Much exciting neuroscience research in the last few years concerns the non-neural cells called glia. Scientists once thought they mainly played a supporting role in the brain, but we are now learning that glia do much, much more. Three sessions in NIDA’s Mini-Convention at the Society for Neuroscience meeting in New Orleans on October 12 showcased new research on glia with direct or indirect implications for addiction research. I want to highlight just a few of the fascinating talks I attended on this subject.
Among their many functions, glia detect damage or infection in the brain and initiate immune responses such as inflammation. We have known for several years that these inflammatory responses somehow are involved in the development of tolerance to opioids and may play a role in addictive disorders. In a session on immune signaling and addiction, Mark Hutchinson (University of Adelaide) discussed his discovery that a specific type of pathogen-detecting receptor called TLR4 receptors, which are found mainly on microglia, are also activated by opioids and may be responsible for the development of tolerance to their pain-relieving effects and possibly also for their rewarding effects.
Special properties of these TLR4 receptors create exciting possibilities for decoupling the positive uses of opioids in pain relief from their negative drawbacks. Many molecules, including opioids, have mirror-image right- and left-handed (or + and -) variants (or isomers); the mu-opioid receptors on neurons respond only to negative (-) isomers of opioid molecules, but TLR4 receptors are activated by both the positive (+) and negative (-) versions. Hutchinson and other researchers have recently used positive isomers of opioid antagonist drugs to enhance the pain-relieving properties of opioid agonists and block drug-seeking and self-administration in animal models. Yavin Shaham (NIDA IRP) described a study in which he used an implant delivering the positive isomer of the opioid antagonist naltrexone to prevent heroin relapse in rats.
Staci Bilbo (Duke) described how glial cells may be permanently primed or sensitized to deliver a heightened proinflammatory response by early stress, including infection, poor nurturance, or exposure to morphine. This can render the animal more vulnerable later not only to stress but also cognitive impairment and addiction if a new trauma or drug exposure activates those same glial pathways. She also presented research showing that the anti-inflammatory drug ibudilast can lessen the rewarding properties of morphine in rats by blunting the expression of inflammatory genes in glial cells.
We are also learning how the immune functions of glia help them play a role in shaping the nervous system over the course of development. From the fetal stage through young adulthood, the brain is fine-tuning its synaptic connections, reinforcing those that fire strongly and getting rid of those that do not. In a session on the role of the immune system in synaptic plasticity, NIH-funded researchers Beth Stevens (Boston Children’s Hospital and Harvard Medical School), Ben Barres (Stanford), and Marc Freeman (UMass Medical School) each presented new research on different ways that microglia and astrocytes recognize weaker synapses so they can engulf and destroy them, through a process similar to the way white blood cells destroy invaders in other parts of the body. Understanding these processes helps us understand not only processes of learning but also the vulnerabilities of the developing brain to environmental factors like addictive drugs.
Astrocytes link neurons to blood vessels and supply them with needed energy. In a session on brain energetics and neurotransmission, Pierre Magistretti (EPFL, Lausanne) described how astrocytes metabolize glycogen (stored glucose) to lactate for use as fuel by neurons. Magistretti’s research has shown that this non-glucose source of energy may be critical in forming long-term memories, and is a signaling molecule in its own right. Another alternative fuel for neurons is acetate, which is elevated when alcohol is consumed. Douglas Rothman (Yale School of Medicine) showed that in heavy drinkers astrocytes show increased acetate metabolism and decreased glucose metabolism. This plasticity of astrocytes is unexpected; that they adapt themselves to an acetate-rich environment may contribute to alcohol dependence and complicate withdrawal, thus making these cells a novel therapeutic target for addressing heavy alcohol use.
Together, these findings suggest the wide and active roles played by glia in basic brain functions throughout the life span. As we learn more about what they do and how they work, scientists may be able to capitalize on their therapeutic potential for a variety of applications including the treatment of addiction.