Drug action at the 5-HT1A receptor in vivo: autoreceptor and postsynaptic receptor occupancy examined with PET and [carbonyl-11C]WAY-100635

3,4-Methylenedioxymethamphetamine (MDMA) or 'ecstasy' has been associated with memory deficits during abstinence and intoxication. The human neuropharmacology of MDMA-induced memory impairment is unknown. This study investigated the role of 5-HT 2A and 5-HT 1A receptors in MDMA-induced memory impairment. Ketanserin is a 5-HT 2A receptor blocker and pindolol a 5-HT 1A receptor blocker. It was hypothesized that pretreatment with ketanserin and pindolol would protect against MDMA-induced memory impairment. Subjects (N ¼ 17) participated in a double-blind, placebo-controlled, within-subject design involving six experimental conditions consisting of pretreatment (T1) and treatment (T2). T1 preceded T2 by 30 min. T1-T2 combinations were: placebo-placebo, pindolol 20 mg-placebo, ketanserin 50 mg-placebo, placebo-MDMA 75 mg, pindolol 20 mg-MDMA 75 mg, and ketanserin 50 mg-MDMA 75 mg. Memory function was assessed at Tmax of MDMA by means of a word-learning task (WLT), a spatial memory task and a prospective memory task. MDMA significantly impaired performance in all memory tasks. Pretreatment with a 5-HT 2A receptor blocker selectively interacted with subsequent MDMA treatment and prevented MDMA-induced impairment in the WLT, but not in the spatial and prospective memory task. Pretreatment with a 5-HT 1A blocker did not affect MDMA-induced memory impairment in any of the tasks. Together, the results demonstrate that MDMA-induced impairment of verbal memory as measured in the WLT is mediated by 5-HT 2A receptor stimulation.

Section: Discussionmentioning

confidence: 99%

Section: Treatments and Proceduresmentioning

confidence: 99%

Blockade of 5-HT2 Receptor Selectively Prevents MDMA-Induced Verbal Memory Impairment

Wel

Kuypers

Theunissen

et al. 2011

“…Additionally, PET neuroreceptor studies may aid in the design and refinement of therapies targeted at reducing the interval between initiating therapy and clinical response. Although clinical trials incorporating strategies of autoreceptor blockade have yielded disappointing results to date (Berman et al, 1997), recent studies suggest that the doses and agents used in these trials were suboptimal (Martinez et al, 2000;Rabiner et al, 2000Rabiner et al, , 2001.…”

Section: Discussionmentioning

confidence: 99%

Serotonin 1A Receptor Binding and Treatment Response in Late-Life Depression

Meltzer

Price

Mathis

et al. 2004

166

117

Depression in late life carries an increased risk of dementia and brittle response to treatment. There is growing evidence to support a key role of the serotonin type 1A (5-HT 1A ) receptor as a regulator of treatment response, particularly the 5-HT 1A autoreceptor in the dorsal raphe nucleus (DRN). We used [ 11 C]WAY 100635 and positron emission tomography (PET) to test our hypothesis that 5-HT 1A receptor binding in the DRN and prefrontal cortex is altered in elderly depressives and that these measures relate to treatment responsivity. We studied 17 elderly subjects with untreated (nonpsychotic, nonbipolar) major depression (four men, 13 women; mean age: 71.475.9) and 17 healthy control subjects (eight men, nine women; mean age: 70.076.7). Patients were subsequently treated with paroxetine as part of a clinical trial of maintenance therapies in geriatric depression.

“…In the case of ziprasidone, the radioligands used to determine the in vitro affinities are documented (Seeger et al, 1995 (Nakayama et al, 2002). Similarly, in two small studies, buspirone did not display an occupancy effect at either a 10 mg dose using the radiotracer [ 18 F]MPPF or a 20 mg dose using [ 11 C]WAY-100635 (Rabiner et al, 2000b). Finally, a between-subject [ 11 C]WAY-100635 PET study in patients with schizophrenia did not demonstrate occupancy of clozapine, an antipsychotic drug with 5-HT 1A receptor partial agonist properties, at the 5-HT 1A receptor (Bantick et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Occupancy of Agonist Drugs at the 5-HT1A Receptor

Bantick

Rabiner

Hirani

et al. 2003

Self Cite

Drugs acting on the 5-HT 1A receptor are used in the treatment of depression, generalized anxiety disorder, and schizophrenia. This study investigated 5-HT 1A receptor occupancy by the 5-HT 1A agonist drugs flesinoxan (a highly selective probe for the 5-HT 1A receptor) and ziprasidone (a novel atypical antipsychotic drug). Using a within-subject design, 14 healthy volunteers each received two positron emission tomography scans using the selective 5-HT 1A antagonist radiotracer [ 11 C]WAY-100635. One scan constituted a baseline, while the other followed either 1 mg flesinoxan or 40 mg ziprasidone orally. In addition, rats were pretreated with intravenous flesinoxan at doses ranging from 0.001 to 5 mg/kg then [ 11 C]WAY-100635 binding measured ex vivo. Cerebral cortical and hippocampal regions of interest, and cerebellar reference regions were sampled to estimate 5-HT 1A receptor occupancy (inferred from reductions in specific radioligand binding). In man, occupancy was not significant despite volunteers experiencing side effects consistent with central serotonergic activity. The mean cerebral cortex occupancy (71 SD) for flesinoxan was 8.7% (713%), and for ziprasidone 4.6% (717%). However, in rats, flesinoxan achieved significant and dose-related occupancy (17-57%) at 0.25 mg/kg and above. We conclude that 5-HT 1A receptor agonists produce detectable occupancy only at higher doses that would produce unacceptable levels of side effects in man, although lower doses are sufficient to produce pharmacological effects. The development of agonist radiotracers may increase the sensitivity of detecting agonist binding, as 5-HT 1A antagonists bind equally to low-and high-affinity receptor states, while agonists bind preferentially to the high-affinity state.