the drug.

Mice that quickly stopped seeking the drug were found to have stronger connections along the indirect pathway — a neural tract that forms indirect projections into the mid-brain and contains cells called medium spiny neurons expressing dopamine D2 receptors (D2-MSNs). A parallel pathway — known as the direct pathway -- forms direct projections into the mid-brain neurons and contains medium spiny neurons expressing D1 receptors (D1-MSNs). These two pathways are thought to work together in complementary but sometimes opposing ways to affect behaviour.

Researchers were very surprised by the results of the study because we were originally looking for vulnerability factors for developing compulsive drug use. Instead,they found changes that only happened in subjects that show a resilience to becoming compulsive drug users. Resilient mice had a strong inhibitory circuit that allowed them to exert better control over their drug intake.

To test this observation, researchers used lasers to activate individual neurons, and found that stimulating D2-MSNs in the nucleus accumbens decreased cocaine seeking in the mice. Blocking D2-MSN signalling with a chemical process increased motivation to obtain cocaine.

This research advances the understanding of how the recruitment, activation and the interaction among brain circuits can either restrain or increase motivation to take drugs.

Previous studies have shown that people with lower levels of dopamine D2 receptors in the striatum, a brain region associated with reward and working memory, are more likely to develop compulsive behaviours toward stimulant drugs.

Dopamine is a key neurotransmitter involved in reward-based learning and addiction. Cocaine disrupts communication between neurons at the synapse, the small junction between nerve cells, by blocking the re-absorption of dopamine into the transmitting neuron. As a result, dopamine continues to stimulate the receiving neuron, causing feelings of alertness and euphoria.