Brainstem 5-hydroxytrytamine1A binding sites are not down-regulated by agonists which induce tolerance in the rat:...

To study the regulation of 5-HT1A receptors in the brainstem, the region most relevant to the serotonin syndrome and to serotonin-responsive human myoclonic disorders, we chronically treated rats with various 5-HT1A agonists and labeled 5-HT1A sites with [3H]8-OH-DPAT. Daily injection for 30 consecutive days of 10 mg/kg ip 8-OH-DPAT (pre- and post-synaptic 5-HT1A agonist) significantly decreased 8-OH-DPAT-evoked flat body posture, forelimb myoclonus, and hypothermia compared to chronic vehicle injection. There was no cross tolerance to 8-OH-DPAT in rats chronically injected with ipsapirone or buspirone (presynaptic 5-HT1A agonists). However, none of the 5HT1A agonists significantly altered Bmax of brainstem 5-HT1A binding sites. Chronic injection with other drugs such as 1-propranolol, (+/-) pindolol and spiperone (5-HT1A and 5-HT2 antagonists), methysergide (5-HT1 and 5-HT2 antagonist), and agonists and antagonists at various other 5-HT receptors also had no effect on binding parameters. These data demonstrate lack of cross-tolerance between pre- and post-synaptically acting 5-HT1A agonists and absence of down-regulation of presynaptic 5-HT1A sites at doses which induced tolerance of 5-HT1A-mediated behaviors of the serotonin syndrome. They suggest changes in the post-synaptic cell rather than the receptor recognition site as the mechanism of tolerance.