Prodynorphin gene deletion increased anxiety-like behaviours, impaired the anxiolytic effect of bromazepam and altered GABA_A receptor subunits gene expression in the amygdala

Abstract

This study evaluated the role of prodynorphin gene in the regulation of anxiety and associated molecular mechanisms. Emotional responses were assessed using the light-dark test, elevated plus maze and social interaction tests in prodynorphin knockout and wild-type mice. Corticotrophin releasing factor and proopiomelanocortin gene expressions in the hypothalamus were evaluated after restraint stress using in situ hybridization. The anxiolytic efficacy of bromazepam and GABA(A) receptor subunits gene expression in the amygdala were also assessed in both genotypes. The deletion of prodynorphin increased anxiety-like behaviours and proopiomelanocortin gene expression in the arcuate nucleus (two-fold). Moreover, the anxiolytic action of bromazepam was significantly attenuated in the mutant mice. Decreased GABA(A)γ(2) and increased GABA(A)β(2) gene expression receptor subunits were found in the amygdala of prodynorphin knockout mice. These results indicate that deletion of prodynorphin gene is associated with increased anxiety-like behaviours, enhanced sensibility response to stress stimuli, reduced anxiolytic efficacy of bromazepam and altered expression of the GABA(A) receptor subunits.

Impaired periamygdaloid-cortex prodynorphin is characteristic of opiate addiction and depression

“…It is also important to emphasize that the relationship between PDYN and different aspects of negative affect is complex and still requires further investigation. For example, although stress-induced aversion is established to be mediated by elevated dynorphin (41,42), a number of investigations have documented that animals lacking the Pdyn gene have enhanced anxiety behavior (43,44). Moreover, our study underscores the heterogeneity of PDYN expression even within discrete brain regions, suggesting different PDYN circuits could contribute to distinct behavioral components relevant to negative affect.…”

Angiotensin II AT1 receptor blocker candesartan prevents the fast up-regulation of cerebrocortical benzodiazepine-1 receptors induced by acute inflammatory and restraint stress

“…Changes in GABA A receptor subunits expression induced by stress will then promote differential clustering of selective subunits conditioning the receptor activity and its participation in stress and anxiety [25,42–46]. While the GABA A γ 2 subunit is essential for the synaptic clustering of the GABA A complex [39,41,47], anti-anxiety effects are commonly linked to receptors highly expressing the GABA A α 2 subunits [42,43,48]. …”

The role of the dynorphin/κ opioid receptor system in anxiety

“…Kuzmin et al (2006) showed that big dynorphin, a prodynorphin-derived precursor peptide, induced anxiolytic-like behavior in mice in the EPM test [47] . Whereas, deletion of the prodynorphin gene increased anxiety-like behaviors in the EPM and light-dark tests [48] . Similarly, ablation of prodynorphin showed increased anxietylike behaviors in zero-maze and startle-response tests [49] .…”