The Role of Hypocretin in the Bidirectional Relationship Between Methamphetamine Use and Sleep Dysfunction

Methamphetamine (MA) is a highly addictive, synthetic psychostimulant that, when used, leads to significant health consequences such as pronounced withdrawal symptoms and disruptions to sleep health. Despite these harms, MA continues to be heavily used in the U.S. with nearly 1% of the population reporting use in 2024. Individuals who use MA also exhibit high rates of relapse, driven in part by negative withdrawal effects including sleep dysfunction. No pharmacological treatment is currently approved for MA use or long-term withdrawal sequelae. The neuropeptide hypocretin (HCRT) is upregulated in both sleep deprivation and stimulant use and is thus a target of interest for treatment of stimulant use disorders (StUDs) and withdrawal. The overarching goal of this preclinical research was to examine the bidirectional relationship between sleep dysfunction and MA exposure and vulnerability to sleep disruption-induced drug-seeking behavior, with particular focus on the HCRT system as a therapeutic target across three integrated studies. In Study 1, male and female rats were exposed to chronic MA vapor, and sleep architecture was assessed using electroencephalography (EEG) and electromyography (EMG) telemetry, with behavioral (novel object recognition; NOR) and physiological (body temperature) measures of withdrawal. MA abstinence elicited withdrawal-associated NOR deficits and increased body temperatures, as well as decreased rapid eye movement (REM) sleep time in males and females and non-REM (NREM) sleep quality in males. Dual HCRT-receptor antagonist lemborexant (LEM) restored healthy REM sleep in males and females. In Study 2, a psychological stressor, dirty cage change (DCC), was used to introduce sleep disruption in male rats, and the impact on sleep and stress was assessed through EEG/EMG and plasma corticosterone levels. DCC exposure decreased REM sleep time and increased corticosterone. LEM pre-treatment effectively restored REM sleep loss. In Study 3, MA self-administration abstinent male rats were exposed to repeated clean or DCC; reinstatement of drug-seeking behavior and corticosterone levels were measured to assess relapse-like behavior and stress responses. Both clean and DCC during withdrawal led to increased reinstatement of MA-seeking that was blocked by LEM pre-treatment. Thus, HCRT antagonism shows promise as a treatment for stimulant abuse and associated sleep dysfunction.