Somatodendritic action of pindolol to attenuate the paroxetine-induced decrease in serotonin release from the rat ventral hippocampus: a microdialysis study

Abstract

We used intracerebral microdialysis to study the role of raphe and presynaptic serotonin (5-HT) autoreceptors in the effect of the selective 5-HT reuptake inhibitor, paroxetine, on 5-HT release from ventral hippocampus of anaesthetised rats. In addition, we have tested the ability of pindolol, a non-selective beta-adrenergic/5-HT(1A) receptor antagonist, to alter the response of hippocampal 5-HT to paroxetine. Doses of paroxetine with maximal effects were near to three-fold less effective when administered systemically than after local infusion at increasing extracellular 5-HT in ventral hippocampus. Moreover, systemic paroxetine treatment resulted in a marked decrease of the extracellular 5-HT in the hippocampus when 5-HT reuptake was blocked with paroxetine 3 microM applied locally, thereby evidencing that systemic treatment induced a decrease of 5-HT release in the neuronal terminal. A similar drop was observed when paroxetine 3 microM was perfused into the median raphe, a region that contains the cell bodies of the neurons innervating the ventral hippocampus. Racemic (+/-)-pindolol (10 mg/kg, s.c.) completely blocked the paroxetine-induced decrease in 5-HT release from rat hippocampus. In addition, the infusion into median raphe of (-)-pindolol, the isoform with highest antagonist activity, at concentrations of 10 microM and 100 microM was able to partially block the decrease of hippocampal 5-HT release after systemic paroxetine. However, perfusion of (-)-pindolol into the hippocampus was without effect on local 5-HT release. These data suggest that pindolol acts preferentially through the blockade of somatodendritic 5-HT(1A) autoreceptors to restore the decline in 5-HT outflow in rat forebrain following systemic administration of selective 5-HT reuptake inhibitors.

Blockade of 5-HT1A Receptors by (±)-Pindolol Potentiates Cortical 5-HT Outflow, but not Antidepressant-Like Activity of Paroxetine: Microdialysis and Behavioral Approaches in 5-HT1A Receptor Knockout Mice

“…Our results show that intra-raphe perfusion of either (7)-pindolol or WAY-100635 had no effects on cortical and DRN dialysate 5-HT levels, when given alone, but potentiated paroxetine's effects on extracellular 5-HT levels in the two brain regions studied. In rats, similar results were found in the ventral hippocampus following the local perfusion of (7)-pindolol in the median raphe nucleus (Miguez et al, 2002).…”

“…Numerous electrophysiological studies performed either in vivo in anesthetized animals or in vitro on brain slices suggested that (7)-pindolol behaves as a 5-HT 1A receptor antagonist by blocking the SSRI-induced inhibition of 5-HT cell firing Corradetti et al, 1998;Rasmussen et al, 2004), while others showed that it has either no effects or an agonistic effect on 5-HT 1A receptors (Fornal et al, 1999;Sprouse et al, 2000). Results of intracerebral in vivo microdialysis studies brought up less discrepancies: almost all studies demonstrated that pindolol can potentiate the effects of SSRI on dialysate 5-HT levels in brain regions enriched in serotonergic nerve terminals (Dreshfield et al, 1996;Hjorth, 1996;Romero et al, 1996;Gobert and Millan, 1999;Dawson and Nguyen, 2000;Cremers et al, 2001;Miguez et al, 2002).…”

Influence of chronic amphetamine treatment and acute withdrawal on serotonin synthesis and clearance mechanisms in the rat ventral hippocampus

“…Rats undergoing 24 h withdrawal from chronic amphetamine treatment exhibited decreased stimulated (KCl‐induced) increases of extracellular 5‐HT in the ventral hippocampus. This effect could not be explained by reduced TpH activity in either the ventral hippocampus or in the mRN, which contains serotonergic cell bodies that project to the ventral hippocampus (Azmitia & Segal, ; Miguez et al ., ). Reduced KCl‐induced ventral hippocampus 5‐HT was also not explained by an apparent change in SERT protein expression or functional expression (as measured by SERT blockade) following chronic amphetamine pre‐treatment and 24 h withdrawal.…”

“…Experiments were initiated following the collection of at least three stable baseline samples of 5‐HT. To assess the effects of acute amphetamine withdrawal on extracellular concentrations of 5‐HT in the ventral hippocampus following blockade of SERT‐mediated 5‐HT, paroxetine [0.1 μ m , n = 5/treatment group; 0.5 μ m , n = 6/treatment group; or 3 μ m , n = 5/treatment group (Miguez et al ., )] was perfused into the ventral hippocampus via the microdialysis probe for 20 min. Paroxetine has a higher affinity for SERT than other selective 5‐HT reuptake inhibitors (Hirano et al ., ).…”

“…The inhibition of AADC prevents 5-HTP conversion to 5-HT, and the accumulation of 5-HTP over a fixed time period serves as a measure of in vivo TpH activity (Johnston & Moore, 1983). The median raphe nucleus (mRN) was also examined, as functional and anatomical evidence suggests that the majority of 5-HT innervation of the ventral hippocampus is from the mRN (Azmitia & Segal, 1978;Miguez et al, 2002).…”