(72) Ketamine Effects on Anxiety and Drug Seeking Behaviors in Methamphetamine-Withdrawn Rats

Background & Introduction: Recently, the recreational and prescription use of methamphetamine and its derivatives have risen among the youth and adult populations. In addition to facilitating dopamine neurotransmission, methamphetamine indirectly increases the release of glutamate which activates N-methyl-D-aspartate receptors (NMDARs). Ketamine noncompetitively blocks NMDARs. Thus, we hypothesized that ketamine may be a potential therapeutic to treat methamphetamine use disorder.

Methods: This was explored using a rodent model of methamphetamine self-administration. Male rats underwent methamphetamine or saline IV self-administration, then extinction training, followed by tests for cue and drug reinstatement. Anxiety-like behaviors were measured 48-hr after methamphetamine self-administration and again after the 10-day extinction period. During extinction only, rats received 5 mg/kg of ketamine or saline via IP injections daily before each session. Methamphetamine increased anxiety-like behaviors on the elevated plus maze and open field test compared to rats that self-administered saline when measured 48-hr after self-administration.

Results: Moreover, anxiety-like behaviors remained elevated in the rats that received saline during extinction, but were significantly attenuated in male rats treated with ketamine. Drug-primed reinstatement was tested 6 days after extinction training. Results showed a significant reduction in active lever presses during reinstatement in rats treated with ketamine during extinction compared with vehicle-treated rats. NMDA and AMPA receptor subunits were quantified in brains obtained after the test for reinstatement by Western blot analysis. In the nucleus accumbens, methamphetamine significantly reduced the levels of NR2A, NR2B, GluA1, and GluA2 receptor subunits, and these reductions were partially rescued in the rats treated with ketamine.

Conclusion & Discussion: Together, these findings demonstrate that ketamine reduced anxiety-like behaviors produced by methamphetamine withdrawal, attenuated methamphetamine-seeking behavior, and normalized glutamate receptor levels in male rats.

This work was supported in part by NIH grant P30 DA013429 (EMU) and the Peter F. McManus Charitable Trust (EMU).

References: Aleksandrova et al., 2017
L.R. Aleksandrova, A.G. Phillips, Y.T. Wang
Antidepressant effects of ketamine and the roles of AMPA glutamate receptors and other mechanisms beyond NMDA receptor antagonism
J. Psychiatry Neurosci., 42 (2017), pp. 222-229, 10.1503/jpn.160175

Anna et al., 2024
O. Anna, A. Michael, M. Apostolakis, E. Mammadov, A. Mitka, M.A. Kalatta, M. Koumas, A. Georgiou, A. Chatzittofis, G. Panayiotou, P. Gergiou, C.A. Zarate, P. Zanos
Ketamine and hydroxynorketamine as novel pharmacotherapies for the treatment of Opioid-Use disorders
Biol. Psychiatry (2024), 10.1016/j.biopsych.2024.09.008