Serial exposure to ethanol drinking and methamphetamine enhances glutamate excitotoxicity.

A significant comorbidity exists between alcohol and methamphetamine (Meth) abuse but the neurochemical consequences of this co-abuse are unknown. Alcohol and Meth independently and differentially affect glutamatergic transmission but the unique effects of their serial exposure on glutamate signaling in mediating damage to dopamine neurons are unknown. Sprague-Dawley rats had intermittent voluntary access to 10% ethanol (EtOH) every other day and water over 28 days and were then administered a binge injection regimen of Meth or saline. EtOH drinking decreased the glutamate aspartate transporter and increased basal extracellular concentrations of glutamate within the striatum when measured after the last day of drinking. Ceftriaxone is known to increase the expression and/or activity of glutamate transporters in the brain and prevented both the decreases in glutamate aspartate transporter and the increases in basal extracellular glutamate when administered during EtOH drinking. EtOH drinking also exacerbated the acute increases in extracellular glutamate observed upon Meth exposure, the subsequent increases in spectrin proteolysis, and the long-term decreases in dopamine content in the striatum, all of which were attenuated by ceftriaxone administration during EtOH drinking only. These results implicate EtOH-induced increases in extracellular glutamate and corresponding decreases in glutamate uptake as mechanisms that contribute to the vulnerability produced by EtOH drinking and the unique neurotoxicity observed after serial exposure to Meth that is not observed with either drug alone. Open Science: This manuscript was awarded with the Open Materials Badge For more information see: https://cos.io/our-services/open-science-badges/.

Neurotoxicity to dopamine neurons after the serial exposure to alcohol and methamphetamine: Protection by COX-2 antagonism.

A significant co-morbidity exists between alcohol and methamphetamine (Meth) in humans but the consequences and mechanisms underlying their co-morbid effects remain to be identified. A consequence associated with the abuse of either alcohol or Meth involves inflammation but little is known about the role of inflammation in a possible neurotoxicity arising from their co-exposure. Sprague Dawley rats were allowed 28 days of intermittent, voluntary access to 10% ethanol (EtOH) followed by a neurotoxic binge administration of Meth. EtOH drinking followed by Meth increased microglial cell counts and produced morphological changes in microglia of the substantia nigra pars compacta 2 h after Meth administration that were distinct from those produced by either EtOH or Meth alone. These effects preceded the activation of cleaved caspase-3 in dopamine cell bodies, as well as decreases in tyrosine hydroxylase (TH) immunoreactivity in the substantia nigra and dopamine transporter (DAT) immunoreactivity in the striatum measured at 7 days after Meth. Intervention with a selective COX-2 inhibitor during EtOH drinking prevented the changes in microglia, and attenuated the increase in cleaved caspase-3, and decreases in TH and DAT after Meth administration. Furthermore, motor dysfunction measured by a rotarod test was evident but only in rats that were exposed to both EtOH and Meth. The motor dysfunction was ameliorated by prior inhibition of COX-2 during EtOH drinking. The exaggerated neurochemical and behavioral deficits indicate that the comorbidity of EtOH and Meth induces a degeneration of the nigrostriatal pathway and support the role of inflammation produced by EtOH drinking that primes and mediates the neurotoxic consequences associated with the common co-morbidity of these drugs.

Methamphetamine-Induced Brain Injury and Alcohol Drinking.

A majority of methamphetamine (Meth) abusers also abuse alcohol but the neurochemical consequences of this co-abuse are unknown. Individually, alcohol and Meth cause inflammation and long-term alterations in dopamine and serotonin signaling within the brain. Experiments were conducted to identify if serial exposure to alcohol and Meth has neurochemical consequences that are greater than after either drug alone. Male Sprague Dawley rats voluntarily drank 10% ethanol (EtOH) every other day for 4 weeks and were then exposed to a binge injection regimen of Meth (10 mg/kg injected every 2 h, for a total of 4 injections). EtOH drinking and preference increased over the 4 weeks and caused inflammation evidenced by increases in serum and brain lipopolysaccharide (LPS) and brain cyclooxygenase-2 (COX-2) 24 h after the last day of drinking. Meth alone depleted dopamine and serotonin in the striatum, as well as serotonin in the prefrontal cortex when measured 1 week later. In contrast, EtOH drinking alone did not affect dopamine and serotonin content in the striatum and prefrontal cortex, but prior EtOH drinking followed by injections of Meth enhanced Meth-induced depletions of dopamine, serotonin, as well as dopamine and serotonin transporter immunoreactivities in a manner that was correlated with the degree of EtOH consumption. Cyclooxygenase inhibition by ketoprofen during EtOH drinking blocked the increases in LPS and COX-2 and the enhanced decreases in dopamine and serotonin produced by Meth. Therefore, prior EtOH drinking causes an increase in inflammatory mediators that mediate a synergistic interaction with Meth to cause an enhanced neurotoxicity.

Interface Engineering of Mn-Doped ZnSe-Based Core/Shell Nanowires for Tunable Host-Dopant Coupling.

Transition metal ion doped one-dimensional (1-D) nanocrystals (NCs) have advantages of larger absorption cross sections and polarized absorption and emissions in comparison to 0-D NCs. However, direct synthesis of doped 1-D nanorods (NRs) or nanowires (NWs) has proven challenging. In this study, we report the synthesis of 1-D Mn-doped ZnSe NWs using a colloidal hot-injection method and shell passivation for core/shell NWs with tunable optical properties. Experimental results show optical properties of the NWs are controlled by the composition and thickness of the shell lattice. It was found that both the host-Mn energy transfer and Mn-Mn coupling are strongly dependent on the type of alloy at the interface of doped core/shell NWs. For Mn-doped type I ZnSe/ZnS core/shell NWs, the ZnS shell passivation can enhance florescence quantum yield with little effect on the location of the incorporated Mn dopant due to the identical cationic Zn2+ site available for Mn dopants throughout the core/shell NWs. However, for Mn-doped quasi type II ZnSe/CdS NWs and ZnSe/CdS/ZnS core/shell NWs, the cation alloying (Zn1-xCdxS(e)) can lead to metal dopant migration from the core to the alloyed interface and tunable host-dopant energy transfer efficiencies and Mn-Mn coupling. As a result, a tunable dual-band emission can be achieved for the doped NWs with the cation-alloyed interface. The interfacial alloying mediated energy transfer and Mn-Mn coupling provides a method to control the optical properties of the doped 1-D core/shell NWs.

Disruption of the Glutamate-Glutamine Cycle Involving Astrocytes in an Animal Model of Depression for Males and Females.

Background: Women are twice as likely as men to develop major depression. The brain mechanisms underlying this sex disparity are not clear. Disruption of the glutamate-glutamine cycle has been implicated in psychiatric disturbances. This study identifies sex-based impairments in the glutamate-glutamine cycle involving astrocytes using an animal model of depression. Methods: Male and female adult Long-Evans rats were exposed to chronic social defeat stress (CSDS) for 21 days, using a modified resident-intruder paradigm. Territorial aggression was used for males and maternal aggression was used for females to induce depressive-like deficits for intruders. The depressive-like phenotype was assessed with intake for saccharin solution, weight gain, estrous cycle, and corticosterone (CORT). Behaviors displayed by the intruders during daily encounters with residents were characterized. Rats with daily handling were used as controls for each sex. Ten days after the last encounter, both the intruders and controls were subjected to a no-net-flux in vivo microdialysis to assess glutamate accumulation and extracellular glutamine in the nucleus accumbens (NAc). The contralateral hemispheres were used for determining changes in astrocytic markers, including glial fibrillary acidic protein (GFAP) and glutamate transporter-1 (GLT-1). Results: Both male and female intruders reduced saccharin intake over the course of CSDS, compared to their pre-stress period and to their respective controls. Male intruders exhibited submissive/defensive behaviors to territorial aggression by receiving sideways threats and bites. These males showed reductions in striatal GLT-1 and spontaneous glutamine in the NAc, compared to controls. Female intruders exhibited isolated behaviors to maternal aggression, including immobility, rearing, and selfgrooming. Their non-reproductive days were extended. Also, they showed reductions in prefrontal and accumbal GFAP+ cells and prefrontal GLT-1, compared to controls. When 10 µM of glutamate was infused, these females showed a significant accumulation of glutamate compared to controls. Infusions of glutamate reduced extracellular glutamine for both male and female intruders compared to their respective controls. Conclusion: Twenty-one days of territorial or maternal aggression produced a depressive-like phenotype and impaired astrocytes in both male and female intruders. Disruption of the glutamate-glutamine cycle in the PFC-striatal network may be linked to depressive-like deficits more in females than in males.

Drosophila muller f elements maintain a distinct set of genomic properties over 40 million years of evolution.

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25-50%) than euchromatic reference regions (3-11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11-27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4-3.6 vs. 8.4-8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu.

Escape and avoidance learning in the earthworm Eisenia hortensis.

Interest in instrumental learning in earthworms dates back to 1912 when Yerkes concluded that they can learn a spatial discrimination in a T-maze. Rosenkoetter and Boice determined in the 1970s that the "learning" that Yerkes observed was probably chemotaxis and not learning at all. We examined a different form of instrumental learning: the ability to learn both to escape and to avoid an aversive stimulus. Freely moving "master" worms could turn off an aversive white light by increasing their movement; the behavior of yoked controls had no effect on the light. We demonstrate that in as few as 12 trials the behavior of the master worms comes under the control of this contingency.