No evidence that post-training dopamine D2 receptor agonism affects fear generalization in male rats.

BACKGROUND: The neurotransmitter dopamine plays an important role in the processing of emotional memories, and prior research suggests that dopaminergic manipulations immediately after fear learning can affect the retention and generalization of acquired fear. AIMS: The current study focuses specifically on the role of dopamine D2 receptors (D2Rs) regarding fear generalization in adult, male Wistar rats, and aims to replicate previous findings in mice. METHODS: In a series of five experiments, D2R (ant)agonists were injected systemically, immediately after differential cued fear conditioning (CS+ followed by shock, CS- without shock). All five experiments involved the administration of the D2R agonist quinpirole at different doses versus saline (n = 12, 16, or 44 rats/group). In addition, one of the studies administered the D2R antagonist raclopride (n = 12). One day later, freezing during the CS+ and CS- was assessed. RESULTS: We found no indications for an effect of quinpirole or raclopride on fear generalization during this drug-free test. Importantly, and contradicting earlier research in mice, the evidence for the absence of an effect of D2R agonist quinpirole (1 mg/kg) on fear generalization was substantial according to Bayesian analyses and was observed in a highly powered experiment (N = 87). We did find acute behavioral effects in line with the literature, for both quinpirole and raclopride in a locomotor activity test. CONCLUSION: In contrast with prior studies in mice, we have obtained evidence against a preventative effect of post-training D2R agonist quinpirole administration on subsequent fear generalization in rats.

No harmful effect of propranolol administered prior to fear memory extinction in rats and humans.

Exposure therapy is an evidence-based treatment option for anxiety-related disorders. Many patients also take medication that could, in principle, affect exposure therapy efficacy. Clinical and laboratory evidence indeed suggests that benzodiazepines may have detrimental effects. Large clinical trials with propranolol, a common beta-blocker, are currently lacking, but several preclinical studies do indicate impaired establishment of safety memories. Here, we investigated the effects of propranolol given prior to extinction training in 9 rat studies (N = 215) and one human study (N = 72). A Bayesian meta-analysis of our rat studies provided strong evidence against propranolol-induced extinction memory impairment during a drug-free test, and the human study found no significant difference with placebo. Two of the rat studies actually suggested a small beneficial effect of propranolol. Lastly, two rat studies with a benzodiazepine (midazolam) group provided some evidence for a harmful effect on extinction memory, i.e., impaired extinction retention. In conclusion, our midazolam findings are in line with prior literature (i.e., an extinction retention impairment), but this is not the case for the 10 studies with propranolol. Our data thus support caution regarding the use of benzodiazepines during exposure therapy, but argue against a harmful effect of propranolol on extinction learning.

A history of avoidance does not impact extinction learning in male rats.

Pervasive avoidance is one of the central symptoms of all anxiety-related disorders. In treatment, avoidance behaviors are typically discouraged because they are assumed to maintain anxiety. Yet, it is not clear if engaging in avoidance is always detrimental. In this study, we used a platform-mediated avoidance task to investigate the influence of avoidance history on extinction learning in male rats. Our results show that having the opportunity to avoid during fear acquisition training does not significantly influence the extinction of auditory-cued fear in rats subjected to this platform-mediated avoidance procedure, which constitutes a realistic approach/avoidance conflict. This holds true irrespective of whether or not avoidance was possible during the extinction phase. This suggests that imposing a realistic cost on avoidance behavior prevents the adverse effects that avoidance has been claimed to have on extinction. However, avoidance does not appear to have clear positive effects on extinction learning nor on retention either.

Reappraisal of threat value: loss of blocking in human aversive conditioning

Non-specificity of fear is a core aspect of what makes anxiety disorders so impairing: Fear does not remain specific to a single stimulus paired with danger, but generalizes to a broad set of stimuli, resulting in a snowballing of threat signals. The blocking procedure can provide a valuable laboratory model for gaining insight into such threat appraisal and generalization processes. We report two experiments in which we induced selective threat appraisal by using a blocking procedure in human aversive conditioning. We subsequently assessed to what extent such selective threat appraisal is sensitive to different kinds of interference. Results illustrate that the maintenance of selective threat appraisal is not guaranteed: Stimuli present during an aversive conditioning event that are initially tagged with a low threat value, can come to be tagged with a higher threat value later on, without additional experience with these stimuli. We argue that such interference in selective threat appraisal might be one of the mechanisms underlying the pathogenesis of non-specific fear (AU)

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