Brain Serotonin1A Receptor Binding Measured by Positron Emission Tomography With [11C]WAY-100635

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.

Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Occupancy of Agonist Drugs at the 5-HT1A Receptor

Bantick

Rabiner

Hirani

et al. 2003

“…Immunohistochemical studies reveal the presence of serotonin-1A (Aznar et al, 2003) and serotonin-2A (Jakab and Goldman-Rakic, 2000;Pazos et al, 1987b) receptors on nearly all CB-IR and PV-IR neurons. Moreover, serotonin-1A receptors are preferentially found in layer II of human prefrontal cortex (Burnet et al, 1995;Pazos et al, 1987a;Varnas et al, 2004) and PET studies show a significant reduction in radioligand binding to serotonin-1A receptors in depressed subjects (Bhagwagar et al, 2004a;Sargent et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

GABAergic Neurons Immunoreactive for Calcium Binding Proteins are Reduced in the Prefrontal Cortex in Major Depression

Rajkowska

O'Dwyer

Teleki

et al. 2006

353

228

Post-mortem morphometric studies report reductions in the average density and size of cortical neurons in the dorsolateral prefrontal cortex (dlPFC) and orbitofrontal cortex (ORB) in major depressive disorder (MDD). The contribution of specific neuronal phenotypes to this general pathology in depression is still unclear. Post-mortem sections from the dlPFC and ORB regions of 14 subjects with MDD and 11 controls were immunostained to visualize calbindin-immunoreactive (CB-IR) and parvalbumin-immunoreactive (PV-IR) presumptive GABAergic neurons. A three-dimensional cell counting probe was used to assess the cell packing density and size of CB-IR neurons in layers II + IIIa and PV-IR neurons in layers III-VI. The density of CB-IR neurons was significantly reduced by 50% in depression in the dlPFC and there was a trend toward reduction in the ORB. The size of CB-IR somata was significantly decreased (18%) in depression in the dlPFC with a trend toward reduction in the ORB. In contrast, there was no difference in the density of PV-IR neurons between the depressed and control groups in the dlPFC. The size of PV-IR neuronal soma was unchanged in depressed compared to control subjects in either dlPFC or ORB. In depression, subpopulations of GABAergic neurons may be affected differently in dlPFC and ORB. A significant reduction in the density and size of GABAergic interneurons immunoreactive for calcium binding proteins was found predominantly in the dlPFC region. These cellular changes are consistent with recent neuroimaging studies revealing a reduction in the cortical levels of GABA in depression.

“…Subtle abnormalities in the availability of [ 11 C]WAY-binding sites were reported in clinical PET studies of personality differences (Borg et al, 2003), depression (Drevets et al, 1999;Bhagwagar et al, 2004;Sargent et al, 2000), schizophrenia (Tauscher et al, 2002), juvenile myoclon epilepsia (JME) (Meschaks et al, 2005), bulimia nervosa (Tiihonen et al, 2004), ALS (Turner et al, 2005), and Parkinson's disease (PD) (Doder et al, 2003). Together, these studies show that [ 11 C]WAY binding, as an index of serotonin 5HT 1A receptor availability, is correlated with scores of personality, increased in specific cortical regions of patients with schizophrenia and bulimia nervosa, globally decreased in patients with depression and ALS, and focally decreased in patients with JME and in the raphé nucleus of PD patients.…”

Section: Introductionmentioning

confidence: 95%

Parametric and Regional Maps of Free Serotonin 5HT1A Receptor Sites in Human Brain as Function of Age in Healthy Humans

Møller

Jakobsen

Gjedde

2007

(Gjedde, 2003;Rosa-Neto et al, 2004), which extrapolates measures of specific binding to an estimated steady-state. We compared these estimates in the two age groups with results obtained with the conventional Logan Plot and Simplified Reference Tissue Method (SRTM) applied to both regions of interestbased as parametric analyses. The regional distribution of specific binding of free sites [ 11 C]WAY-100635 was similar to that reported in previous studies, with the highest pBs in limbic structures and the raphé nuclei. Although the results of the three methods differed, pBs in the elderly subjects consistently were lower than those of young subjects. Thus, the correlation between pB and age applied to regionsof-interest revealed significant decline of pB at the rate of 3 or 4% per decade, and a 10% decline of the global mean 5HT 1A receptor-pB in elderly relative to young subjects. The results demonstrate that the number of available 5HT 1A -binding sites declines with age.