Diabetic encephalopathy-related depression: experimental evidence that insulin and clonazepam restore antioxidant status in rat brain.

There is increasing evidence suggesting that oxidative stress plays an important role in the development of many chronic and degenerative conditions such as diabetic encephalopathy and depression. Considering that diabetic rats and mice present higher depressive-like behaviour when submitted to the forced swimming test and that treatment with insulin and/or clonazepam is able to reverse the behavioural changes of the diabetic rats, the present work investigated the antioxidant status, specifically total antioxidant reactivity and antioxidant potential of insulin and clonazepam, as well as the effect of this drugs upon protein oxidative damage and reactive species formation in cortex, hippocampus and striatum from diabetic rats submitted to forced swimming test. It was verified that longer immobility time in diabetic rats and insulin plus clonazepam treatment reversed this depressive-like behaviour. Moreover, data obtained in this study allowed to demonstrate through different parameters such as protein carbonyl content, 2'7'-dichlorofluorescein oxidation, catalase, superoxide dismutase, glutathione peroxidase assay, total radical-trapping antioxidant potential and total antioxidant reactivity that there is oxidative stress in cortex, hippocampus and striatum from diabetic rats under depressive-like behaviour and highlight the insulin and/or clonazepam effect in these different brain areas, restoring antioxidant status and protein damage.

The effect of intra-nucleus accumbens administration of allopregnanolone on δ and γ2 GABA(A) receptor subunit mRNA expression in the hippocampus and on depressive-like and grooming behaviors in rats.

Alterations in GABA(A) receptor expression have been associated with the allopregnanolone (3α-hydroxy-5α-pregnan-20-one; 3α,5α-THP) antidepressant-like effect in rats. The present study aimed to verify the effect of bilateral, intra-nucleus accumbens core (intra-AcbC) administration of the neurosteroid allopregnanolone on behaviors in the forced swim and grooming microstructure tests and in the δ and γ2 GABA(A) receptor subunit mRNA expression in right and left hippocampus of rats. The results of this study showed that bilateral, intra-AcbC allopregnanolone administration (5µg/rat) presented antidepressant-like activity in the forced swim test concomitant with an increase in climbing. Allopregnanolone at doses of 1.25 and 5µg/rat also decreased the percentage of correct transitions in the grooming microstructure test. Both δ and γ2 GABA(A) subunit expressions increased in the rat hippocampus after allopregnanolone intra-AcbC treatment. Our findings point to asymmetrical GABA(A) receptor expression changes in the hippocampus of animals treated with allopregnanolone. Further investigation should evaluate the antidepressant-like effect of allopregnanolone not only in other directly infused regions but also with respect to changes in other brain areas of the limbic system to understand allopregnanolone's mechanism of action.

Anxiolytic effect of clonazepam in female rats: grooming microstructure and elevated plus maze tests.

Grooming behavior is an adaptation to a stressful environment that can vary in accordance with stress intensity. Direct and indirect GABA(A) receptor agonists decrease duration, frequency, incorrect transitions and uninterrupted bouts of grooming. Hormonal variation during the different phases of the estrous cycle of female rats also changes the grooming behavior. It is known that GABA(A) agonists and endogenous hormones change anxiety-like behaviors observed in the elevated plus maze test, a classical animal model of anxiety. This study was designed to determine the anxiolytic effect of clonazepam in female rats in different estrous phases and to correlate anxiety behaviors in the elevated plus maze and grooming microstructure tests. Our results show that female rats displayed higher anxiety-like behavior scores during the estrus and proestrus phases in the elevated plus maze and that clonazepam (0.25 mg/kg; i.p.) had an anxiolytic effect that was independent of the estrous phase. Grooming behaviors were higher in the proestrus phase but were decreased by clonazepam administration, independent of the estrous phase, demonstrating the anxiolytic effect of this drug in both animal models. Grooming behaviors were moderately associated with anxiolytic-like behaviors in the elevated plus maze test. Here, we describe the anxiolytic effect of clonazepam and the influence of estrous phase on anxiety. Moreover, we show that the grooming microstructure test is a useful tool for detecting anxiolytic-like behaviors in rats.

Protein and lipid oxidative damage in streptozotocin-induced diabetic rats submitted to forced swimming test: the insulin and clonazepam effect.

Diabetes may modify central nervous system functions and is associated with moderate cognitive deficits and changes in the brain, a condition that may be referred to as diabetic encephalopathy. The prevalence of depression in diabetic patients is higher than in the general population, and clonazepam is being used to treat this complication. Oxidative stress may play a role in the development of diabetes complications. We investigated oxidative stress parameters in streptozotocin-induced diabetic rats submitted to forced swimming test (STZ) and evaluated the effect of insulin (STZ-INS) and/or clonazepam (STZ-CNZ and STZ-INS-CNZ) acute treatment on these animal model. Oxidative damage to proteins measured as carbonyl content in plasma was significantly increased in STZ group compared to STZ treated groups. Malondialdehyde plasma levels were significantly reduced in STZ-INS and STZ-INS-CNZ groups when compared to STZ rats, being significantly reduced in STZ-INS-CNZ than STZ-INS rats. The activities of the antioxidant enzymes catalase, superoxide dismutase and glutathione peroxidase showed no significant differences among all groups of animals. These findings showed that protein and lipid damage occurs in this diabetes/depression animal model and that the associated treatment of insulin and clonazepam is capable to protect against oxidative damage in this experimental model.