Tempol treatment reduces anxiety-like behaviors induced by multiple anxiogenic drugs in rats.

We have published that pharmacological induction of oxidative stress (OS) causes anxiety-like behavior in rats. Using animal models, we also have established that psychological stress induces OS and leads to anxiety-like behaviors. All evidence points towards the causal role of OS in anxiety-like behaviors. To fully ascertain the role of OS in anxiety-like behaviors, it is reasonable to test whether the pro-anxiety effects of anxiogenic drugs caffeine or N-methyl-beta-carboline-3-carboxamide (FG-7142) can be mitigated using agents that minimize OS. In this study, osmotic pumps were either filled with antioxidant tempol or saline. The pumps were attached to the catheter leading to the brain cannula and inserted into the subcutaneous pocket in the back pocket of the rat. Continuous i.c.v. infusion of saline or tempol in the lateral ventricle of the brain (4.3 mmol/day) was maintained for 1 week. Rats were intraperitoneally injected either with saline or an anxiogenic drug one at a time. Two hours later all groups were subjected to behavioral assessments. Anxiety-like behavior tests (open-field, light-dark and elevated plus maze) suggested that tempol prevented anxiogenic drug-induced anxiety-like behavior in rats. Furthermore, anxiogenic drug-induced increase in stress examined via plasma corticosterone and increased oxidative stress levels assessed via plasma 8-isoprostane were prevented with tempol treatment. Protein carbonylation assay also suggested preventive effect of tempol in the prefrontal cortex brain region of rats. Antioxidant protein expression and pro-inflammatory cytokine levels indicate compromised antioxidant defense as well as an imbalance of inflammatory response.

High aggression in rats is associated with elevated stress, anxiety-like behavior, and altered catecholamine content in the brain.

The social defeat paradigm involves aggressive encounters between Long-Evans (L-E) (resident) and Sprague-Dawley (S-D) (intruder) rats. Successful application of chronic social defeat stress in S-D rats is dependent upon selection of highly aggressive L-E rats. Half of the L-E rats screened for aggression did not meet the criterion for aggression (L-E rats performing a defeat, characterized by the intruder surrendering or acquiring a supine position for at least 3s). The observation of the differences in the level of aggression between age and weight matched L-E rats was quite compelling which led us to the present study. Herein, we measured behavioral differences between aggressor and non-aggressor L-E rats. We analyzed their anxiety-like behavior using open-field and elevated plus maze tests. We also measured aggression/violence-like behavior using two tests. In one, time taken to defeat the intruder S-D rat was recorded. In the second test, time taken to attack a novel object was compared between the two groups. We observed a significant increase in anxiety-like behavior in aggressor rats when compared to the non-aggressive group. Furthermore, time taken to defeat the intruder rat and to attack a novel object was significantly lower in aggressive L-E rats. Biochemical data suggests that heightened anxiety-like behavior and aggression is associated with increased plasma levels of corticosterones and elevated oxidative stress. Significant alterations in dopamine (DA), norepinephrine (NE) and epinephrine (EPI) were observed within the hippocampus, amygdala, and the prefrontal cortex, suggesting potential involvement of dopaminergic and noradrenergic systems in regulation of aggressive behaviors.

Grape powder prevents cognitive, behavioral, and biochemical impairments in a rat model of posttraumatic stress disorder.

Previously, using the single-prolonged stress (SPS) rat model of posttraumatic stress disorder, we reported that moderate treadmill exercise, via modulation of oxidative stress-related mechanisms, rescued anxiety- and depression-like behaviors and reversed SPS-induced memory impairment. In this study using the SPS model (2-hour restrain, 20-minute forced swimming, 15-minute rest, and 1-2-minute diethyl ether exposure), we hypothesized that antioxidant rich grape powder (GP) prevents SPS-induced behavioral and memory impairment in rats. Male Sprague Dawley rats were randomly assigned into control (CON) (provided tap water), SPS (provided tap water), GP-SPS (provided 15 g/L GP in tap water for 3 weeks followed by SPS), or GP-CON (3 weeks of GP followed by CON exposure). Anxiety- and depression-like behaviors were significantly greater in SPS rats, when compared with CON- or GP-treated rats, and GP reversed these behavioral deficits. Single-prolonged stress rats made significantly more errors in both short- and long-term memory tests compared with CON- or GP-treated rats, which were prevented in GP-SPS rats. Grape powder prevented SPS-induced increase in plasma corticosterone level. Furthermore, brain-derived neurotrophic factor levels were significantly decreased in amygdala of SPS rats but not in GP-SPS rats compared with CON or (GP-CON) rats. In addition, GP significantly increased acetylated histone 3 and histone deacetylase 5 in hippocampus and amygdala of SPS rats as compared with CON or GP-CON rats. In conclusion, we suggest protective role of GP in SPS-induced behavioral, cognitive, and biochemical impairments in rats. Perhaps, epigenetic regulation of brain-derived neurotrophic factor enables GP-mediated prevention of SPS-induced deficits in rats.