Effect of single doses of pindolol and d-fenfluramine on flumazenil-induced anxiety in panic disorder patients

• Published in: Behavioural brain research 2019-01, Vol.357-358, p.82-87
• Main Authors: Bernik, M., Ramos, R.T., Hetem, L.A.B., Graeff, F.
• Format: Article
• Language: English
• Subjects: D-fenfluramine; Flumazenil; Panic disorder; Pindolol; Serotonin
• ISSN: 0166-4328; 1872-7549
• DOI: 10.1016/j.bbr.2017.11.002

Identity lines showing pre and post flumazenil infusion EPSS scale scores. [Display omitted] •Deakin and Graeff [5] model on the dual role of serotonin in the brain defense systems proposes that acute increases of serotonergic output from the dorsal raphe nucleus would increase anxiety through its projections on the amygdala while decreasing fear/panic propensity by the inhibition of the dorsal periaqueductal grey matter in the midbrain.•Strategies to acutely increase the bioavailability of extracellular serotonin in the CNS include the use of pindolol or d-fenfluramine. Pindolol is a beta-adrenoceptor ligand with high-affinity for native human presynaptic (somatodendritic) serotonin 1A receptors. Antagonist actions on these receptors by the association of pindolol and SSRIs have been shown to increase 2–3 fold extracellular serotonin concentration compared to the SSRI alone.•D-fenfluramine was a drug widely used for appetite suppression until its withdrawn from the market. D-fenfluramine increases in the release of serotonin from nerve terminals while inhibiting its reuptake by the pre-synaptic neuron. These complementary actions result in major increases in extracellular levels of 5-HT, particularly in structures receiving the dorsal raphe nucleus projections.•Flumazenil is a benzodiazepine receptor antagonist with anxiogenic properties in panic disorder. The panicogenic effect of flumazenil has been associated to a state of chronically decreased GABAergic functioning, postulated as one major pathophysiologic mechanism in PD.•Against our predictions, neither pindolol nor d-fenfluramine pre-treatment decreased the rate of flumazenil-induced panic. On the contrary, d-fenfluramine to increased (nonsignificantly) the rate of panic attacks. This study suggests that flumazenil induced anxiety reaction is not a good pharmacological model of panic attacks, considering the absence of serotonergic modulation of its effects. The effects of the 5-HT1A receptor blocker pindolol and the 5-HT releasing and uptake blocking agent d-fenfluramine, both used as indirect serotonin agonists, on flumazenil-induced acute anxiety reactions were studied in panic disorder patients to test the hypothesis that serotonin (5-HT) inhibits neural systems mediating panic attacks. Thirty never treated or drug free PD patients (16 females) aged 22–49 y (mean ± SD, 32.9 ± 8) received single doses of d-fenfluramine (n = 10; 30 mg, p.o.), pindolol (n = 10; 5 mg, p.o.), or placebo (n = 10) 90