Class I histone deacetylases inhibition reverses memory impairment induced by acute stress in mice.

While chronic stress induces learning and memory impairments, acute stress may facilitate or prevent memory consolidation depending on whether it occurs during the learning event or before it, respectively. On the other hand, it has been shown that histone acetylation regulates long-term memory formation. This study aimed to evaluate the effect of two inhibitors of class I histone deacetylases (HDACs), 4-phenylbutyrate (PB) and IN14 (100 mg/kg/day, ip for 2 days), on memory performance in mice exposed to a single 15-min forced swimming stress session. Plasma corticosterone levels were determined 30 minutes after acute swim stress in one group of mice. In another experimental series, independent groups of mice were trained in one of three different memory tasks: Object recognition test, Elevated T maze, and Buried food location test. Subsequently, the hippocampi were removed to perform ELISA assays for histone deacetylase 2 (HDAC2) expression. Acute stress induced an increase in plasma corticosterone levels, as well as hippocampal HDAC2 content, along with an impaired performance in memory tests. Moreover, PB and IN14 treatment prevented memory loss in stressed mice. These findings suggest that HDAC2 is involved in acute stress-induced cognitive impairment. None of the drugs improved memory in non-stressed animals, indicating that HDACs inhibitors are not cognitive boosters, but rather potentially useful drugs for mitigating memory deficits.

Biochemical and Behavioral Characterization of IN14, a New Inhibitor of HDACs with Antidepressant-Like Properties.

Evidence suggests that histone deacetylases (HDACs) inhibitors could be used as an effective treatment for some psychiatric and neurological conditions such as depression, anxiety and age-related cognitive decline. However, non-specific HDAC inhibiting compounds have a clear disadvantage regarding their efficacy and safety, thus the need to develop more selective ones. The present study evaluated the toxicity, the capacity to inhibit HDAC activity and antidepressant-like activity of three recently described class I HDAC inhibitors IN01, IN04 and IN14, using A.salina toxicity test, in vitro fluorometric HDAC activity assay and forced-swimming test, respectively. Our data show that IN14 possesses a better profile than the other two. Therefore, the pro-cognitive and antidepressant effects of IN14 were evaluated. In the forced-swimming test model of depression, intraperitoneal administration of IN14 (100 mg/Kg/day) for five days decreased immobility, a putative marker of behavioral despair, significantly more than tricyclic antidepressant desipramine, while also increasing climbing behavior, a putative marker of motivational behavior. On the other hand, IN14 left the retention latency in the elevated T-maze unaltered. These results suggest that novel HDAC class I inhibitor IN14 may represent a promising new antidepressant with low toxicity and encourages further studies on this compound.

The neonatal treatment with clomipramine decreases sexual motivation and increases estrogen receptors expression in the septum of male rats: Effects of the apomorphine.

Administering clomipramine during the early days of life induced several behavioral and neurochemical alterations in adult male rats, which resemble major depression disorder. The alterations included poor sexual performance, which is considered a reward-seeking behavior regulated by dopaminergic system. Given that estrogen receptors are expressed in different areas of the brain involved in regulating reproductive behavior, motivation and mood. The objective of this study was to analyze the effect of a non-selective dopamine agonist (apomorphine) on sexual incentive motivation in rats exposed to clomipramine (CMI) in the neonatal period. In addition, we evaluated the expression of mRNA ERα and ERß in nucleus accumbens (NAcc) and septum of CMI rats. We found that only a few rats subjected to neonatal CMI treatment performed mounts, intromissions and ejaculations. Also, those rats spent less time exploring the sexual incentive zone and had lower preference scores; this effect was reverted by administering 0.1 mg/kg of apomorphine. Finally, the CMI rats presented higher levels of mRNA ERα and ERß, only in septum area. These data indicate that neonatal treatment with CMI altered the expression of mRNA ERα and ERß in the septum, which participates in regulating the motivational component of sexual behavior.