Tolerance and Cross-Tolerance among Psychedelic and Nonpsychedelic 5-HT_2A Receptor Agonists in Mice

Abstract

Classical psychedelics represent a subgroup of serotonergic psychoactive substances characterized by their distinct subjective effects on the human psyche. Another unique attribute of this drug class is that such effects become less apparent after repeated exposure within a short time span. The classification of psychedelics as a subgroup within the serotonergic drug family and the tolerance to their effects are replicated by the murine head twitch response (HTR) behavioral paradigm. Here, we aimed to assess tolerance and cross-tolerance to HTR elicited by psychedelic and nonpsychedelic serotonin 2A receptor (5-HT 2A R) agonists in mice. We show that repeated (4 days) administration of the psychedelic 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) induced a progressive decrease in HTR behavior. Tolerance to DOI-induced HTR was also observed 24 h after a single administration of this psychedelic. Pretreatment with the 5-HT 2A R antagonist M100907 reduced not only the acute manifestation of DOI-induced HTR, but also the development of tolerance to HTR. Additionally, cross-tolerance became apparent between the psychedelics DOI and lysergic acid diethylamide (LSD), whereas repeated administration of the nonpsychedelic 5-HT 2A R agonist lisuride did not affect the ability of these two psychedelics to induce HTR. At the molecular level, DOI administration led to down-regulation of 5-HT 2A R density in mouse frontal cortex membrane preparations. However, development of tolerance to the effect of DOI on HTR remained unchanged in β-arrestin-2 knockout mice. Together, these data suggest that tolerance to HTR induced by psychedelics involves activation of the 5-HT 2A R, is not observable upon repeated administration of nonpsychedelic 5-HT 2A R agonists, and occurs via a signaling mechanism independent of β-arrestin-2.

Psychedelic-Induced Serotonin 2A Receptor Downregulation Does Not Predict Swim Stress Coping in Mice

“…These differences in downstream effects and recycling kinetics could be associated with variations in 5-HT 2A phosphorylation induced by non-psychedelic and psychedelic ligands [ 16 ]. Our results support the notion that DOI elicits the downregulation of 5-HT 2A receptors in the cortex for at least 24 h. Previous studies similarly found that the single and repeated administration of DOI resulted in functional desensitization and reduced 5-HT 2A receptor binding in rodents [ 31 , 32 ]. However, functional 5-HT 2A receptor desensitization does not necessarily correspond to decreased total 5-HT 2A protein levels but may reflect redistribution from the plasma membrane to the cytosol [ 31 ].…”

“…Importantly, the genetic ablation of 5-HT 2A receptors in mice does not induce an antidepressant-like response per se [ 99 ], but interferes with the antidepressant-like responses to SSRI [ 100 ]. DOI-induced desensitization and the internalization of 5-HT 2A receptors have been observed previously [ 16 , 32 , 101 ], and 5-HT 2A receptors present a cross-tolerance effect to psychedelics, related to the downregulation of these receptors independent of β-arrestin 2, a protein typically involved in the trafficking of 5-HT 2A receptors after its interaction with non-psychedelic agonists [ 16 , 32 ]. Interestingly, while non-psychedelic 5-HT 2A agonists (such as 5-HT) or inverse agonists (such as clozapine) were shown to elicit rapid internalization with recycling in approximately 2.5 h, the psychedelic agonist DOI induced slow internalization with recycling in approximately 7.5 h [ 101 ].…”

“…Mice received a single administration of DOI on day 6. The forced swim test was performed on day 7 to exclude the possible locomotor effects of the compound and to ensure sufficient time for 5-HT 2A receptor downregulation [ 32 ]. Prior exposure to swim stress significantly reduced the latency to immobility during the forced swim test as mice readily adopted a passive stress-coping strategy.…”

“…Interestingly, while non-psychedelic 5-HT 2A agonists (such as 5-HT) or inverse agonists (such as clozapine) were shown to elicit rapid internalization with recycling in approximately 2.5 h, the psychedelic agonist DOI induced slow internalization with recycling in approximately 7.5 h [ 101 ]. In addition, repeated administration with a non-psychedelic agonist of the 5-HT 2A receptor does not have an effect on the efficacy of LSD or DOI to induce a behavioral response [ 32 ]. These differences in downstream effects and recycling kinetics could be associated with variations in 5-HT 2A phosphorylation induced by non-psychedelic and psychedelic ligands [ 16 ].…”

“…Serotoninergic psychedelics induce 5-HT 2A receptor internalization from the plasma membrane to the cytoplasm [ 30 , 31 , 32 ]. Paradoxically, atypical antipsychotics that act as 5-HT 2A receptor antagonists also elicit 5-HT 2A receptor internalization [ 33 , 34 ].…”