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Acute stress has been demonstrated to alter sensory gating processes, measured by the prepulse inhibition of the startle response (PPI). It is well known that brain and plasma levels of the neurosteroid allopregnanolone (ALLO) increase after acute environmental stress, fact that has been considered a homeostatic mechanism in restoring normal function following stress. Thus, it is of great interest to study the contribution of stress-altered plasma ALLO levels on PPI function. For this purpose, animals were injected with finasteride, an ALLO synthesis inhibitor, and submitted to swim stress before PPI testing. In order to obtain ALLO plasma levels, a separate set of animals that followed the same experimental procedure was used. We hypothesize that the blockade of ALLO production in response to stress can increase the stress-induced PPI disruption. In accordance with other authors, our results indicate that acute swim stress disrupted the normal PPI evolution (increase) related to the increase in prepulse intensities, and also decreased PPI at the highest prepulse intensity level (15 db above background). Finasteride potentiated the PPI decrease induced by swim stress in the intermediate prepulse intensity (10 db above background). As expected, plasma ALLO levels were increased in stressed animals and this increase was neutralized by prior finasteride administration. These results indicate that the neutralization of the physiological plasma ALLO levels increase after acute stress potentiates stress-induced PPI disruption. This data suggests that alterations in homeostatic ALLO synthesis mechanism may be linked to some neuropsychiatric disorders related to stress, such as anxiety/depression disorders. [ABSTRACT FROM AUTHOR]

Abstract: The effects of intrahippocampal administration of nicotine and the neurosteroids pregnenolone sulfate and allopregnanolone on acquiring the lever-press response and extinction in a Skinner box were examined using voluntary alcohol-drinking rats. A free-choice drinking procedure that implies early availability of the alcoholic solution (10% ethanol v/v+3% glucose w/v in distilled water) was used. Alcohol and control rats were deprived of food and assigned at random to six groups. Each group received two consecutive intrahippocampal (dorsal CA1) injections immediately after 1-h of drinking ethanol and before the free lever-press response shaping and extinction session. The groups were: saline–saline; saline–pregnenolone sulfate (5 ng, 24μM); saline–allopregnanolone (0.2μg, 1.26μM); nicotine (4.6μg, 20mM)–saline; nicotine–pregnenolone sulfate; nicotine–allopregnanolone. Blood alcohol concentrations were assessed the day before conditioning. The combination of the oral self-administration of ethanol and the intrahippocampal injection of nicotine deteriorated the ability to acquire the lever-press response. This effect was neutralized by intrahippocampal pregnenolone sulfate (negative modulator of the GABAA receptor complex), and it was not affected by intrahippocampal allopregnanolone (positive GABA receptor complex A modulator). Pregnenolone sulfate and allopregnanolone had no effects per se on lever-press acquisition, neither in alcohol-drinking rats nor in controls. Alcohol consumption facilitated operant extinction just as anxiolytics that act as positive modulators of the GABA receptor complex A receptors do, possibly reducing the anxiety or aversion related to non-reinforcement. This effect was increased by intrahippocampal nicotine. [Copyright &y& Elsevier]

Abstract: Objectives: Vorinostat or suberoylanilide hydroxamic acid (SAHA) is a novel histone deacetylase inhibitor with demonstrated antiproliferative effects due to drug-induced accumulation of acetylated proteins, including the heat shock protein 90. We prospectively studied the activity of vorinostat plus erlotinib in EGFR-mutated NSCLC patients with progression to tyrosine kinase inhibitors. Patients and methods: We conducted this prospective, non-randomized, multicenter, phase I/II trial to evaluate the maximum tolerated dose, toxicity profile and efficacy of erlotinib and vorinostat. Patients with advanced NSCLC harboring EGFR mutations and progressive disease after a minimum of 12 weeks on erlotinib were included. The maximum tolerated dose of vorinostat plus erlotinib was used as recommended dose for the phase II (RDP2) to assess the efficacy of the combination. The primary end point was progression-free-survival rate at 12 weeks (PFSR12w). Pre-treatment plasma samples were required to assess T790M resistant mutation. Results: A total of 33 patients were enrolled in the phase I–II trial. The maximum tolerated dose was erlotinib 150mg p.o., QD, and 400mg p.o., QD, on days 1–7 and 15–21 in a 28-day cycle. Among the 25 patients treated at the RDP2, the most common toxicities included anemia, fatigue and diarrhea. No responses were observed. PFSR12w was 28% (IC95%: 18.0–37.2); median progression-free survival (PFS) was 8 weeks (IC 95%: 7.43–8.45) and overall survival (OS) 10.3 months (95% CI: 2.4–18.1). Conclusion: Full dose of continuous erlotinib with vorinostat 400mg p.o., QD on alternative weeks can be safely administered. Still, the combination has no meaningful activity in EGFR-mutated NSCLC patients after TKI progression. [Copyright &y& Elsevier]

Highlights: [•] Alterations in neonatal allopregnanolone affect adult emotional and novelty seeking, behavior. [•] Alterations in neonatal allopregnanolone affect sensory gating in adult age. [•] Neonatal allopregnanolone participates in the maturation of the hippocampus. [•] Alterations in neonatal allopregnanolone affect GABAAR expression in neonatal and, adult hippocampus. [ABSTRACT FROM AUTHOR]