Effects of estradiol and progesterone administration on human serotonin 2A receptor binding: a PET study.

BACKGROUND: Preclinical studies demonstrate that 17beta-estradiol (E(2)) increases serotonin-2A receptor (5-HT(2A)R) density in rat frontal cortex. METHODS: We investigated the impact of hormone replacement therapy on 5-HT(2A)R binding potential (BP) using positron emission tomography and [(18)F]altanserin in five postmenopausal women. Subjects were imaged at baseline, following 8 to 14 weeks of transdermal E(2), 0.1 mg/d, and following 2 to 6 weeks of E(2) plus micronized progesterone (P) 100 mg per os twice daily. Regional BPs in the anterior cingulate cortex, dorsolateral prefrontal cortex, and lateral orbitofrontal cortex were calculated by Logan analysis. RESULTS: There was a main effect of time (p = .017) for 5-HT(2A)R BP, which increased 21.2%+/-2.6% following combined E(2) and P administration relative to baseline. This effect was evident in all cerebral cortex regions examined. CONCLUSIONS: 5-HT(2A)R BP increased in widespread areas of the cerebral cortex following combined E(2) + P administration.

Metabolites of haloperidol display preferential activity at sigma receptors compared to dopamine D-2 receptors.

Haloperidol bound with equal affinity to sigma and dopamine D-2 receptors (KI = 2.8 nM). Compared to haloperidol, its carbonyl-reduced metabolite bound to sigma receptors with nearly equal affinity. However, reduced haloperidol bound to dopamine receptors with 85-fold lower affinity compared to haloperidol (KI = 239 nM). The chlorophenyl-hydroxy-piperidine metabolite of haloperidol lacked affinity for dopamine receptors, but bound with moderate affinity to sigma receptors (KI = 326 nM). The carboxylic acid metabolite lacked affinity for either receptor. Like haloperidol, (+)-pentazocine, and 1,3-di-o-tolylguanidine, reduced haloperidol potently inhibited the phosphoinositide response to muscarinic agonists in rat brain synaptoneurosomes, an assay which monitors sigma agonist activity. This metabolite also produced a dystonic alteration of head position in rats when microinjected into the red nucleus. However, unlike observations with haloperidol and other sigma ligands, this effect was associated with pathological changes in the red nucleus. Therefore, it cannot be attributed to sigma receptor interactions with certainty. These findings suggest that administration of haloperidol results initially in effects mediated through both dopamine and sigma receptors, but as metabolism proceeds the sigma actions would be expected to decline at a significantly slower rate than the dopaminergic actions.