Microglia suppresses drug effect!

Microglia suppresses drug effect!

The discovery, published in the journal Neuron, establishes 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.

Microglia may not be as well known as neurons, the brain cells that relay messages, but they have many important functions. They constantly monitor their environment, and can act to 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).

Using a mouse model, researchers detected this microglia-mediated reversal by looking at how TNF acts on a particular set of synapses in the brain. "These connections are really important for regulating the behavior response in animal models to drugs of abuse such as cocaine," says co-first author.

The team found that TNF suppresses specific synaptic changes caused by cocaine-changes that are thought to underlie addiction.  Researchers show that TNF-α, an inflammatory cytokine released by activated glia, can drive the internalization of synaptic AMPA receptors on striatal medium spiny neurons.

They also show that repeated administration of cocaine activates striatal microglia and induces TNF-α production, which in turn depresses glutamatergic synaptic strength in the nucleus accumbens core and limits the development of behavioral sensitization.

Critically, following a period of abstinence, a weak TLR4 agonist can reactivate microglia, increase TNF-α production, depress striatal synaptic strength, and suppress cocaine-induced sensitization. Thus, cytokine signaling from microglia can regulate both the induction and expression of drug-induced behaviors.