5HT-2 mediation of acute behavioral effects of hallucinogens in rats

Summary

In rats, acute injections of 5HT-2 agonists including mescaline, quipazine, DOI, DOM, and DOET suppressed locomotor and investigatory behavior during the first 30 minutes in a novel environment. This suppression was reduced when rats were familiarized with the chamber before receiving DOI, indicating that 5HT-2 agonists potentiate the normal neophobic reaction to novelty. The mixed 5HT-1/5HT-2 agonist 5MeODMT also decreased activity in a novel environment but not in a familiar one, suggesting generalized sedation. Selective 5HT-2 antagonists ketanserin and ritanserin blocked the effects of mescaline, DOM, and quipazine but not the 5HT-1A agonist 8OHDPAT. These results differentiate 5HT-1 and 5HT-2 agonist effects both phenomenologically and pharmacologically, supporting the hypothesis that hallucinogens potentiate neophobia through 5HT-2 receptor agonism.

Study at a glance

Abstract

In rats tested during their first exposure to a Behavioral Pattern Monitor chamber, acute injections of the 5HT-2 agonists mescaline, quipazine, 2,5-dimethoxy-4-iodoamphetamine (DOI), 2,5-dimethoxy-4-methylamphetamine (DOM), or 2,5-dimethoxy-4-ethylamphetamine (DOET) produced an inhibition of locomotor and investigatory behavior during the first 30 min of the test session. This suppression of exploratory behavior was attenuated when rats were familiarized with the testing chamber prior to the administration of DOI. Hence, as previously observed with both LSD and DOM, 5HT-2 agonists appear to potentiate the normal neophobic reaction to a novel environment. The mixed 5HT-1 and 5HT-2 agonist 5-methoxy-N,N-dimethyltryptamine (5MeODMT) also produced a decrease in activity when animals were tested in the novel environment. However, as previously found with 5HT-1A agonists, this effect was unchanged when animals were tested in the familiar environment and may therefore reflect a generalized sedation. The receptor specificity of these differential effects of 5HT-1 and 5HT-2 agonists in this paradigm was tested by assessing the ability of selective 5HT-2 antagonists to block the effects of the agonists. A dose of the 5HT-2 antagonist ketanserin which had no effect by itself significantly reduced the behavioral effects of mescaline, DOM, and quipazine. Similarly, the selective 5HT-2 antagonist ritanserin blocked the effect of quipazine. In contrast, ketanserin had no significant effect on the suppression of activity produced by the 5HT-1A agonist 8-hydroxy-2(di-n-propylamino)tetralin (8OHDPAT). These results demonstrate that the behavioral effects of 5HT-1 and 5HT-2 agonists can be differentiated both phenomenologically and pharmacologically within a single paradigm. The findings provide further support for the hypothesis that the potentiation of neophobia produced by hallucinogens in rats is attributable to their agonist actions at 5HT-2 receptors.