Varenicline as a DREADD Actuator Elicits Off-Target Effects on Somatosensation, Locomotion, and Anxiety-Related Behaviors in Rats.

Off-targets effects of CNO on somatosensory and anxiety-related behaviors in rats.

No detectable changes in anxiety-related and locomotor behaviors in adult ovariectomized female rats exposed to estradiol, the ERβ agonist DPN or the ERα agonist PPT

Both the amygdala and the bed nucleus of the stria terminalis (BNST) have been implicated in maladaptive anxiety characteristics of anxiety disorders. However, the underlying circuit and cellular mechanisms have remained elusive. Here we show that mice with Erbb4 gene deficiency in somatostatin-expressing (SOM+) neurons exhibit heightened anxiety as measured in the elevated plus maze test and the open field test, two assays commonly used to assess anxiety-related behaviors in rodents. Using a combination of electrophysiological, molecular, genetic, and pharmacological techniques, we demonstrate that the abnormal anxiety in the mutant mice is caused by enhanced excitatory synaptic inputs onto SOM+ neurons in the central amygdala (CeA), and the resulting reduction in inhibition onto downstream SOM+ neurons in the BNST. Notably, our results indicate that an increase in dynorphin signaling in SOM+ CeA neurons mediates the paradoxical reduction in inhibition onto SOM+ BNST neurons, and that the consequent enhanced activity of SOM+ BNST neurons is both necessary for and sufficient to drive the elevated anxiety. Finally, we show that the elevated anxiety and the associated synaptic dysfunctions and increased dynorphin signaling in the CeA-BNST circuit of the Erbb4 mutant mice can be recapitulated by stress in wild-type mice. Together, our results unravel previously unknown circuit and cellular processes in the central extended amygdala that can cause maladaptive anxiety.SIGNIFICANCE STATEMENT The central extended amygdala has been implicated in anxiety-related behaviors, but the underlying mechanisms are unclear. Here we found that somatostatin-expressing neurons in the central amygdala (CeA) controls anxiety through modulation of the stria terminalis, a process that is mediated by an increase in dynorphin signaling in the CeA. Our results reveal circuit and cellular dysfunctions that may account for maladaptive anxiety.

Diazepam effects on anxiety-related defensive behavior of male and female high and low open‐field activity inbred mouse strains

Involvement of Serotonergic and Relaxin-3 Neuropeptide Systems in the Expression of Anxiety-like Behavior

Aerobic exercise prevents age-dependent cognitive decline and reduces anxiety-related behaviors in middle-aged and old rats

Medial amygdala lesions differentially influence stress responsivity and sensorimotor gating in rats

Vasopressin administration modulates anxiety-related behavior in rats

Corticotropin-releasing factor (CRF) in the medial prefrontal cortex (mPFC) is suggested to play an important role in mediating fear, anxiety, and depression. The results of the studies of the actions of CRF in the mPFC regarding anxiety-related behavior, however, seem contradictory. In one study, microinjection of CRF into the mPFC produced an increase in anxiety-related behavior on the elevated plus maze, whereas in another study CRF produced an anxiolytic-like effect. To test whether the different doses of CRF used in these experiments are responsible for the differing results, we examined the dose-dependent effects of CRF (0.015, 0.05, 0.15, 0.5, and 1.0 µg/0.5 µL/site) microinjected into the bilateral mPFC of male Wistar rats on anxiety-related behavior in the elevated plus maze. We found that microinjection of 0.05 µg CRF significantly decreased the number of open-arm entries, whereas 1.0 µg CRF significantly increased the time spent on the open arms. The results indicate that CRF has effects opposing anxiety-related behavior in the elevated plus maze: anxiety-related behavior at a lower dose and an anxiolytic-like effect at a higher dose.

Reports indicate that histamine and histaminergic agents can change anxiety-related behaviours in both animals and humans. The amygdala is an important brain site in the modulation of fear or anxiety. In the present study, we investigated the effects of intracentral amygdala microinjection of histaminergic agents on anxiety-related behaviours in rats, using the elevated plus-maze test of anxiety. Intracentral amygdala administration of histamine (0.01-0.5 microg/0.5 microl bilateral) decreased %open armtime and % open arm entries, but not locomotor activity, showing an anxiogenic response. Intracentral amygdala microinjection of pyrilamine (H1 receptor antagonist) and ranitidine (H2 receptor antagonist) (both at 1-20 microg/0.5 microl bilateral) did not change anxiety-related parameters in our experiments. In another series of experiments, histamine (0.5 microg/0.5 microl bilateral) was coadministrated with pyrilamine and ranitidine (both at 1-20 mg/0.5 microl bilateral). The results showed that pyrilamine but not ranitidine could significantly reverse the anxiogenic effect of histamine at doses of 10 and 20 microg/0.5 microl bilateral. The results suggest that histamine may modulate anxiety via H1 but not H2 receptors in the rat central amygdala.

Synchronized Activity between the Ventral Hippocampus and the Medial Prefrontal Cortex during Anxiety

The aim of this study was to examine the effects of a methionine-enriched diet on anxiety-related behavior in rats and to determine the role of the brain oxidative status in these alterations. Adult male Wistar rats were fed from the 30th to 60th postnatal day with standard or methionine-enriched diet (double content comparing with standard diet: 7.7 g/kg). Rats were tested in open field and light-dark tests and afterwards oxidative status in the different brain regions were determined. Hyperhomocysteinemia induced by methionine-enriched diet in this study decreased the number of rearings, as well as the time that these animals spent in the center of the open field, but increased index of thigmotaxy. Oxidative status was selectively altered in the examined regions. Lipid peroxidation was significantly increased in the cortex and nc. caudatus of rats developing hyperhomocysteinemia, but unaltered in the hippocampus and thalamus. Based on the results of this research, it could be concluded that hyperhomocysteinemia induced by methionine nutritional overload increased anxiety-related behavior in rats. These proanxiogenic effects could be, at least in part, a consequence of oxidative stress in the rat brain.

C-type natriuretic peptide exerts effects opposing those of atrial natriuretic peptide on anxiety-related behaviour in rats

The characteristic feature of Alzheimer's disease (AD) is the deposition of amyloid beta inside the brain mainly consisting of Aβ 40 and 42 aggregates. Soluble aggregates of Aβ 42 are reported to be more toxic and exert their neurotoxicity by the induction of oxidative damage and cognitive deficits such as anxiety-like behavior. These alterations emerge due to the induction of gap junction communication through increased activity and expression of connexins such as connexin43 (Cx43) leading to the release of small neurotoxic molecules. In the present study, single intracerebroventricular (icv) injection of Aβ 42 oligomers (10μl/rat) was used to induce oxidative damage and anxiety-related behavior in rats. Carbenoxolone (Cbx), a gap junction blocker, was tested (20mg/kg body weight, i.p., for 6weeks) against these alterations. Cbx supplementation reversed the Aβ 42 oligomer-induced alterations in the antioxidant defense system. The levels ROS, lipid peroxidation, and protein carbonyls were normalized with Cbx co-treatment leading to the decreased DNA fragmentation and pyknosis in different regions of the rat brain. Cbx induced the anxiolytic behavior and ameliorated the cognitive decline in rats post Aβ 42 oligomer injection. The increased expression of Cx43 post Aβ 42 oligomer injection was also reduced with Cbx supplementation, which might have inhibited the release of small neurotoxic molecules. Our results showed that Cbx prevents the Aβ 42 oligomer-induced oxidative damage and anxiety-like behavior partly by blocking the gap junction communication, which suggests that the therapeutic potential of Cbx may be explored in the progression of AD.

4-Nonylphenol and 4-tert-octylphenol induce anxiety-related behaviors through alternation of 5-HT receptors and transporters in the prefrontal cortex