AUTORADIOGRAPHIC CHARACTERIZATION OF [H-3] IMIPRAMINE AND [H-3] CITALOPRAM BINDING IN RAT AND HUMAN BRAIN - SPECIES-DIFFERENCES AND RELATIONSHIPS TO SEROTONIN INNERVATION PATTERNS

The neuroanatomical distribution of binding sites for [H-3]imipramine and [H-3]citalopram was assessed by in vitro autoradiography in select regions of the rat and human forebrain. To determine involvement of serotonin-containing terminals in the binding of [H-3]imipramine and [H-3]citalopram, binding of these compounds was measured in rats after destroying serotonin-containing neurons with 5,7-dihydroxytryptamine (5,7-DHT). Treatment with this neurotoxin decreased serotonin content by 90% and reduced [H-3]citalopram binding to a similar extent. These results demonstrate that [H-3]citalopram binding is a reliable marker for serotonin-containing terminals. Binding of [H-3]imipramine was reduced by only 15-35% after 5,7-DHT treatment. These latter results suggest that only a small fraction of [H-3]imipramine binding to brain sections is associated with serotonergic terminals under standard conditions used in autoradiographic studies with the ligand. Dose-response effects of fluoxetine and desipramine on displacement of [H-3]imipramine binding in forebrain regions indicate that the ligand labels predominantly high capacity, low affinity binding sites. To determine the utility of the rat brain as a model for [H-3]imipramine and [H-3]citalopram binding in the human brain, binding of the ligands was compared in human and rat hypothalamus, amygdala, and hippocampus. The pharmacological characteristics of [H-3]imipramine and [H-3]citalopram binding were similar in the rat and human brain. However, substantial species differences were observed in topographic pattern of[H-3]imipramine binding within the hippocampus and hypothalamus. The distribution of [H-3]citalopram binding sites within the amygdala and hypothalamus were also strikingly different in rats compared to humans. This work provides the first demonstration that marked species differences exist in the topography of serotonergic innervation and in the distribution of [H-3]imipramine binding sites within the rat and human brain regions examined.