The relation of central 5-HT1A and 5-HT2 receptors: low dose agonist-induced selective tolerance in the rat.

To study the purported relation of 5-HT1A and 5-HT2 receptors, we chronically injected rats with a low dose of selective 5-HT agonists to induce behavioral tolerance and then tested for cross-tolerance. Acutely, in naive rats, both the putative 5-HT2 agonist DOI and 5-HT1A agonist 8-OH-DPAT induced some behaviors of the "serotonin syndrome" but the two drugs could be differentiated. Only DOI evoked shaking behavior, "skin jerks" (spinal myoclonus), and hyperthermia. Only 8-OH-DPAT induced flat body posture, head weaving, hypothermia, and occasional hindlimb hyperextension (dystonic posture). Both drugs, especially 8-OH-DPAT, evoked forepaw tapping. Chronic (21 day) treatment with DOI prevented DOI-evoked behaviors but not behaviors evoked by 8-OH-DPAT. Behaviors evoked by 8-OH-DPAT and not DOI decreased significantly after chronic 8-OH-DPAT treatment. Development of selective tolerance suggests that putative selective 5-HT2 and 5-HT1A agonists exert both shared and distinctive behavioral effects through separate sites whose relation is behavior-specific. For some behaviors (forepaw myoclonus, shaking behavior, thermoregulation), there is a functional interaction between 5-HT1A and 5-HT2 sites, while for other behaviors (skin jerks, flat body posture, head weaving), there is no interaction.