Evidence for hyperdensity of 5HT1B binding sites in the substantia nigra of the rat after 5,7-dihydroxytryptamine intraventricular injection.

High affinity serotonin (5HT) binding sites have been found highly concentrated in the substantia nigra (SN) of the rat brain in each classical anatomical subdivisions of this structure, SN reticulata (SNR), SN lateralis (SNL), SN compacta (SNC). In all of the anatomical samples examined along the posteroanterior brain axis (at 200 um intervals), they corresponded to 5HT1B binding sites. The analysis of their distribution performed in rats 15 days after 5,7-DHT intraventricular injection has revealed : (1) the post-synaptic localization of these 5HT1B sites ; (2) the selective increase in their density at the level of SNR. This increase was found heterogeneously distributed inside the SNR and clearly differentiated in external and internal portions of this structure. This hyperdensity in 5HT1B sites in the SNR likely explains the functional hypersensitivity previously demonstrated by local injection of exogenous 5HT into the SN and systemic administration of RU 24969, a preferential 5HT1B agonist.

Evidence for the localization of 5HT1A binding sites on serotonin containing neurons in the raphe dorsalis and raphe centralis nuclei of the rat brain.

Precise anatomical distribution of 5HT1 binding sites has been investigated in the nuclei raphe dorsalis, raphe centralis and locus caeruleus of the rat brain. An original pattern of distribution was observed in the raphe nuclei, closely correlated to the already known distribution of 5HT containing elements. This pattern, more pronounced when 5HT1A sites were labelled, completely disappeared after lesioning by 5, 7DHT indicating the presence of this subtype of 5HT1 binding sites on 5HT containing neurons. It is postulated that these 5HT1A sites correspond in these raphe nuclei to 5HT autoreceptors.

Inhibition of vasopressinergic neurons by central injection of a specific aminopeptidase A inhibitor.

The brain angiotensin (Ang) system plays an important role in the central control of vasopressin release. Using EC33, a selective aminopeptidase A inhibitor which blocks the metabolism of Ang II in Ang III, we previously reported that vasopressin release was under the control of Ang III and not Ang II. To determine accurately the action of EC33, the effects of intracerebroventricular injection of Ang peptides or EC33 on extracellular unit activity of vasopressinergic neurons in the supraoptic nucleus of urethane-anaesthetized rats were examined. Angiotensin II (15-30 ng) or Ang III (15 ng) increased the firing rate of all neurons tested. Conversely, EC33 (10 microg) reduced or completely abolished (30-60 microg) the basal firing rate for 4-6 min in all eight neurons tested. EC33 (30 microg) also inhibited the activity induced by 30 ng Ang II. It was concluded that the observed activity of Ang II required its conversion to Ang III and that endogenous Ang III may exert a tonic control on the basal firing level of vasopressinergic neurons.

Tolerance to the serotonin 5-HT1 agonist RU 24969 and effects on dopaminergic behaviour.

The pharmacological responses to intraperitoneal injection of the serotonin (5-HT) 5-HT1 agonist RU 24969 (0.25-5 mg/kg) were studied in rats either after single administrations or after repeated treatment (5 mg/kg per day for 3 days). The following effects were recorded after a single dose: (A) a strong increase in locomotor activity in intact rats and its potentiation after 5,7-dihydroxytryptamine lesion of 5-HT neurons; (B) at a low dose, a potent enhancement of the circling behaviour induced by the dopamine (DA) D2 agonist LY 171555 in 6-hydroxydopamine-lesioned rats; (C) an early reduction (2 h) of 5-hydroxyindole acetic acid levels in the striatum and the nucleus accumbens followed by a late increase (24 h) in the latter structure. The following modifications were observed 24 h after the repeated treatment with RU 24969: (A) the locomotor effect of the drug was strikingly reduced both in intact and 5,7-dihydroxytryptamine-lesioned animals. On the contrary, the locomotion elicited by the DA releaser d-amphetamine, or the 5-HT1A agonist 8-OH-DPAT, was unchanged; (B) the rotation scores of 6-hydroxydopamine-lesioned rats injected with LY 171555 after a low dose of RU 24969, were greatly reduced. Moreover, the circling response was almost abolished in rats treated with the DA agonist alone; (C) the early reduction of 5-hydroxyindole acetic acid levels was antagonized while the late increase was enhanced. It is concluded that both the state of tolerance and the reversal of the action of RU 24969 that followed repeated treatment might be related to down-regulation of a subtype of the 5-HT1 receptor, possibly the 5-HT1B subtype, that would play a critical role in the expression of DA-mediated behaviour, locomotor activity and 5-HT metabolism.