CalDAG-GEFI mediates striatal cholinergic modulation of dendritic excitability, synaptic plasticity and psychomotor behaviors.

CalDAG-GEFI (CDGI) is a protein highly enriched in the striatum, particularly in the principal spiny projection neurons (SPNs). CDGI is strongly down-regulated in two hyperkinetic conditions related to striatal dysfunction: Huntington's disease and levodopa-induced dyskinesia in Parkinson's disease. We demonstrate that genetic deletion of CDGI in mice disrupts dendritic, but not somatic, M1 muscarinic receptors (M1Rs) signaling in indirect pathway SPNs. Loss of CDGI reduced temporal integration of excitatory postsynaptic potentials at dendritic glutamatergic synapses and impaired the induction of activity-dependent long-term potentiation. CDGI deletion selectively increased psychostimulant-induced repetitive behaviors, disrupted sequence learning, and eliminated M1R blockade of cocaine self-administration. These findings place CDGI as a major, but previously unrecognized, mediator of cholinergic signaling in the striatum. The effects of CDGI deletion on the self-administration of drugs of abuse and its marked alterations in hyperkinetic extrapyramidal disorders highlight CDGI's therapeutic potential.

Are Patients with Asthma and Chronic Obstructive Pulmonary Disease Preferred Targets of COVID-19?

The coronavirus pandemic, known as coronavirus disease 2019 (COVID-19), is an infectious respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus first identified in patients from Wuhan, China. Since December 2019, SARS-CoV-2 has spread swiftly around the world, infected more than 25 million people, and caused more than 800,000 deaths in 188 countries. Chronic respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD) appear to be risk factors for COVID-19, however, their prevalence remains controversial. In fact, studies in China reported lower rates of chronic respiratory conditions in patients with COVID-19 than in the general population, while the trend is reversed in the United States and Europe. Although the underlying molecular mechanisms of a possible interaction between COVID-19 and chronic respiratory diseases remain unknown, some observations can help to elucidate them. Indeed, physiological changes, immune response, or medications used against SARS-CoV-2 may have a greater impact on patients with chronic respiratory conditions already debilitated by chronic inflammation, dyspnea, and the use of immunosuppressant drugs like corticosteroids. In this review, we discuss importance and the impact of COVID-19 on asthma and COPD patients, the possible available treatments, and patient management during the pandemic.

Causes of hospitalization and characteristics of Algerian chronic obstructive pulmonary disease patients in Tizi-Ouzou: a retrospective study.

Chronic obstructive pulmonary disease (COPD) is a progressive chronic inflammatory disease and the third cause of death worldwide in 2016. COPD epidemiology is well documented in high-income countries where the disease is well managed. However, the disease is neglected in low-income countries and there is lack of data. Our study aims to identify COPD patients' characteristics and hospital admission causes, and to determine disease etiologies and associated factors. A retrospective study was conducted in COPD Algerian patients using medical record data collected from January 2007 to May 2017 at the pulmonology department of the Belloua Hospital of Tizi-Ouzou city. Out of 133 hospital admissions for COPD during the study period, only 120 records were found and analyzed. Most of the admitted patients were men (96%) and the mean age was 74.29±9.56 years. Among them, 78.7% were in the GOLD stage III or IV and 9 deaths (7.5%) were recorded during the study period. Interestingly, disease severity is associated with increasing age of the patients and mortality (p=0.01 and p=0.02, respectively). Risk factors include cigarette smoking (93%), history of medical conditions (36.66%) with the most prevalent conditions being emphysema (38.63%) and asthma (27.27%), the cold season (47%), and occupational exposures (58%). Most of the admissions (64.16%) were due to acute dyspnea and 21.66 % to respiratory infections, however, 34.16 % of patients were readmitted at least one time. Comorbidities were observed in 57.5% of the patients, including cardiovascular diseases (63.76%) and diabetes (18.84%). These results show that COPD severity is associated with age and mortality. Better understanding of the COPD etiologies and the causes of hospital admission will lead to more effective management of the disease.

Conditioned taste avoidance induced by the combination of heroin and cocaine: Implications for the use of speedball.

Speedball (heroin + cocaine) is a prevalent drug combination among intravenous drug users. Although its use is generally discussed to be a function of changes in the rewarding effects of either or both drugs, changes in the aversive effects of either drug may also be impacted (weakened) by the combination. To address this latter possibility and its potential role in the use of speedball, the present studies examined the interaction of cocaine and heroin in taste avoidance conditioning. In Experiment 1, male Sprague-Dawley rats were given access to a novel saccharin solution and then injected with either vehicle or heroin (3.2 mg/kg, IP) followed immediately by various doses of cocaine (10, 18 or 32 mg/kg, SC). At the two lowest doses of cocaine, only animals injected with the drug combination (H + C) displayed a taste avoidance relative to control subjects (taste avoidance was induced with both the combination and the high dose of cocaine). At no dose did animals injected with the combination of heroin and cocaine drink more than animals injected with cocaine alone. In Experiment 2, male Sprague-Dawley rats were similarly treated but injected with vehicle or cocaine (10 mg/kg) followed by injections of various doses of heroin (1.8, 3.2, 5.6 or 10 mg/kg). At the three highest doses of heroin, only animals injected with the drug combination (C + H) displayed significant avoidance relative to control subjects (no avoidance was evident with the combination of cocaine and the low dose of heroin). At no dose did animals injected with the combination of cocaine and heroin drink more than animals injected with heroin alone. Together, these results suggest that the aversive effects of heroin and cocaine are not attenuated by co-administration by cocaine and heroin, respectively. The importance of this for the use of speedball was discussed.

Behavioral and transcriptome alterations in male and female mice with postnatal deletion of TrkB in dorsal striatal medium spiny neurons.

BACKGROUND: The high affinity tyrosine kinase receptor, TrkB, is the primary receptor for brain derived neurotrophic factor (BDNF) and plays an important role in development, maintenance and plasticity of the striatal output medium size spiny neuron. The striatal BDNF/TrkB system is thereby implicated in many physiologic and pathophysiologic processes, the latter including mood disorders, addiction, and Huntington's disease. We crossed a mouse harboring a transgene directing cre-recombinase expression primarily to postnatal, dorsal striatal medium spiny neurons, to a mouse containing a floxed TrkB allele (fB) mouse designed for deletion of TrkB to determine its role in the adult striatum. RESULTS: We found that there were sexually dimorphic alterations in behaviors in response to stressful situations and drugs of abuse. Significant sex and/or genotype differences were found in the forced swim test of depression-like behaviors, anxiety-like behaviors on the elevated plus maze, and cocaine conditioned reward. Microarray analysis of dorsal striatum revealed significant dysregulation in individual and groups of genes that may contribute to the observed behavioral responses and in some cases, represent previously unidentified downstream targets of TrkB. CONCLUSIONS: The data point to a set of behaviors and changes in gene expression following postnatal deletion of TrkB in the dorsal striatum distinct from those in other brain regions.

A role for delta opioid receptors in the central nucleus of the amygdala in anxiety-like behaviors.

RATIONALE: Compounds acting on delta opioid receptors (DOR) modulate anxiety-like behaviors, yet the site of action underlying this effect is unknown. DOR mRNA and protein are expressed in the central nucleus of the amygdala, a region that plays an important role in processing fear, stress, and anxiety. We hypothesized that this brain region may contribute to the modulation of anxiety by DOR drugs. OBJECTIVE: The present study investigated the role of DOR in the central amygdala in anxiety-like behaviors. METHODS: The selective DOR agonist [D-Pen 2,5]-enkephalin (DPDPE) or antagonist naltrindole was bilaterally microinjected into the central nucleus of the amygdala of adult male Sprague Dawley rats and anxiety-like behaviors were assessed using the elevated plus maze. The effects of DOR agonists on heightened anxiety produced by stress were also investigated. RESULTS: Rats injected with DPDPE into the central nucleus of the amygdala demonstrated less anxiety-like behavior, as evidenced by significantly greater number of open-arm entries and time spent in the open arms than controls. Naltrindole administered alone did not affect the duration or number of entries onto the open arms; however, naltrindole pre-treatment blocked the anxiolytic effects produced by DPDPE. Systemic administration of the selective DOR agonist, SNC80, or microinjection of DPDPE into the central amygdala prior to a swim stress blocked the anxiogenic effect produced by the swim stress. CONCLUSIONS: These findings provide direct evidence that activation of DOR in the central amygdala reduces anxiety-like behavior and suggest that DOR in this area are important for regulating anxious states.

Strain differences in the acquisition of nicotine-induced conditioned taste aversion.

Lewis (LEW) and Fischer (F344) rat strains differ on a variety of physiological and behavioral endpoints, including reactivity to drugs of abuse. Although they differ in drug reactivity, such assessments are generally limited to morphine and cocaine. To determine if these differences generalize to other drugs, the present study examined these strains for their reactivity to the affective properties of nicotine, specifically their sensitivity to nicotine in the conditioned taste aversion preparation. For four or five conditioning cycles given every other day, rats from both strains were allowed access to saccharin and injected with nicotine (0.1, 0.4, 0.8 mg/kg) or vehicle. On intervening days, all rats were given access to water and injected with vehicle. Under this one-bottle training and testing procedure, neither strain displayed aversions at the lowest dose of nicotine (0.1 mg/kg). Aversions were evident for both strains at 0.4 and 0.8 mg/kg, although the F344 rats acquired the aversions at 0.4 mg/kg faster and displayed a significantly greater aversion at 0.8 mg/kg than subjects from the LEW strain. For both strains, aversions were evident at all doses (and in a dose-dependent manner) when subjects were given access to saccharin and water in a two-bottle test. There were, however, no strain differences on this test. Differences between the two strains in their acquisition of nicotine-induced taste aversions were discussed in the context of aversion assessments with other compounds as well as in relation to differences in the self-administration of nicotine in the two strains.