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Abstract
Methamphetamine (Meth) is a widely abused stimulant drug, but this abuse is associated with an increased risk of developing psychosis. In addition to its well-known action on brain dopamine, Meth also affects serotonergic (5-HT) neurons. The aim of this study was to investigate this role in mice, which lack one of the main serotonin receptors, the 5-HT1A receptor, which has been implicated in both schizophrenia and Meth-induced psychosis. Male and female wild-type or 5-HT1A knockout (KO) mice received daily treatment with increasing doses of methamphetamine from 6 to 9 weeks of age (1–4 mg/kg/day twice a day). At least 2 weeks after the last injection, the mice underwent a battery of behavioral tests focusing on psychosis-related behaviors, including Meth-induced hyperactivity, prepulse inhibition (PPI), social interaction, elevated plus maze (EPM), and Y-maze. Meth pretreatment resulted in significantly increased hyperlocomotion in response to an acute Meth challenge, but this effect was independent of genotype. Chronic Meth treatment resulted in decreased levels of anxiety in the EPM in both sexes, as well as increased startle responses in female mice only, again independent of genotype. 5-HT1A KO mice showed an increased locomotor response to acute Meth in both sexes, as well as increased PPI and decreased startle responses in female mice only, independent of Meth pretreatment. In conclusion, the effects of chronic Meth appear unaffected by the absence of the 5-HT1A receptor. These results do not support a role of the 5-HT1A receptor in Meth-induced psychosis.
Highlights
Methamphetamine (Meth) use and availability has been increasing worldwide and is placing a huge burden on users, their relatives and friends, and society at large [1]
This study showed that, while both the Meth binge dosing and 5-HT1A receptor KO genotype alter behavior in mice, 5-HT1A KO mice did not respond differently to chronic Meth pretreatment in any of the behaviors tested
Meth pretreatment resulted in a heightened response to acute Meth and decreased levels of anxiety in both sexes, as well as increased startle responses in female mice only, independent of genotype
Summary
Methamphetamine (Meth) use and availability has been increasing worldwide and is placing a huge burden on users, their relatives and friends, and society at large [1]. At least 2 weeks after the chronic treatment ended, the long-lasting effects of chronic Meth on a locomotor hyperactivity model of psychosis, as well as on cognition and other behaviors with relevance to psychiatric symptoms, were studied [6,7,8]. Acute amphetamine- or Meth-induced locomotor hyperactivity is a widely used behavioral test in preclinical schizophrenia research, as it models the increase in dopamine signaling thought to contribute to psychosis [9]. Sensitization of this dopaminergic signaling has been postulated to mimic developmental mechanisms in psychosis [10, 11]. Further studies showed that the chronic dosing protocol altered social novelty behavior but not short-term memory in the Y-maze [8]
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