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.
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Funding
This work was supported by institutional funds, US Public Health Service grant DA 033358, and the intramural research programs of the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism, National Institute on Health.
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Brown, K.T., Levis, S.C., O’Neill, C.E. et al. Toll-like receptor 4 antagonists reduce cocaine-primed reinstatement of drug seeking. Psychopharmacology 240, 1587–1600 (2023). https://doi.org/10.1007/s00213-023-06392-w
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DOI: https://doi.org/10.1007/s00213-023-06392-w