Tolerance and Cross-Tolerance among Psychedelic and Nonpsychedelic 5-HT2A Receptor Agonists in Mice.

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-HT2AR) 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-HT2AR 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-HT2AR 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-HT2AR density in mouse frontal cortex membrane preparations. However, development of tolerance to the effect of DOI on HTR remained unchanged in ß-arrestin-2 knockout mice. Together, these data suggest that tolerance to HTR induced by psychedelics involves activation of the 5-HT2AR, is not observable upon repeated administration of nonpsychedelic 5-HT2AR agonists, and occurs via a signaling mechanism independent of ß-arrestin-2.

Do ring-necked snakes choose retreat sites based upon thermal preferences?

Biochemical reaction rates are highly sensitive to temperature, and the body temperatures of ectotherms covary with their immediate environment. Therefore, ectotherms should choose microhabitats that permit the maintenance of physiological function. While some previous studies have found that squamate reptiles choose retreat sites that allow them to maintain physiologically optimal body temperatures, this research has been limited in context and taxonomic scope. We sought to test these empirical patterns by studying the properties of retreat sites in the context of physiological preferences and tolerances in a population of semifossorial ring-necked snakes (Diadophis punctatus). We measured environmental temperature distributions of retreat sites, field body temperatures, thermal preferences, and both upper voluntary temperature and critical thermal minima of snakes. We found that ring-necked snakes are under larger and warmer rocks, but that body temperatures in the field do not match thermal preferences measured in the laboratory. Specifically, we found aggregated ring-necked snakes (those occurring with multiple conspecifics) select rocks providing environmental temperatures averaging 3°C higher than their preferred temperature. By contrast, solitary snakes select rocks that allowed them to maintain their body temperatures very close to their preferred temperatures. These results imply that there is substantial within and among-species variation in the role of thermal considerations in retreat-site selection. Our work also highlights the complex tradeoffs between physiological and ecological requirements that organisms must navigate in heterogeneous habitats.