Microglia-based mechanism that reduces effect of cocaine on the brain identified.
It is known that repeated cocaine-use results in the development of behavioural sensitization, accompanied by a decrease in excitatory synaptic strength in the nucleus accumbens (NAc). Furthermore, glial cells in the NAc are activated by drugs of abuse, however, the contribution of glia to the development of addictive behaviours is unknown. Now, a study from researchers at McGill University shows that a type of brain cell, known as microglia, plays a key role in reducing the effects of cocaine in the brain. The team state that their findings establish for the first time that microglia can diminish the adverse changes to neural circuitry brought on by the chronic use of cocaine and has significant implications for developing an effective treatment for addiction. The opensource study is published in the journal Neuron.
Previous studies show that microglia constantly monitor their environment, and maintain normal brain functioning. When they find something amiss, they can produce molecules that instruct neurons to make adaptive changes to their connections. One such example is the inflammatory molecule known as tumor necrosis factor (TNF). TNF is an inflammatory cytokine released by activated glia, which can drive the internalization of synaptic AMPA receptors on striatal medium spiny neurons. The current study shows that repeated administration of cocaine activates striatal microglia, which causes the release of the TNF inflammatory signal, with TNF then attempting to reverse the changes induced by the cocaine in neurons.
The current study utilised a mouse-model to investigate this microglia-mediated reversal by looking at how TNF acts on a particular set of synapses in the brain. Results show that TNF suppresses specific synaptic changes caused by cocaine-changes that are thought to underlie addiction. Data findings show that this beneficial mechanism doesn’t last with microglia response fading over time. The lab state that one of the things that could transition somebody from just casual use into chronic dependency might be the fading of this adaptive signal which then allows the drugs to solidify their change to the neural circuitry.
The group then performed further tests to see if the microglia-response can be stimulated to last longer. To find out, the researchers used a pharmaceutical agent that stimulates microglial production of TNF. The lab observed that a cocaine-induced behavioural change in mice, the progressive increase in movement induced by cocaine, was reduced in the animals who received this agent.
The team surmise that their results hold promise for developing treatments that cut down on drug relapse rates. For the future, the researchers state that they are now investigating if the stimulated release of TNF can actually suppress cravings for cocaine, with view to applying findings to other drug-types.