Neuropharmacology Poster Session
The acute administration of selective serotonin (5-HT) reuptake inhibitors (SSRIs) was shown to decrease 5-HT release through an increase in the extracellular 5-HT levels in the dorsal and medial raphe nuclei, which, in turn, activates the somatodendritic autoreceptors (1). Moreover, recent evidence suggests that the efficiency of the SSRIs to increase extracellular 5-HT levels at 5-HT nerve terminal regions in rat brain may be potentiated with the simultaneous administration of antagonists of 5-HT1A autoreceptors (2).
Preliminary studies showed that combined therapy with (-)-pindolol, a beta-adrenergic/5-HT1A receptor antagonist, and the SSRI paroxetine reduced the latency to antidepressive response and elicited antidepressant response in refractory patients (3). In addition, the sistemic treatment with (-)-pindolol was able to potentiate the increase in 5-HT release induced by SSRIs, such as fluoxetine or paroxetine, in the rat (4).
Presynaptic inhibition of 5-HT release also occurs in projecting regions through terminal 5-HT1B autoreceptors, although the contribution of these receptors to the mechanism of action of (-)-pindolol is not well known. In the present study we have used in vivo microdialysis to examine the effects of (-)-pindolol administered locally in the median raphe region on the paroxetine-dependent inhibitory effect in 5-HT release from the ventral hippocampus of the rat.
Materials and Methods
ANIMALS: Male Sprague-Dawley rats weighting 320±70 g were used. In the day of the experiment, rats were anesthesized under cloral hidrate anesthesia (450 mg/kg, i.p.) and received suplementary dosis of anesthesic (50 mg/kg, i.p.) for each hour.
MICRODIALYSIS AND TREATMENTS: The rats were implanted with microdialysis probes of a membrane length of 3mm and 2mm located, repectively, in the ventral hippocampus and the median raphe nucleus by using a stereotaxic instrument. Artificial cerebrospinal fluid (CSF) containing 3 micromolar paroxetine was perfused through the probe located in the hippocampus at a flow rate of 1 microliter/min. After three hours of stabilization, rats were injected with saline, paroxetine (10 mg/kg, i.p.) or a combined treatment with systemic paroxetine plus (-)-pindolol perfused continuosly through the probe located in the raphe nuclei at doses of 10 and 100 micromolar. The effect of treatments was monitorized for 4 hours following the application and dialysates were collected each 30 min.
MEASURES:The content of 5-HT in the dialysates was measured by HPLC with coulochemical detection.
Systemic paroxetine administration caused a maximum of 56% inhibition of the increase in extracellular 5-HT induced with the local aplication of paroxetine 3 microM (Table 1). When the percentage of total 5-HT released during the experiment was considered, the paroxetine-treated group showed a 43% lower 5-HT than animals treated with saline.
TABLE 1. Mean percentage (with respect to pretreatment levels) of 5-HT released from the hippocampus of the rat treated with paroxetine (10 mg/kg, i.p.) or paroxetine plus (-)-pindolol (10 and 100 micromolar) continuosly perfused in the median raphe. Dialysates were obtained in presence of 3 microM paroxetine perfused through the probe.
Saline Paroxetine Paroxetine Paroxetine +pindolol 10 microM +Pindolol 100 microM ----------------------------------------------------------------------- 108.3±11.7 61.2±5.9 77.7±7.2 91.8±11.4 -----------------------------------------------------------------------
The treatment with (-)-pindolol (10 and 100 micromolar) applied locally in the raphe nucleus reversed dose-dependently the paroxetine-induced inhibition of 5-HT release in ventral hippocampus. In fact, release of 5-HT in the hippocampus of rats receiving paroxetine and pindolol 10 micromolar was a 28% less than that of animals receiving saline; while the group of rats treated with pindolol 100 micromolar showed only a 15% of reduction in the percentage 5-HT release as compared to saline-treated rats.
Discussion and Conclusion
The major finding of the present study is that local administration of (-)-pindolol 10 to 100 micromolar in the median raphe nucleus, reduced dose-dependently the decrease in extracellular 5-HT levels induced by the systemic treatment of paroxetine. These data agree with other works showing that pindolol coadministered by continuos s.c. infusion with an acute dose of SSRIs increased 5-HT levels over those obtained from rats treated with SSRIs alone (4). Similar responses were also reported following treatments that combinated systemic aplication of SSRIs and 5-HT1A antagonists more selective that (-)-pindolol (3, 5).
Since samples were collected in presence of 3 micromolar paroxetine applied continuosly through the probe located in the hippocampus, it seems to be likely that the effect of (-)-pindolol on hippocampal extracellular 5-HT was due to its antagonistic properties on the somatodendritic 5-HT1A receptors, thus restoring neuronal activity and enhancing 5-HT release in the projection areas.
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|Míguez, J.M.; Paz-Valiñas, L.; Aldegunde, M.; (1998). The Ability of (-)-Pindolol to Block the Paroxetine-Induced Decrease in the Release of Serotonin in the Ventral Hippocampus of the Rat.. Presented at INABIS '98 - 5th Internet World Congress on Biomedical Sciences at McMaster University, Canada, Dec 7-16th. Available at URL http://www.mcmaster.ca/inabis98/neuropharm/miguez0725/index.html|
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