The Effects of Ketamine on Methamphetamine Withdrawal-Induced Anxiety and Drug-Seeking Behaviors in the Rat

BackgroundThe use of methamphetamine has continued to rise in the US. In addition to facilitating dopamine neurotransmission, methamphetamine indirectly increases glutamate release which activates N-methyl-D-aspartate receptors (NMDARs). Ketamine is a noncompetitive NMDAR antagonist. Ketamine also has actions on -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and promotes synaptogenesis. Thus, we hypothesized that ketamine may be a potential therapeutic to reduce methamphetamine-seeking behaviors and associated negative affect in a rat model. MethodsMale and female rats underwent methamphetamine or saline intravenous self-administration for 10 sessions, followed by extinction training. Rats received ketamine or saline treatment either prior to 10 daily extinction sessions or only prior to the last extinction session. Anxiety-like behaviors were measured 24 hours after extinction, followed by cue-induced and drug-primed reinstatement two and six days later respectively. ResultsMethamphetamine withdrawal increased anxiety-like behaviors in male rats on the elevated plus maze test compared to rats that self-administered saline. Moreover, anxiety-like behaviors were significantly attenuated by daily ketamine treatment during extinction. Drug-primed but not cue-induced reinstatement, tested six days after the last extinction session, was significantly attenuated in male rats that received ten or one ketamine treatments during extinction compared with rats receiving vehicle during extinction. Ketamine was ineffective in female rats in reducing cue-induced or drug-primed reinstatement. ConclusionsKetamine may confer sex-specific benefits during methamphetamine withdrawal and relapse vulnerability, particularly by reducing anxiety-like behaviors and attenuating drug-primed reinstatement in males. These results support the potential of ketamine as a targeted adjunct therapy during early methamphetamine abstinence in males.