Acute Ketamine Facilitates Fear Memory Extinction in a Rat Model of PTSD Along With Restoring Glutamatergic Alterations and Dendritic Atrophy in the Prefrontal Cortex

Stress represents a major risk factor for psychiatric disorders, including post-traumatic stress disorder (PTSD). Recently, we dissected the destabilizing effects of acute stress on the excitatory glutamate system in the prefrontal cortex (PFC). Here, we assessed the effects of single subanesthetic administration of ketamine (10 mg/kg) on glutamate transmission and dendritic arborization in the PFC of footshock (FS)-stressed rats, along with changes in depressive, anxious, and fear extinction behaviors. We found that ketamine, while inducing a mild increase of glutamate release in the PFC of na\uefve rats, blocked the acute stress-induced enhancement of glutamate release when administered 24 or 72 h before or 6 h after FS. Accordingly, the treatment with ketamine 6 h after FS also reduced the stress-dependent increase of spontaneous excitatory postsynaptic current (sEPSC) amplitude in prelimbic (PL)-PFC. At the same time, ketamine injection 6 h after FS was found to rescue apical dendritic retraction of pyramidal neurons induced by acute stress in PL-PFC and facilitated contextual fear extinction. These results show rapid effects of ketamine in animals subjected to acute FS, in line with previous studies suggesting a therapeutic action of the drug in PTSD models. Our data are consistent with a mechanism of ketamine involving re-establishment of synaptic homeostasis, through restoration of glutamate release, and structural remodeling of dendrites

Ketamine alters excitatory synaptic currents in the medial prefrontal cortex of acutely stressed rats

Ketamine alters excitatory synaptic currents in the medial prefrontal cortex of acutely stressed rats E. SCHIAVON1, F. SALERNO SCARZELLA1, L. MUSAZZI2, M. POPOLI2, L. FORTI1. 1Dept. of Biotech. and Life Sci., Univ. of Insubria, Busto Arsizio, Italy; 2Dept. Pharmacol. and Biomolecular Sci., Univ. degli Studi di Milano, Milano, Italy Abstract: The cellular and functional changes underlying the adaptive or maladaptive behavioral effects of an acute stressor are not well understood. In the medial prefrontal cortex (mPFC) of male rats, 40 min foot-shock protocol (FS), rapidly (~1 hr) increases the number of excitatory synapses, the readily releasable Glu vesicle pool in synaptosomes, and the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) recorded in L2/3 pyramidal neurons (Pyr). Within 24 hrs, FS induces shrinkage of apical dendrites, while no information exists for sEPSCs. Miniature excitatory synaptic currents (mEPSCs) have been suggested to have a neurotrophic and homeostatic role, but the effects of FS on mEPSCs are unknown. To understand the sustained effects of FS on Glu transmission in the mPFC and its regulation by ketamine at antidepressant dosage, synaptic currents were recorded 24 hrs after FS in visually identified layer 2/3 Pyr of prelimbic mPFC in slices from adult male rats. Animals subjected to a 40-min session of inescapable FS (FS group), animals injected with ketamine (10mg/kg) 6 hrs after FS, and controls (CTR) were compared. The amplitude, area, rise, decay, and inter-event intervals of mEPSCs and sEPSCs were analyzed. mEPSCs in the FS group showed a tendency to minor changes in frequency (small increase) and ampitude (small decrease) vs CTR. Ketamine after FS increased mEPSC frequency and peak amplitude and accelerated rise and decay with no change in area, as compared to CTR. sEPSCs frequency in the FS group had a tendency to a small decrease, with no change in waveform vs CTR. Ketamine after FS produced similar effects on sESPCs as for mEPSCs. Overall, this work indicates that, 24 hrs after FS, no or minor changes occur in miniature and spontaneous synaptic currents at layer 2/3 excitatory synapses of the mPFC. Ketamine modulation of the Glu synaptic currents of stressed animals suggests changes in synapse morphology and/or dendritic localization

Mortality rate and risk factors for gastrointestinal bleeding in elderly patients

Background: Gastrointestinal bleeding (GIB) is burdened by high mortality rate that increases with aging. Elderly patients may be exposed to multiple risk factors for GIB. We aimed at defining the impact of GIB in elderly patients.Methods: Since 2008, samples of elderly patients (age >= 65 years) with multimorbidity admitted to 101 internal medicine wards across Italy have been prospectively enrolled and followed-up (REPOSI registry). Diagnoses of GIB, length of stay (LOS), mortality rate, and possible risk factors, including drugs, index of comorbidity (Cumulative Illness Rating Scale [CIRS]), polypharmacy, and chronic diseases were assessed. Adjusted multivariate logistic regression models were computed.Results: 3872 patients were included (mean age 79 +/- 7.5 years, F:M ratio 1.1:1). GIB was reported in 120 patients (mean age 79.6 +/- 7.3 years, F:M 0.9:1), with a crude prevalence of 3.1%. Upper GIB occurred in 72 patients (mean age 79.3 +/- 7.6 years, F:M 0.8:1), lower GIB in 51 patients (mean age 79.4 +/- 7.1 years, F:M 0.9:1), and both upper/lower GIB in 3 patients. Hemorrhagic gastritis/duodenitis and colonic diverticular disease were the most common causes. The LOS of patients with GIB was 11.7 +/- 8.1 days, with a 3.3% in-hospital and a 9.4% 3-month mortality rates. Liver cirrhosis (OR 5.64; CI 2.51-12.65), non-ASA antiplatelet agents (OR 2.70; CI 1.23-5.90), and CIRS index of comorbidity > 3 (OR 2.41; CI 1.16-4.98) were associated with GIB (p < 0.05).Conclusions: A high index of comorbidity is associated with high odds of GIB in elderly patients. The use of non-ASA antiplatelet agents should be discussed in patients with multimorbidity