Fuxe K, Ogren SO, Agnati LF, Jonssen G, Gustafsson JA.
“5,7-Dihydroxytryptamine as a Tool to Study the Functional Role of Central 5-Hydroxytryptamine Neurons”.
The use of 5,7-dihydroxytryptamine (5,7-DHT) as a tool to study the functional role of central 5-HT neurons is reported. The ascending 5-HT pathways to the telencephalon and diencephalon in Sprague-Dawley (300-350 g) rats were lesioned by stereotaxic injections of 5,7-DHT into the dorsomedial tegnentum of the midbrain, resulting in damage to the ascending 5-HT axons. This lesion produced a narked deficit in the forced extinction of a one-day active avoidance response 5 days after the operation. 10 Days after the operation, the deficit was no longer observed. Measuremeats of doparrine (DA), noradrenaline (NA) and 5-HT levels in the cerebral cortex, including the hippocanpal formation, and in the rest of the brain in front of the 5,7-DHTinduced lesion, indicated that this behavioral deficit noted 5 days after the operation was related to a degeneration of 5-HT nerve terminals in the telencephalon and diencephalon. By pretreatment with the 5-HT uptake-blocking agent, zimelidine (20 mg/kg), 1 hr earlier, it was possible to partially protect the ascending 5-HT axons from the neurotoxic action of 5,7-DHT. This protection became significant in 5-HT axons projecting into subcortical regions. In behavioral experiments, zimelidine blocked the behavioral deficit produced by 5,7-DHT. Results indicate that ascending 5-HT pathways are involved in the control of forced extinction of a one-way active avoidance response. In order to understand the mechanism responsible for the behavioral deficit seen and its recovery after Z wk. specific (3HN-5-HT- and (H)-dLSD-binding sites vere analyzed Z,7, and 14 days after 5,7-DHTlesioning in the cerebral cortex. 2 Days after lesioning, there was a marked reduction in the number of 5-HT-binding sites; 2 wk after operation, they had partly recovered, and an increase in the affinity of the 5-HT-binding sites was noted. A conformational change towards positive cooperativity occurred within the few binding sites that rerrain Z days after lesioning. Changes in dLSD-binding sites were also noted after 5-HT denervation of the cerebral cortex. 14 Days after lesioning, there was a doubling of d-LSD-binding sites; 2 days after operation, results obtained suggested a plasticity change within d-LSD- and 5-HTbinding sites. Hence, the saturation curve changes from the Langmuir type into a sigmoid type, suggesting a change towards positive cooperative interactions within the binding sites for dLSD and 5-HT, respectively. The effects of 5,7-HDT and p-chloroamphetamine on the 5-HT system were compared by fluorescence histochemical analysis.