Biology subjects

Moszczynska, A.

Publications and source records attributed to Moszczynska, A..

3 recordsLinked to original sources

bioRxiv2024

Neurotoxic Methamphetamine Doses Alter CDCel-1 Levels and Its Interaction with Vesicular Monoamine Transporter-2 in Rat Striatum

In recent years, methamphetamine METH misuse in the US has been rapidly increasing and there is no FDA-approved pharmacotherapy for METH use disorder (MUD). In addition to being dependent on the drug, people with MUD develop a variety of neurological problems related to the toxicity of this drug. A variety of molecular mechanisms underlying METH neurotoxicity has been identified, including dysfunction of the neuroprotective protein parkin. However, it is not known whether parkin loss of function within striatal dopaminergic (DAergic) terminals translates into a decrease in DA storage capacity. This study examined the relationship between parkin, its substrate cell division cycle related-1 (CDCrel-1), and vesicular monoamine transporter-2 (VMAT2) in METH neurotoxicity in male Sprague Dawley rats. To also assess individual differences in response to METHs neurotoxic effects, a large group of rats was treated with binge METH or saline and sacrificed 1h or 24h later. This study is the first to show that binge METH alters the levels and subcellular localization of CDCrel-1 and that CDCrel-1 interacts with VMAT2 and increases its levels at the plasma membrane. Furthermore, we found wide individual differences in the responses of measured indices to METH. Proteomic analysis of VMAT-2-associated proteins revealed upregulation of several proteins involved in the exocytosis/endocytosis cycle. The results suggest that at 1h after METH binge, DAergic neurons are engaged in counteracting METH-induced toxic effects, including oxidative stress- and hyperthermia-induced inhibition of synaptic vesicle cycling, with the responses varying between individual rats. Studying CDCrel-1, VMAT2, and other proteins in large groups of outbred rats can help define individual genetic and molecular differences in responses to METH neurotoxicity which, in turn, will aid treating humans suffering from METH use disorder and its neurological consequences.

neuroscience↗

bioRxiv2022

Methamphetamine induced regional-specific transcriptomic and epigenetic changes in the rat brain

BackgroundMethamphetamine (METH) is a highly addictive central nervous system stimulant. Chronic use of METH is associated with multiple neurological and psychiatric disorders. An overdose of METH can cause brain damage and even death. Mounting evidence indicates that epigenetic changes and functional impairment in the brain occur due to addictive drug exposures. However, the responses of different brain regions to a METH overdose remain unclear. ResultsWe investigated the transcriptomic and epigenetic responses to a METH overdose in four regions of the rat brain, including the nucleus accumbens, dentate gyrus, Ammons horn, and subventricular zone. We found that 24 hours after METH overdose, 15.6% of genes showed changes in expression and 27.6% of open chromatin regions exhibited altered chromatin accessibility in all four rat brain regions. Interestingly, only a few of those differentially expressed genes and differentially accessible regions were affected simultaneously. Among four rat brain regions analyzed, 149 transcription factors and 31 epigenetic factors were significantly affected by METH overdose. METH overdose also resulted in opposite-direction changes in regulation patterns of both gene and chromatin accessibility between the dentate gyrus and Ammons horn. Approximately 70% of chromatin-accessible regions with METH-induced alterations in the rat brain are conserved at the sequence level in the human genome, and they are highly enriched in neurological processes. Many of these conserved regions are active brain-specific enhancers and harbor SNPs associated with human neurological functions and diseases. ConclusionOur results indicate strong region-specific transcriptomic and epigenetic responses to a METH overdose in distinct rat brain regions. We describe the conservation of region-specific gene regulatory networks associated with METH overdose. Overall, our study provides clues toward a better understanding of the molecular responses to METH overdose in the human brain.

bioinformatics↗

bioRxiv2020

PARKIN REGULATES DRUG TAKING-BEHAVIOR IN RAT MODEL OF METHAMPHETAMINE USE DISORDER

There is no FDA-approved medication for Methamphetamine (METH) Use Disorder. New therapeutic approaches are needed, especially for people who use METH heavily and are at high risk for overdose. This study used genetically engineered rats to evaluate PARKIN as a potential target for METH Use Disorder. PARKIN knockout, PARKIN-overexpressing and wild-type young adult male Long Evans rats were trained to self-administer high doses of METH using an extended-access METH self-administration paradigm. Reinforcing/rewarding properties of METH were assessed by quantifying drug-taking behavior and time spent in a METH-paired environment. PARKIN knockout rats self-administered more METH and spent more time in the METH-paired environment than wild-type rats. Wild-type rats overexpressing PARKIN self-administered less METH and spent less time in the METH-paired environment. PARKIN knockout rats overexpressing PARKIN self-administered less METH during the first half of drug self-administration days than PARKIN-deficient rats. The results indicate that rats with PARKIN excess or PARKIN deficit are useful models for studying neural substrates underlying "resilience" or vulnerability to METH Use Disorder, and identify PARKIN as a novel potential drug target to treat heavy use of METH.

neuroscience↗