The Toll‐Like Receptor 3 Agonist Poly(I:C) Induces Rapid and Lasting Changes in Gene Expression Related to Glutamatergic Function and Increases Ethanol Self‐Administration in Rats

<jats:sec><jats:title>Background</jats:title><jats:p>Growing evidence suggests that neuroimmune signaling via Toll‐like receptors (<jats:styled-content style="fixed-case">TLR</jats:styled-content>s) alters brain circuitry related to alcohol use disorders. Both ethanol (EtOH) exposure and the <jats:styled-content style="fixed-case">TLR</jats:styled-content>3 agonist, poly(I:C), increase brain <jats:styled-content style="fixed-case">TLR</jats:styled-content>3 expression in neurons and glia. Furthermore, previous studies have shown that cortical <jats:styled-content style="fixed-case">TLR</jats:styled-content>3 expression is correlated with lifetime EtOH intake in humans.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>The current experiments investigated the consequences of poly(I:C) treatment on gene expression in 2 brain regions contributing to alcohol reinforcement, the insular cortex (<jats:styled-content style="fixed-case">IC</jats:styled-content>) and nucleus accumbens (Acb) and on operant EtOH self‐administration, in Long Evans rats.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p><jats:styled-content style="fixed-case">TLR</jats:styled-content>3 activation increased <jats:styled-content style="fixed-case">mRNA</jats:styled-content> levels of neuroimmune genes (<jats:italic><jats:styled-content style="fixed-case">TLR</jats:styled-content>3, <jats:styled-content style="fixed-case">COX</jats:styled-content>2</jats:italic>), glutamatergic genes (<jats:italic><jats:styled-content style="fixed-case">mG</jats:styled-content>luR2, <jats:styled-content style="fixed-case">mG</jats:styled-content>luR3, <jats:styled-content style="fixed-case">GLT</jats:styled-content>1</jats:italic>), and the trophic factor <jats:italic><jats:styled-content style="fixed-case">BDNF</jats:styled-content></jats:italic> in Acb and <jats:styled-content style="fixed-case">IC</jats:styled-content>. Furthermore, increases in each of these genes were correlated with increases in <jats:styled-content style="fixed-case">TLR</jats:styled-content>3 <jats:styled-content style="fixed-case">mRNA</jats:styled-content>, suggesting that <jats:styled-content style="fixed-case">TLR</jats:styled-content>3 induction of these genes may impact excitatory transmission in <jats:styled-content style="fixed-case">IC</jats:styled-content> and Acb. <jats:styled-content style="fixed-case">TLR</jats:styled-content>3 activation also increased EtOH self‐administration 18 days postinjection and enhanced the effects of the <jats:styled-content style="fixed-case">mG</jats:styled-content>luR2/3 agonist <jats:styled-content style="fixed-case">LY</jats:styled-content>379268 to reduce EtOH self‐administration following poly(I:C).</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Together, these findings suggest lasting consequences of <jats:styled-content style="fixed-case">TLR</jats:styled-content>3 activation on gene expression including increases in Group <jats:styled-content style="fixed-case">II mG</jats:styled-content>luRs in the Acb. Furthermore, we show an important role for <jats:styled-content style="fixed-case">TLR</jats:styled-content>3 signaling in EtOH intake, and a functional involvement of Group <jats:styled-content style="fixed-case">II mG</jats:styled-content>luRs.</jats:p></jats:sec>