Tolerance to neurochemical and behavioral effects of the hallucinogen 25I-NBOMe

RATIONALE: 4-Iodo-2,5-dimethoxy-N-(2-methoxybenzyl)phenethylamine (25I-NBOMe) is a potent serotonin 5-HT(2A/2C) receptor agonist with hallucinogenic activity. There is no data on the 25I-NBOMe effect on brain neurotransmission and animal performance after chronic administration. OBJECTIVES: We examined the effect of a 7-day treatment with 25I-NBOMe (0.3 mg/kg/day) on neurotransmitters’ release and rats’ behavior in comparison to acute dose. METHODS: Changes in dopamine (DA), serotonin (5-HT), acetylcholine (ACh), and glutamate release were studied using microdialysis in freely moving rats. The hallucinogenic activity was measured in the wet dog shake (WDS) test. The animal locomotion was examined in the open field (OF) test, short-term memory in the novel object recognition (NOR) test. The anxiogenic/anxiolytic properties of the drug were tested using the light/dark box (LDB) test. RESULTS: Repeated administration of 25I-NBOMe decreased the response to a challenge dose of DA, 5-HT, and glutamatergic neurons in the frontal cortex as well as weakened the hallucinogenic activity in comparison to acute dose. In contrast, striatal and accumbal DA and 5-HT release and accumbal but not striatal glutamate release in response to the challenge dose of 25I-NBOMe was increased in comparison to acute treatment. The ACh release was increased in all brain regions. Behavioral tests showed a motor activity reduction and memory deficiency in comparison to a single dose and induction of anxiety after the drug’s chronic and acute administration. CONCLUSIONS: Our findings suggest that multiple injections of 25I-NBOMe induce tolerance to hallucinogenic activity and produce alterations in neurotransmission. 25I-NBOMe effect on short-term memory, locomotor function, and anxiety seems to be the result of complex interactions between neurotransmitter pathways. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00213-021-05860-5.