Blunted Cystine–Glutamate Antiporter Function in the Nucleus Accumbens Promotes Cocaine-induced Drug Seeking

Repeated cocaine alters glutamate neurotransmission, in part, by reducing cystine–glutamate exchange via system xc−, which maintains glutamate levels and receptor stimulation in the extrasynaptic compartment. In the present study, we undertook two approaches to determine the significance of plasticity involving system xc−. First, we examined whether the cysteine prodrug N-acetylcysteine attenuates cocaine-primed reinstatement by targeting system xc−. Rats were trained to self-administer cocaine (1 mg/kg/200 μl, i.v.) under extended access conditions (6 h/day). After extinction training, cocaine (10 mg/kg, i.p.) primed reinstatement was assessed in rats pretreated with N-acetylcysteine (0–60 mg/kg, i.p.) in the presence or absence of the system xc− inhibitor (S)-4-carboxyphenylglycine (CPG; 0.5 μM; infused into the nucleus accumbens). N-acetylcysteine attenuated cocaine-primed reinstatement, and this effect was reversed by co-administration of CPG. Secondly, we examined whether reduced system xc− activity is necessary for cocaine-primed reinstatement. To do this, we administered N-acetylcysteine (0 or 90 mg/kg, i.p.) prior to 12 daily self-administration sessions (1 mg/kg/200 μl, i.v.; 6 h/day) since this procedure has previously been shown to prevent reduced activity of system xc−. On the reinstatement test day, we then acutely impaired system xc− in some of the rats by infusing CPG (0.5 μM) into the nucleus accumbens. Rats that had received N-acetylcysteine prior to daily self-administration sessions exhibited diminished cocaine-primed reinstatement; this effect was reversed by infusing the cystine–glutamate exchange inhibitor CPG into the nucleus accumbens. Collectively these data establish system xc− in the nucleus accumbens as a key mechanism contributing to cocaine-primed reinstatement

Population dynamics of grape phylloxera in California vineyards

Field monitoring was conducted to investigate population growth of grape phylloxera, Daktulosphaira vitifoliae (Fitch), in commercial grapevines in California. Phylloxera populations started from very low densities each spring, they increased exponentially and peaked during mid-summer, and then declined from mid-to late-summer. A second population peak was observed in the fall. Populations increased and declined simultaneously across all age classes. Egg populations were highest, followed by 1st and 2nd and then 3rd and 4th instars; adult populations were the lowest. The distribution of age classes as a proportion of the total population indicated a higher intrinsic rate of increase in field vines in spring and early summer than was observed in the laboratory. Densities of phylloxera on tuberosities were highest during the summer and coincided with the population maximum. Densities of phylloxera on nodosities were highest in early spring and in the fall and coincided with periods of root flush. Evaluation of the relationship of soil temperatures to developing phylloxera suggested that decline of phylloxera populations in mid-and late-summer cannot be attributed to temperatures below a developmental threshold. Decreased root quality or quantity and mortality factors may explain this decline. Phylloxera overwintered as 1st or 2nd instars. Analysis of spatial distribution of phylloxera using Taylor's power law and Iwao's patchiness regression indicated that phylloxera populations are aggregated. The significance of this research with respect to phylloxera management is discussed

Fungal infections of grapevine roots in phylloxera-infested vineyards

Wounds caused by feeding of grape phylloxera on grape roots can become infected with a variety of fungi. Fusarium roseum, F. oxysporum and Pythium ultimum are important in Vitis vinifera Chardonnay wounds whereas F. oxysporum and Cephalosporium sp. are important for the moderately tolerant rootstock AXR#1. Proportion of root lengths infected in the phloem parenchyma were measured in two vineyards through the 1996 growing season and into the winter. Infection rates were highest in spring (as measured in May) but decreased to a low level by the end of summer. There was a second infection peak in fall. We suggest that the decline in fungal infections was due to death of highly infected roots and their removal from the sampled pool of roots. Loss of roots is a logical cause of vine decline and explains why there have been poor correlations between phylloxera populations and vine damage symptoms

Repeated \u3cem\u3eN\u3c/em\u3e-Acetylcysteine Administration Alters Plasticity-Dependent Effects of Cocaine

Cocaine produces a persistent reduction in cystine–glutamate exchange via system xc− in the nucleus accumbens that may contribute to pathological glutamate signaling linked to addiction. System xc− influences glutamate neurotransmission by maintaining basal, extracellular glutamate in the nucleus accumbens, which, in turn, shapes synaptic activity by stimulating group II metabotropic glutamate autoreceptors. In the present study, we tested the hypothesis that a long-term reduction in system xc− activity is part of the plasticity produced by repeated cocaine that results in the establishment of compulsive drug seeking. To test this, the cysteine prodrug N-acetylcysteine was administered before daily cocaine to determine the impact of increased cystine–glutamate exchange on the development of plasticity-dependent cocaine seeking. Although N-acetylcysteine administered before cocaine did not alter the acute effects of cocaine on self-administration or locomotor activity, it prevented behaviors produced by repeated cocaine including escalation of drug intake, behavioral sensitization, and cocaine-primed reinstatement. Because sensitization or reinstatement was not evident even 2–3 weeks after the last injection of N-acetylcysteine, we examined whether N-acetylcysteine administered before daily cocaine also prevented the persistent reduction in system xc− activity produced by repeated cocaine. Interestingly, N-acetylcysteine pretreatment prevented cocaine-induced changes in [35S]cystine transport via system xc−, basal glutamate, and cocaine-evoked glutamate in the nucleus accumbens when assessed at least 3 weeks after the last N-acetylcysteine pretreatment. These findings indicate that N-acetylcysteine selectively alters plasticity-dependent behaviors and that normal system xc− activity prevents pathological changes in extracellular glutamate that may be necessary for compulsive drug seeking

Effects of fungal root infection on the vigor of grapevines infested by root-feeding grape phylloxera

The role of fungal pathogens in damage of grapevines (Vitis vinifera L.; cv. Chardonnay) associated with grape phylloxera (Daktulosphaira vitifoliae FITCH) was investigated. Seven different genera of secondary fungi were isolated from surface-disinfected feeding sites of phylloxera but none from surface-disinfected root tissues undamaged by phylloxera. Damage in vines infested with phylloxera and infected with Fusarium solani (MART.) or with F. solani and Pythium ultimum TROW. was significantly greater than damage in vines infested with phylloxera only. In a greenhouse experiment, total biomass was reduced by 16% in vines infested with phylloxera and 24 to 29% in vines infested with phylloxera and infected with fungus in comparison with control vines. Chlorophyll content, average internode length, shoot biomass, and root biomass in the uninfested, uninfected vines were significantly greater than vines infested with phylloxera or vines infested with phylloxera and infected with F. solani or P. ultimum, or both. Preventative treatment with metalaxyl, benomyl or copper quinolinolate fungicides significantly decreased damage in phylloxera-infested vines in comparison with untreated vines. The implications of this research with respect to management of grape phylloxera are discussed

An asymptomatic case of peritoneal encapsulation: case report and review of the literature

Peritoneal encapsulation is a rare congenital anomaly characterised by a thin membrane of peritoneum encasing the small bowel to form an accessory peritoneal sac. We present a case of peritoneal encapsulation diagnosed incidentally in an 82 year old man undergoing laparotomy for colonic cancer. The sac was easily excised and surgery was otherwise uneventful. A discussion of the case and a review of the literature are presented

Gravitational Collapse of Dust with a Cosmological Constant

The recent analysis of Markovic and Shapiro on the effect of a cosmological constant on the evolution of a spherically symmetric homogeneous dust ball is extended to include the inhomogeneous and degenerate cases. The histories are shown by way of effective potential and Penrose-Carter diagrams.Comment: 2 pages, 2 figures (png), revtex. To appear in Phys. Rev.

Human 3D cellular model of hypoxic brain injury of prematurity.

Owing to recent medical and technological advances in neonatal care, infants born extremely premature have increased survival rates1,2. After birth, these infants are at high risk of hypoxic episodes because of lung immaturity, hypotension and lack of cerebral-flow regulation, and can develop a severe condition called encephalopathy of prematurity3. Over 80% of infants born before post-conception week 25 have moderate-to-severe long-term neurodevelopmental impairments4. The susceptible cell types in the cerebral cortex and the molecular mechanisms underlying associated gray-matter defects in premature infants remain unknown. Here we used human three-dimensional brain-region-specific organoids to study the effect of oxygen deprivation on corticogenesis. We identified specific defects in intermediate progenitors, a cortical cell type associated with the expansion of the human cerebral cortex, and showed that these are related to the unfolded protein response and changes. Moreover, we verified these findings in human primary cortical tissue and demonstrated that a small-molecule modulator of the unfolded protein response pathway can prevent the reduction in intermediate progenitors following hypoxia. We anticipate that this human cellular platform will be valuable for studying the environmental and genetic factors underlying injury in the developing human brain