The effects of lorazepam on extrastriatal dopamine D(2/3)-receptors-A double-blind randomized placebo-controlled PET study.

Lorazepam is a widely used anxiolytic drug of the benzodiazepine class. The clinical actions of benzodiazepines are thought to be mediated via specific allosteric benzodiazepine binding sites and enhancement of GABAergic neurotransmission in the brain. However, the indirect effects of benzodiazepines on other neurotransmitter systems have not been extensively studied. Previous experimental evidence suggests that benzodiazepines inhibit striatal dopamine release by enhancing the GABAergic inhibitory effect on dopamine neurons whereas very little is known about cortical or thalamic gamma-amino-butyric (GABA)-dopamine interactions during benzodiazepine administration. We explored the effects of lorazepam (a single 2.5 mg dose) on cortical and thalamic D(2/3) receptor binding using Positron-Emission Tomography (PET) and the high-affinity D(2/3)-receptor ligand [(11)C]FLB 457 in 12 healthy male volunteers. We used a randomized, double-blind and placebo-controlled study design. Dopamine D(2)/D(3) receptor binding potential was measured with the reference tissue method in several extrastriatal D(2)-receptor areas including frontal, parietal, temporal cortices and thalamus. The main subjective effect of lorazepam was sedation. Lorazepam induced a statistically significant decrease of D(2)/D(3) receptor BP(ND) in medial temporal and dorsolateral prefrontal cortex (DLPFC) that was also confirmed by a voxel-level analysis. The sedative effect of lorazepam was associated with a decrease in D(2)/D(3) receptor BP(ND) in the DLPFC. In conclusion, lorazepam decreased [(11)C]FLB 457 binding in frontal and temporal cortex, suggesting that cortical GABA-dopamine interaction may be involved in the central actions of lorazepam in healthy volunteers. The correlation between lorazepam-induced sedation and D(2)/D(3) receptor binding potential (BP) change further supports this hypothesis.

Measurement of serotonin 5-HT1A receptor binding using positron emission tomography and [carbonyl-(11)C]WAY-100635-considerations on the validity of cerebellum as a reference region.

[Carbonyl-(11)C]WAY-100635 has been used extensively in positron emission tomography (PET) imaging of serotonin 1A receptors (5-HT1A) in vivo in the human brain. Specific binding to receptors is usually estimated using compartmental modeling with arterial plasma input function. The use of reference tissue input (cerebellum) enables quantification without the need of arterial blood sampling, but the accuracy of this method is highly dependent on the validity of the reference region in terms of both specific and nonspecific binding. In this paper, we report exceptionally high uptake of [carbonyl-(11)C]WAY-100635 in the gray matter of cerebellum in one healthy male subject, which was reproducible in repeated PET scanning and most likely represents specific binding to 5-HT1A receptors in cerebellar gray matter. Serotonin 1A receptors are transiently expressed in the human cerebellum during early childhood and usually level off until adolescence but may persist in some individuals. As a methodological implication, the results of this study with regard to test-retest characteristics of [carbonyl-(11)C]WAY-100635 measurements in healthy volunteers using both arterial plasma and reference tissue input functions support the use of cerebellar white matter as reference region, to avoid the potential bias originating from binding of [carbonyl-(11)C]WAY-100635 to 5-HT1A receptors in cerebellar gray matter.

Brain serotonin 1A receptor binding in bulimia nervosa.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are the first choice for the pharmacologic treatment of bulimia nervosa, but there are no published data on the putative altered serotonin (5-HT) receptor characteristics in patients with bulimia. Experimental studies suggest that the therapeutic antidepressant effect of SSRIs is mediated via 5-HT(1A) receptors. The aim of this study was to measure brain 5-HT(1A) receptor binding among nonmedicated patients with bulimia nervosa. METHODS: Positron emission tomography (PET) with a selective 5-HT(1A) ligand, [11C]WAY-100635, was performed on eight unmedicated patients with bulimia and 10 healthy comparison subjects. RESULTS: The binding potential values were greater in patients than in control subjects in all brain regions studied. The most robust differences were observed in the angular gyrus, the medial prefrontal cortex, and the posterior cingulate cortex. CONCLUSIONS: These results suggest that brain 5-HT(1A) receptor binding is increased in several cortical areas in patients with bulimia nervosa during their state of impulsive binge eating.