Inhibition Of Serotonergic Neurons Research Articles

Effects of the Serotonin 5-HT1A Receptor Biased Agonists, F13714 and F15599, on Striatal Neurotransmitter Levels Following L-DOPA Administration in Hemi-Parkinsonian Rats.

Peak-dose dyskinesia is associated with the dramatic increase in striatal dopamine levels that follows L-DOPA administration. The 'false neurotransmitter' hypothesis postulates that the latter is likely due to an aberrant processing of L-DOPA by serotonergic neurons. In keeping with this hypothesis, two highly selective 'biased agonists' of 5-HT1A receptors-namely F13714 and F15599 (NLX-101)-were recently shown to exhibit exceptionally potent anti-dyskinetic activity without impairing L-DOPA therapeutic properties despite their differential targeting of 5-HT1A receptor sub-populations. In this study, we investigated whether these two compounds dampened peak L-DOPA-induced dopamine microdialysate levels in the striatum of hemi-parkinsonian rats. Acute administration of either F13714 (0.04 and 0.16mg/kg i.p.) or F15599 (0.16 and 0.64mg/kg, i.p.) blunted L-DOPA (2mg/kg)-induced increases in dopamine microdialysate levels in the denervated striatum (following unilateral injection of 6-OHDA into the medial forebrain bundle). No significant changes were observed on the intact side of the brain. Concurrently, both drugs profoundly reduced striatal serotonin levels on both sides of the brain. In addition, F13714 and F15599, in the presence of L-DOPA, produced a dose-dependent increase in glutamate levels, but this effect was restricted to later time points. These finding support the interpretation that F13714 and F15599 mediate their anti-dyskinetic effects by blunting of the peak in dopamine levels via activation of somatodendritic serotonin 5-HT1A receptors and the consequent inhibition of serotonergic neurons. This study adds to the growing body of evidence supporting the development of a potent 5-HT1A receptor agonist for treatment of peak-dose dyskinesia.

Prostaglandin-mediated inhibition of serotonin signaling controls the affective component of inflammatory pain.

Pain is fundamentally unpleasant and induces a negative affective state. The affective component of pain is mediated by circuits that are distinct from those mediating the sensory-discriminative component. Here, we have investigated the role of prostaglandins in the affective dimension of pain using a rodent pain assay based on conditioned place aversion to formalin injection, an inflammatory noxious stimulus. We found that place aversion induced by inflammatory pain depends on prostaglandin E2 that is synthesized by cyclooxygenase 2 in neural cells. Further, mice lacking the prostaglandin E2 receptor EP3 selectively on serotonergic cells or selectively in the area of the dorsal raphe nucleus failed to form an aversion to formalin-induced pain, as did mice lacking the serotonin transporter. Chemogenetic manipulations revealed that EP3 receptor activation elicited conditioned place aversion to pain via inhibition of serotonergic neurons. In contrast to their role in inflammatory pain aversion, EP3 receptors on serotonergic cells were dispensable for acute nociceptive behaviors and for aversion induced by thermal pain or a κ opioid receptor agonist. Collectively, our findings show that prostaglandin-mediated modulation of serotonergic transmission controls the affective component of inflammatory pain.

Elevated plasma paroxetine concentrations in a patient treated with a combination of paroxetine and pindolol

Paroxetine and pindolol have been used in combination to augment the antidepressant response of SSEIs. The rationale given involves the prevention of a negative feedback inhibition of serotonergic neurons but few studies have addressed potential pharmacokinetic interactions. This paper reports on elevated plasma paroxetine concentrations in a 37-year-old depressed woman following the introduction of pindolol. This case study supports the possibility of competitive drug-drug interactions in combinations of paroxetine and pindolol.