Editors' ChoiceNeuroscience

Microglia combat addiction

Sci. Signal.  10 May 2016:
Vol. 9, Issue 427, pp. ec110
DOI: 10.1126/scisignal.aag0803

Acutely, cocaine stimulates dopamine release in the striatum in the brain. Chronic use dampens glutamatergic excitatory signaling in striatal neurons. During periods of withdrawal, the excitatory glutamatergic synapses recover, which stimulates drug craving. Maintaining the depression of excitatory glutamatergic synapses may be a key to preventing relapse, and tumor necrosis factor–α (TNF-α) promotes synaptic depression by stimulating the internalization of excitatory AMPA-type glutamate receptors. Lewitus et al. found that activated microglia produce TNF-α in response to chronic cocaine administration in mice. 5 days of daily cocaine injection into the peritoneum of mice increased the abundance of TNF-α in the nucleus accumbens (NAc) of the brain. Administration of cocaine in vivo or TNF-α to ex vivo slices decreased excitatory transmission and AMPA receptor abundance in NAc neurons. Both transmission and AMPA receptor abundance were increased in response to cocaine in mice lacking TNF-α, and administration of a dominant-negative variant of TNF-α during cocaine conditioning, but not during the period of abstinence, enhanced the locomotor response (an indication of craving behavior) in mice. Various experimental approaches in mice revealed that five days of daily cocaine injection activated microglia, that microglia rather than astrocytes are the major source of chronic cocaine-induced TNF-α, and that microglia activity decreases during periods of withdrawal. Pharmacological experiments with microglia cultures revealed that dopamine acts through D2 receptors to stimulate their activation. Activating microglia with MPLA, a detoxified variant of lipopolysaccharide, suppressed the locomotor response to cocaine in mice that had undergone a period of withdrawal. The findings suggest that microglial agonists might reduce cocaine craving.

G. M. Lewitus, S. C. Konefal, A. D. Greenhalgh, H. Pribiag, K. Augereau, D. Stellwagen, Microglial TNF-α suppresses cocaine-induced plasticity and behavioral sensitization. Neuron 90, 483–491 (2016). [PubMed]

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