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.
Turku PET Centre, University of Turku, Turku, Finland.
Harry
H
Vilkman
Jaana
J
Kajander
Sargo
S
Aalto
Tero
T
Vahlberg
Kjell
K
Någren
Topias
T
Allonen
Erkka
E
Syvälahti
Jarmo
J
Hietala
D000328:Adult; D000704:Analysis of Variance; D001931:Brain Mapping; D002247:Carbon Isotopes / Q000378:metabolism; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000187:drug effects*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004311:Double-Blind Method; D018757:GABA Modulators / Q000097:blood / Q000494:pharmacology*; D006801:Humans; D008140:Lorazepam / Q000097:blood / Q000494:pharmacology*; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods*; D011485:Protein Binding / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism; D050637:Receptors, Dopamine D3; D012457:Salicylamides / Q000494:pharmacology; D013788:Thalamus / Q000000981:diagnostic imaging / Q000187:drug effects*; D013997:Time Factors; D055815:Young Adult
D002247:Carbon Isotopes; D018492:Dopamine Antagonists; D018757:GABA Modulators; D011759:Pyrrolidines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D012457:Salicylamides; C065065:FLB 457; D008140:Lorazepam