Genetic Deletion of Neuronal PPARγ Enhances the Emotional Response to Acute Stress and Exacerbates Anxiety: An Effect Reversed by Rescue of Amygdala PPARγ Function

Domi, Esi; Uhrig, Stefanie; Soverchia, Laura; Spanagel, Rainer; Hansson, Anita C.; Barbier, Estelle; Heilig, Markus; Ciccocioppo, Roberto; Ubaldi, Massimo

doi:10.1523/jneurosci.4127-15.2016

Cited by 50 publications

(67 citation statements)

References 55 publications

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“…Additionally, repeated stress decreased PPARγ expression in the amygdala, and treatment with buspirone or minocycline, two drugs having anxiolytic effects, recovered PPARγ expression in the same region [49]. Furthermore, PPARγ blockade or knockout was shown to have anxiogenic effects in mice [12]. These studies, together with our data herein, suggest an anti-aversive/anxiolytic effect of PPARγ signalling.…”

Section: Discussionsupporting

confidence: 73%

Pharmacological Blockade of PPAR Isoforms Increases Conditioned Fear Responding in the Presence of Nociceptive Tone

et al. 2020

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Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors with three isoforms (PPARα, PPARβ/δ, PPARγ) and can regulate pain, anxiety, and cognition. However, their role in conditioned fear and pain-fear interactions has not yet been investigated. Here, we investigated the effects of systemically administered PPAR antagonists on formalin-evoked nociceptive behaviour, fear-conditioned analgesia (FCA), and conditioned fear in the presence of nociceptive tone in rats. Twenty-three and a half hours following fear conditioning to context, male Sprague-Dawley rats received an intraplantar injection of formalin and intraperitoneal administration of vehicle, PPARα (GW6471), PPARβ/δ (GSK0660) or PPARγ (GW9662) antagonists, and 30 min later were re-exposed to the conditioning arena for 15 min. The PPAR antagonists did not alter nociceptive behaviour or fear-conditioned analgesia. The PPARα and PPARβ/δ antagonists prolonged context-induced freezing in the presence of nociceptive tone without affecting its initial expression. The PPARγ antagonist potentiated freezing over the entire trial. In conclusion, pharmacological blockade of PPARα and PPARβ/δ in the presence of formalin-evoked nociceptive tone, impaired short-term, within-trial fear-extinction in rats without affecting pain response, while blockade of PPARγ potentiated conditioned fear responding. These results suggest that endogenous signalling through these three PPAR isoforms may reduce the expression of conditioned fear in the presence of nociceptive tone.

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Section: Discussionsupporting

confidence: 73%

Pharmacological Blockade of PPAR Isoforms Increases Conditioned Fear Responding in the Presence of Nociceptive Tone

et al. 2020

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“…Others have documented elevated thalamic glutamine levels in patients with SAD (Pollack et al, 2008). Furthermore, preclinical rodent studies have established a strong link between glutamate regulation and anxiety (Domi et al, 2016;Donahue et al, 2014;Johnson et al, 2005;McGowan et al, 2017;Walker and Davis, 2002).…”

Section: Introductionmentioning

confidence: 99%

Ketamine for Social Anxiety Disorder: A Randomized, Placebo-Controlled Crossover Trial

Taylor

Landeros-Weisenberger

Coughlin

et al. 2017

Neuropsychopharmacol.

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Many patients with social anxiety disorder (SAD) experience inadequate symptom relief from available treatments. Ketamine is a potent N-methyl-D-aspartate receptor antagonist with a potentially novel mechanism of action for the treatment of anxiety disorders. Therefore, we conducted a double-blind, randomized, placebo-controlled crossover trial in 18 adults with DSM-5 SAD and compared the effects between intravenous ketamine (0.5 mg/kg over 40 min) and placebo (normal saline) on social phobia symptoms. Ketamine and placebo infusions were administered in a random order with a 28-day washout period between infusions. Ratings of anxiety were assessed 3-h post-infusion and followed for 14 days. We used linear mixed models to assess the impact of ketamine and placebo on anxiety symptoms. Outcomes were blinded ratings on the Liebowitz Social Anxiety Scale (LSAS) and self-reported anxiety on a visual analog scale (VAS-Anxiety). We also used the Wilcoxon signed-rank test to compare the proportion of treatment responders. Based on prior studies, we defined response as a greater than 35% LSAS reduction and 50% VAS-Anxiety reduction. We found ketamine resulted in a significantly greater reduction in anxiety relative to placebo on the LSAS (Time × Treatment: F=2.6, p=0.01) but not the VAS-Anxiety (Time × Treatment: F=0.4, p=0.95). Participants were significantly more likely to exhibit a treatment response after ketamine infusion relative to placebo in the first 2 weeks following infusion measured on the LSAS (33.33% response ketamine vs 0% response placebo, Wilcoxon signed-rank test z=2.24, p=0.025) and VAS (88.89% response ketamine vs 52.94% response placebo, Wilcoxon signed-rank test z=2.12, p=0.034). In conclusion, this proof-of-concept trial provides initial evidence that ketamine may be effective in reducing anxiety.

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“…Concerning preclinical findings with nicotine, PPAR alpha agonists have been found to block nicotine reward and induced reinstatement of drug seeking (Mascia et al, 2011; Panlilio et al, 2012). Additionally, genetic deletion of neuronal PPARγ has been shown to reduce anxiety evoked by stress exposure and attenuates the expression of somatic and affective nicotine withdrawal symptoms in rodent models (Domi et al, 2016). …”

Section: Introductionmentioning

confidence: 99%

Pioglitazone, a PPARγ agonist, reduces nicotine craving in humans, with marginal effects on abuse potential

Jones

Comer

Metz

et al. 2017

Pharmacology Biochemistry and Behavior

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Possibly through their actions upon glia, peroxisome proliferator-activated receptor agonists (PPAR) have been shown to alter the abuse potential of addictive drugs in several preclinical models. The current study extends this research into the human laboratory as the first clinical study into the effects of the PPAR gamma agonist, pioglitazone, on the abuse potential of nicotine. Heavy smokers were recruited for this 3-week study. Upon admission, participants were randomized to either active (45 mg, n = 14) or placebo (0 mg, n = 13) PIO maintenance conditions for the duration of the study. After 5–7 days of stabilization on a 7 mg nicotine patch, participants began laboratory testing. On the 1st–4th test days, participants could self-administer cigarettes or receive money by making verbal choices for either option. On the 5th day, participants were administered 10 puffs of their usual brand of cigarette in the morning and later chose between smoking and money by making finger presses on a computer mouse in a progressive ratio self-administration task. Later on the 5th day participants also underwent a smoking cue exposure session. The 8th–11th test days were identical to the 1st–4th test days with the exception that during one of the test weeks de-nicotinized cigarettes were available, and during the other nicotinized cigarettes were available. Nicotinized cigarettes were always administered on the 5th and 12th days. On some measures PIO increased indicators of abuse potential, though this effect was typically not statistically significant. However, PIO did significantly reduce measures of craving.

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Genetic Deletion of Neuronal PPARγ Enhances the Emotional Response to Acute Stress and Exacerbates Anxiety: An Effect Reversed by Rescue of Amygdala PPARγ Function

Abstract: PPAR␥ is one of the three isoforms of the Peroxisome Proliferator-Activated Receptors (PPARs).

Cited by 50 publications

References 55 publications

Pharmacological Blockade of PPAR Isoforms Increases Conditioned Fear Responding in the Presence of Nociceptive Tone

Pharmacological Blockade of PPAR Isoforms Increases Conditioned Fear Responding in the Presence of Nociceptive Tone

Ketamine for Social Anxiety Disorder: A Randomized, Placebo-Controlled Crossover Trial

Pioglitazone, a PPARγ agonist, reduces nicotine craving in humans, with marginal effects on abuse potential

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