Clinical manifestations of methamphetamine use include anxiety, cognitive dysfunction, and exacerbation of pre-existing psychiatric symptoms (McKetin et al., 2016, Paulus and Stewart, 2020). In 2021, approximately 2.5 million people aged 12 and older reported using methamphetamine, with around 1.6 million developing methamphetamine use disorder (MUD) (Key Substance Use and Mental Health Indicators in the United States: Results from the 2021 National Survey on Drug Use and Health, 2021). No pharmacological treatment has proven effective in treating MUD (NIDA. 2021).

The pharmacological action of methamphetamine is characterized by a prolonged rise in synaptic monoamine levels caused by the modulation of pre-synaptic neurotransmission. Methamphetamine-stimulated dopamine release is crucial for its reinforcing and neurobehavioral effects (Kogan et al., 1976, Parsegian and See, 2014, Fleckenstein et al., 2007). Acute or repeated exposure to methamphetamine also dysregulates glutamate transmission. Methamphetamine induces glutamate release and activation of NMDA receptors, while methamphetamine abstinence is associated with reduced basal glutamate in both rodent models and persons with MUD (Shrestha et al., 2022, Mark et al., 2004, Parsegian and See, 2014; Pena-Bravo et al., 2019; Kalivas and Volkow, 2005; Hámor et al., 2023; Nordahl et al., 2003). Reduced glutamate during abstinence is a result of increased excitotoxic glutamate activity during active methamphetamine exposure and the associated neuronal injury (Shrestha et al., 2022, Szumlinski et al., 2017, Smith et al., 2008). A prominent sequel to chronic methamphetamine use is the sudden surge of glutamate that occurs after a period of abstinence in response to re-exposure to methamphetamine or methamphetamine-associated cues (Mark et al., 2004, Parsegian and See, 2014). Maintaining a balance of glutamate is crucial for the processes of neuroplasticity and synaptogenesis (Mattson, 2008). As such, disrupted glutamate during methamphetamine use likely contributes to dysregulated neuroplasticity and associated neurocognitive and behavioral deficits.

Given the impact of methamphetamine on the glutamate system, this study investigated the potential of ketamine to mitigate the adverse behavioral effects of chronic methamphetamine exposure in a rat model of methamphetamine self-administration. Ketamine is a non-competitive antagonist of NMDA receptors. It can act on three distinct NMDA receptor populations: receptors on GABA interneurons, on dopaminergic pre-synaptic neurons, and on neurons post-synaptic to dopamine terminals (Zanos and Gould, 2018). The effects of ketamine are numerous and include disinhibiting glutamate transmission, blocking NMDA receptor currents in GABAergic interneurons, raising extracellular glutamate concentrations in the prefrontal cortex (PFC), and activating AMPA receptors (Moghaddam et al., 1997, Zarate and Manji, 2008, Aleksandrova et al., 2017, Suzuki et al., 2023, Zaytseva et al., 2023). Ketamine administration and its antidepressant-like effects are associated with a higher AMPA/NMDA receptor density ratio in rat hippocampus (Tizabi et al., 2012). Enhanced glutamatergic activity mediated by AMPA receptors may be responsible for increased synaptic potentiation and activation of early neuroplastic genes observed after ketamine (Machado-Vieira et al., 2009). Because of the ability of ketamine to modulate glutamate transmission, the objective of this study was to test the effectiveness of ketamine in reducing methamphetamine-seeking and anxiety-like behaviors produced by methamphetamine withdrawal in a rat model.