Investigating the Role of Serotonin in Methamphetamine Psychosis: Unaltered Behavioral Effects of Chronic Methamphetamine in 5-HT1A Knockout Mice

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.

GAL3 receptor knockout mice exhibit an alcohol‐preferring phenotype

“…Y‐maze testing was conducted using a gray plexiglass Y‐maze which consisted of three arms measuring 10.5 × 31.5 × 15.5 cm (width × length × height) with each arm set at a 120° angle from the next, as previously described (Jaehne et al . ). Briefly, the Y‐maze was set up in a quiet, isolated room under normal lighting conditions.…”

“…Social interaction testing was adapted from a protocol previously described (Jaehne et al . ). Briefly, the test mouse was placed in the center compartment and allowed to explore all three chambers for 5 minutes.…”

“…Fear memory was measured over 3 consecutive days using fear conditioning chambers from Med Associates Inc. (Fairfax, VT, USA), as previously described (Jaehne et al . ). Briefly, mice were randomly assigned to one of two contexts, which differed by lux, scent, bedding and structure of chamber.…”

“…Protocol was adapted from that previously described (Jaehne et al . ). During each 2‐hour session, mice were placed in the arena, and baseline activity was recorded for 30 minutes.…”

Methamphetamine and the risk of pulmonary arterial hypertension

“…Many of the neuropsychiatric effects methamphetamine exerts are linked to direct alterations in serotonin [5-hydroxytryptamine AKA serotonin (5HT)] signaling activity. Serotonin is a neurotransmitter known for its involvement in the regulation of mood and appetite, but it is also produced by platelets to induce vasoconstriction at sites of vascular injury [33]. The biological effects of serotonin are mediated in two ways: through interaction with surface receptors (5HT 1A and 5HT 1B ) and internalization via the serotonin transporter [serotonin transporter or 5HT transporter (5HTT)].…”