JQ1 attenuates psychostimulant- but not opioid-induced conditioned place preference

Abstract

Epigenetic mechanisms play important roles in the neurobiology of substance use disorder. In particular, bromodomain and extra-terminal domain (BET) proteins, a class of histone acetylation readers, have been found to regulate cocaine conditioned behaviors, but their role in the behavioral response to other drugs of abuse remains unclear. To address this knowledge gap, we examined the effects of the BET inhibitor, JQ1, on nicotine, amphetamine, morphine, and oxycodone conditioned place preference (CPP). Similar to previous cocaine studies, systemic administration of JQ1 caused a dose-dependent reduction in the acquisition of amphetamine and nicotine CPP in male mice. However, in opioid studies, JQ1 did not alter morphine or oxycodone CPP. Investigating the effects of JQ1 on other types of learning and memory, we found that JQ1 did not alter the acquisition of contextual fear conditioning. Together, these results indicate that BET proteins play an important role in the acquisition of psychostimulant-induced CPP but not the acquisition of opioid-induced CPP nor contextual fear conditioning.

Keywords: Amphetamine; BET; Bromodomain; Epigenetics; JQ1; Morphine; Nicotine; Oxycodone.

Figure 1.. JQ1 attenuates the acquisition of amphetamine and nicotine CPP.

(A) Amphetamine CPP was significantly reduced by JQ1 (25 and 50 mg/kg) compared to vehicle, but the inactive enantiomer (−)JQ1 had no significant effect compared to vehicle treated mice. (B) JQ1 (25 and 50 mg/kg) significantly attenuated the acquisition of nicotine CPP compared to vehicle treated mice. *P < 0.05 and **P < 0.01 indicate a significant difference using Newman-Keuls post hoc test. Data are mean ±SEM.

Figure 2.. JQ1 does not affect the acquisition of morphine and oxycodone CPP.

Mice were conditioned with 10 mg/kg of morphine (A), 5 mg/kg of morphine (B), or 3 mg/kg of oxycodone (C). Compared to vehicle treated mice, JQ1 (25 and 50 mg/kg) had no effect on the acquisition of morphine (A-B) and (C) oxycodone CPP. Data are mean ±SEM.

Figure 3.. JQ1 does not affect the acquisition of contextual fear conditioning.

Immediately following fear conditioning training, mice were injected with vehicle or JQ1 (25 or 50 mg/kg). The next day, mice were returned to the test chamber and freezing behavior was recorded. Compared to vehicle treated mice, JQ1 had no significant effect on freezing behavior. Data are mean ±SEM.