Growing awareness of cerebellar involvement in addiction is based on the cerebellum’s intermediary position between motor and reward, potentially acting as an interface between motivational and cognitive functions. Here, we examined the impact of acute and repeated cocaine exposure on the two main signaling systems in the mouse cerebellum: the endocannabinoid (eCB) and glutamate systems. To this end, we investigated whether eCB signaling-related gene and protein expression {cannabinoid receptor type 1 receptors and enzymes that produce [diacylglycerol lipase alpha/beta (DAGLα/β) and N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD)] and degrade [monoacylglycerol lipase (MAGL) and fatty acid amino hydrolase (FAAH)] eCB} were altered. In addition, we analyzed the gene expression of relevant components of the glutamate signaling system [glutamate synthesizing enzymes liver-type glutaminase isoform (LGA) and kidney-type glutaminase isoform (KGA), metabotropic glutamatergic receptor (mGluR3/5), NMDA-ionotropic glutamatergic receptor (NR1/2A/2B/2C) and AMPA-ionotropic receptor subunits (GluR1/2/3/4)] and the gene expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, because noradrenergic terminals innervate the cerebellar cortex. Results indicated that acute cocaine exposure decreased DAGLα expression, suggesting a down-regulation of 2-arachidonylglycerol (2-AG) production, as well as gene expression of TH, KGA, mGluR3 and all ionotropic receptor subunits analyzed in the cerebellum. The acquisition of conditioned locomotion and sensitization after repeated cocaine exposure were associated with an increased NAPE-PLD/FAAH ratio, suggesting enhanced anandamide production, and a decreased DAGLβ/MAGL ratio, suggesting decreased 2-AG generation. Repeated cocaine also increased LGA gene expression but had no effect on glutamate receptors. These findings indicate that acute cocaine modulates the expression of the eCB and glutamate systems. Repeated cocaine results in normalization of glutamate receptor expression, although sustained changes in eCB is observed. We suggest that cocaine-induced alterations to cerebellar eCB should be considered when analyzing the adaptations imposed by psychostimulants that lead to addiction.

Funding Acknowledgements VII Convocatoria del Banco de Santander and Alfonso X el Sabio University. Background Detection of symptoms in geriatric population with aortic stenosis (AS) is challenging, especially when they associate other comorbidities or frailty. Left ventricular global longitudinal strain (GLS) occurs before left ventricular ejection fraction impairment and could be useful for risk stratification and management of these patients. Purpose We sought to analyze the usefulness of GLS for predicting major cardiovascular adverse events (MACEs) in geriatric patients with asymptomatic severe AS. Material and Methods: Prospective study on 54 patients older than 70 years old with severe asymptomatic AS. Patient evaluation included biochemistry tests, electrocardiogram and echocardiography. We use a GLS cut-off point of 18% to dichotomize patients. Outcomes were defined as the composite of MACEs – occurrence of death from any cause, hospitalization for heart failure, appearance of symptoms or change in treatment. Results The mean age was 83.2 ± 7.1, with 60.4% of women. 24.5% showed atrial fibrillation. At 6 months of follow-up, 33% of patients reached the endpoint: 5.6% CHF, 11.1% death, 3.7% symptoms without changes in management and 13% were referred to an invasive treatment. The event-free survival rate at 6 months for the global population was 83%. 41.5 % of the subjects had GLS < 18%. Kaplan Meier analysis showed that the probability of freedom from MACEs was not significant in patients with lower GLS (Log Rank p = 0.39). In the multivariate analysis only AVA was an inverse predictor of events (AVA) HR 0.05 (95% CI 0.007- 0.471, p < 0.05). Conclusions The value of GLS was not a predictor of short term events in geriatric patients. Only assessment of AVA was an independent marker of MACES and in this kind of subjects. Charasteristics of the global population Global N = 53 (%) GLS ≥ 18 N = 31 (58.5%) GLS < 18 N = 22 (41.5%) (p) HBP 42 (79.2) 27 (87.1) 19 (82.6) 0.09 Atrial fibrillation 13 (24.5) 6 (19.4) 7 (31.8) 0.29 CVD 6 (11.3) 1 (3.2) 5 (22.7) 0.02 LVEF: Normal >50% 48 (92) 31 (100) 17 (77.2) 0.05 Peak velocity 3.72 ± 0.72 3.81 ± 0.71 3.60 ± 0.74 0.315 Mean gradient 34.01 ± 14.06 35.61 ± 13.54 32.09 ± 15.07 0.29 Integral ratio 0.25 ± 0.08 0.26 ± 0.09 0.25 ± 0.08 0.83 AVA 0.8 ± 0.26 0.78 ± 0.27 0.83 ± 0.26 0.651 Indexed AVA 0.48 ± 0.16 0.48 ± 0.17 0.48 ± 0.16 0.9 AVA Aortic valve area; CVD: cerebro vascular disease; HBP: High blood presure; LVEF: left ventricule ejection fraction. Abstract P905 Figure. Kapplan-Meier event-free survival curves