Methamphetamine addiction causes serious public health problems worldwide. However, there is no effective medication licensed for
methamphetamine addiction. The endogenous
opioid system is considered to be a common substrate in
drug addiction due to its regulation of
dopamine release. In recent clinical trials, (-)-
naltrexone, an
opioid receptors and
Toll-like receptor 4 antagonist, has exhibited encouraging findings for treating
methamphetamine addiction; however, the understanding of its pharmacological mechanisms remains insufficient. By using mice models of behavioral sensitization and conditioned place preference (
CPP), the present study was performed to investigate the effects of
naltrexone on the
methamphetamine-associated properties of incentive salience and reward-related memory, the two crucial factors for the development of addictive process and relapse. We found that
naltrexone reduced single
methamphetamine-induced hyperlocomotion in mice. In the paradigm of
methamphetamine-induced behavioral sensitization paired with contextual cues in mice,
naltrexone suppressed the development and expression of locomotor sensitization, suggesting the decrease in incentive salience to
methamphetamine and context. In the
methamphetamine-induced
CPP paradigm in mice,
naltrexone attenuated both the expression and
methamphetamine-priming reinstatement of
CPP response, suggesting the impairment of either contextual cue- or drug-induced retrieval of
methamphetamine-associated memory. After the establishment of
methamphetamine-induced
CPP in mice,
naltrexone treatment during the extinction training produced conditioned place adverse response, suggesting that
naltrexone facilitated negative affection-associated extinction learning. Taken together, these findings demonstrate that
naltrexone could intervene in the properties of incentive salience and reward-related memory in
methamphetamine addiction, which may contribute to its
therapeutic effects on
methamphetamine addicts in clinical studies.