Microglial TNF-α Suppresses Cocaine-Induced Plasticity and Behavioral Sensitization

Abstract

Summary Repeated administration of cocaine results in the development of behavioral sensitization, accompanied by a decrease in excitatory synaptic strength in the nucleus accumbens (NAc) through an unknown mechanism. Furthermore, glial cells in the NAc are activated by drugs of abuse, but the contribution of glia to the development of addictive behaviors is unknown. Tumor necrosis factor alpha (TNFα), an inflammatory cytokine released by activated glia, can drive the internalization of synaptic AMPA receptors on striatal medium spiny neurons. Here we show that repeated administration of cocaine activates striatal microglia and induces TNFα production, which in turn depresses glutamatergic synaptic strength in the NAc core and limits the development of behavioral sensitization. Critically, following a period of abstinence, a weak TLR4 agonist can re-activate microglia, increase TNFα 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.

A metaplasticity view of the interaction between homeostatic and Hebbian plasticity

“…Additionally, IB cells showed input-specific potentiation (Hebbian LTP) that required CaMKII autophosphorylation. Although the molecular and cellular pathway leading from neuronal activity to TNFa biosynthesis has yet to be discovered, recent studies show that striatal microglial produce TNFa [126,127]. As opposed to its role in hippocampus, where it mediates excitatory synaptic strengthening, in striatum, TNFa was shown to drive synaptic AMPA receptor internalization, thus reducing glutamatergic synaptic strength.…”

“…As opposed to its role in hippocampus, where it mediates excitatory synaptic strengthening, in striatum, TNFa was shown to drive synaptic AMPA receptor internalization, thus reducing glutamatergic synaptic strength. In the ventral striatum or nucleus accumbens core, cocaine administration specifically activates TNFa production, reduces excitatory synaptic transmission and limits the development of behavioural sensitization [126]. The opposite effect of TNFa on excitatory transmission and AMPA receptor surface expression in hippocampal and cortical neurons versus striatal neurons is interesting, and may suggest a context-dependent influence of TNFa signalling on synaptic strength.…”

Alcohol and Stress Activation of Microglia and Neurons: Brain Regional Effects

“…Furthermore, microglia can also modulate neuronal function. Studies find that microglia release cytokines, such as TNF‐ α (Lewitus et al., 2016), and neurotrophins, such as brain‐derived neurotrophic factor (Parkhurst et al., 2013), that can impact neuronal activity. These data suggest alcohol and stress may impact neurons through microglia.…”

Tumour necrosis factor-mediated homeostatic synaptic plasticity in behavioural models: testing a role in maternal immune activation

“…This suggests a role for cytokines in regulating depressive behaviours. Further, TNF mediates synaptic changes within the striatum and acts to reduce the behavioural consequences of chronic administration of antipsychotics [17] and drugs of abuse [35]. As noted above, TNF drives the endocytosis of AMPARs on the GABAergic MSNs of the striatum, reducing excitatory synaptic strength [17].…”

“…Cocaine also activates striatal microglia, which increase TNF production that, in turn, reduces excitatory synaptic strength on MSNs and decreases the locomotor sensitization to cocaine [35]. Importantly, increasing the microglial response can reduce previously established cocaineinduced sensitization [35]. As the development of addiction is thought to be an aberrant form of learning [36], these data suggest that Hebbian and homeostatic plasticity can act to counterbalance each other, with a TNF-mediated homeostatic rstb.royalsocietypublishing.org Phil.…”