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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
Author(s) -
Randall Patrick A.,
Vetreno Ryan P.,
Makhijani Viren H.,
Crews Fulton T.,
Besheer Joyce
Publication year - 2019
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.13919
Subject(s) - glutamatergic , agonist , nucleus accumbens , receptor , gene expression , endocrinology , chemistry , tlr4 , medicine , pharmacology , biology , microbiology and biotechnology , gene , glutamate receptor , biochemistry
Background Growing evidence suggests that neuroimmune signaling via Toll‐like receptors ( TLR s) alters brain circuitry related to alcohol use disorders. Both ethanol (EtOH) exposure and the TLR 3 agonist, poly(I:C), increase brain TLR 3 expression in neurons and glia. Furthermore, previous studies have shown that cortical TLR 3 expression is correlated with lifetime EtOH intake in humans. Methods 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 ( IC ) and nucleus accumbens (Acb) and on operant EtOH self‐administration, in Long Evans rats. Results TLR 3 activation increased mRNA levels of neuroimmune genes ( TLR 3, COX 2 ), glutamatergic genes ( mG luR2, mG luR3, GLT 1 ), and the trophic factor BDNF in Acb and IC . Furthermore, increases in each of these genes were correlated with increases in TLR 3 mRNA , suggesting that TLR 3 induction of these genes may impact excitatory transmission in IC and Acb. TLR 3 activation also increased EtOH self‐administration 18 days postinjection and enhanced the effects of the mG luR2/3 agonist LY 379268 to reduce EtOH self‐administration following poly(I:C). Conclusions Together, these findings suggest lasting consequences of TLR 3 activation on gene expression including increases in Group II mG luRs in the Acb. Furthermore, we show an important role for TLR 3 signaling in EtOH intake, and a functional involvement of Group II mG luRs.