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

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

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

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

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

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

\u3ci\u3eDrosophila\u3c/i\u3e 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