Effect of clozapine and risperidone on 5-HT2 and D2-dopamine receptor binding in the post-mortem human brain. An autoradiographic study.
Effects of the antipsychotics risperidone and clozapine on 5-HT2 and D2-dopamine receptor binding were examined using [3H]N-methylspiperone ([3H]NMSP) and in vitro receptor autoradiography on human whole hemisphere cryosections. The 5-HT2 receptor antagonist ketanserin and the D2-dopamine receptor antagonist raclopride were used as references. [3H]NMSP binding was observed in caudate nucleus, putamen, and cerebral cortex indicating binding to D2-dopamine and 5-HT2 receptors. Risperidone and clozapine counteracted the binding to both receptor types. This was in contrast to raclopride, which selectively blocked the D2-dopamine receptors in the basal ganglia, and ketanserin, which selectively blocked the 5-HT2 receptors in the cerebral cortex. Risperidone (100 nM and 10 microM) blocked up to 90% of [3H]NMSP binding to both receptor types, whereas the blocking capacity of clozapine (10 microM) was lower (approximately 60%). The lack of total blockade of D2-dopamine receptors is in line with results obtained in with [11C]raclopride and positron emission tomography studies of clozapine treated human subjects. However, autoradiographic studies of clozapine competition of [3H]raclopride binding show total displacement of the binding at high clozapine concentrations, thus contradicting the PET results with [11C]raclopride, as well as the autoradiographic results obtained with [3H]NMSP. In conclusion it can be stated that pharmacological concentrations of the two drugs clozapine and risperidone block a large proportion of D2-dopamine receptors and 5-HT2 receptors in the human brain. Moreover, the study shows the usefulness of human whole hemisphere autoradiography for the study of interaction of drugs with different central neurotransmitter receptors.
Hall
H
H
Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry and Psychology Section, Karolinska Hospital, Stockholm, Sweden.
Halldin
C
C
Nyberg
S
S
Farde
L
L
Sedvall
G
G
D000328:Adult; D014150:Antipsychotic Agents / Q000494:pharmacology; D001344:Autopsy; D001345:Autoradiography; D001665:Binding Sites; D001921:Brain; D003024:Clozapine / Q000494:pharmacology*; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D010880:Piperidines / Q000494:pharmacology*; D017448:Receptors, Dopamine D2 / Q000187:drug effects*; D011985:Receptors, Serotonin / Q000187:drug effects*; D018967:Risperidone
D014150:Antipsychotic Agents; D007555:Isoxazoles; D010880:Piperidines; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin; D003024:Clozapine; D018967:Risperidone