The effects of lorazepam on extrastriatal dopamine D2/3-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 γ-amino-butyric (GABA)–dopamine interactions during benzodiazepine administration. We explored the effects of lorazepam (a single 2.5 mg dose) on cortical and thalamic D2/3 receptor binding using Positron-Emission Tomography (PET) and the high-affinity D2/3-receptor ligand [11C]FLB 457 in 12 healthy male volunteers. We used a randomized, double-blind and placebo-controlled study design. Dopamine D2/D3 receptor binding potential was measured with the reference tissue method in several extrastriatal D2-receptor areas including frontal, parietal, temporal cortices and thalamus. The main subjective effect of lorazepam was sedation. Lorazepam induced a statistically significant decrease of D2/D3 receptor BPND 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 D2/D3 receptor BPND in the DLPFC. In conclusion, lorazepam decreased [11C]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 D2/D3 receptor binding potential (BP) change further supports this hypothesis.