Toll-like receptor 4 antagonists reduce cocaine-primed reinstatement of drug seeking

Abstract

Rationale: Cocaine can increase inflammatory neuroimmune markers, including chemokines and cytokines characteristic of innate inflammatory responding. Prior work indicates that the Toll-like receptor 4 (TLR4) initiates this response, and administration of TLR4 antagonists provides mixed evidence that TLR4 contributes to cocaine reward and reinforcement.

Objective: These studies utilize (+)-naltrexone, the TLR4 antagonist, and mu-opioid inactive enantiomer to examine the role of TLR4 on cocaine self-administration and cocaine seeking in rats.

Methods: (+)-Naltrexone was continuously administered via an osmotic mini-pump during the acquisition or maintenance of cocaine self-administration. The motivation to acquire cocaine was assessed using a progressive ratio schedule following either continuous and acute (+)-naltrexone administration. The effects of (+)-naltrexone on cocaine seeking were assessed using both a cue craving model and a drug-primed reinstatement model. The highly selective TLR4 antagonist, lipopolysaccharide from Rhodobacter sphaeroides (LPS-Rs), was administered into the nucleus accumbens to determine the effectiveness of TLR4 blockade on cocaine-primed reinstatement.

Results: (+)-Naltrexone administration did not alter the acquisition or maintenance of cocaine self-administration. Similarly, (+)-naltrexone was ineffective at altering the progressive ratio responding. Continuous administration of (+)-naltrexone during forced abstinence did not impact cued cocaine seeking. Acute systemic administration of (+)-naltrexone dose-dependently decreased cocaine-primed reinstatement of previously extinguished cocaine seeking, and administration of LPS-Rs into the nucleus accumbens shell also reduced cocaine-primed reinstatement of cocaine seeking.

Discussion: These results complement previous studies suggesting that the TLR4 plays a role in cocaine-primed reinstatement of cocaine seeking, but may have a more limited role in cocaine reinforcement.

Keywords: Addiction; Cocaine; Drug seeking; Immune; Reinstatement; Self-administration; Substance use disorders; Toll-like receptor.