Striatal Dopamine and Norepinephrine Levels in Conjunction with OCD-like Behaviors in a Novel Animal Model of Obsessive-Compulsive Disorder

This study evaluated behaviors and monoamine levels of the neonatal clomipramine (neoCLOM) model of Obsessive Compulsive Disorder (OCD) in male and female rats (36 of each). Subjects were injected with 15 mg/kg of the serotonin-norepinephrine uptake inhibitor clomipramine during a developmentally sensitive period. A unique combination of Hole Board (HB) and Elevated Plus Maze (EPM) apparatuses was used to evaluate compulsiveness and anxiety. There was a significant effect of Treatment in the HB. Male neoCLOMs had increased hole poke and repeats versus control male neoSALs. In contrast, there was a significant effect of Sex in the EPM. Female neoCLOMs spent more time in open arms than male neoCLOMs. HB and EPM behaviors did not correlate for any group. Serotonin (5-HT), dopamine (DA), and norepinephrine (NE) levels in post mortem tissue homogenates from the hypothalamus and amygdala were analyzed using High Performance Liquid Chromatography. There were significant effects of Treatment and Sex. Neurochemical abnormalities reflect monoamine dysfunction in OCD patients. Results support some aspects of the face and construct validity of the model. Further research is needed to evaluate the model\u27s predictive validity, sensitivity to sex differences, and potential usefulness in identification of new treatment methods for OCD patients.https://orb.binghamton.edu/research_days_posters_spring2020/1004/thumbnail.jp

The Effects of Vilazodone, YL-0919, and Vortioxetine in L-DOPA Treated Hemiparkinsonian Rats

Parkinson\u27s Disease (PD) is a debilitating, neurodegenerative disorder characterized by motor symptoms, including bradykinesia, tremor, stiffness, and postural instability, that result from significant nigrostriatal dopamine (DA) loss. The current gold standard treatment for PD involves replacement therapy via the DA precursor L-3,4-dihydroxyphenylalanine (L-DOPA); however, 90% of patients eventually experience choreic and dystonic side effects termed L-DOPA induced dyskinesia (LID). A key driver of LID is neuroplasticity within the serotonin (5-HT) system leading to the unregulated release of L-DOPA derived DA from 5-HT terminals into the striatum. Previous work has implicated the dual action of 5-HT1A receptor agonism and 5-HT transporter (SERT) blockade as an effective therapeutic method for attenuating LID. The present study examined 3 purportedly similar pharmacological drugs, Vilazodone, YL-0919, and Vortioxetine, that act as 5-HT1A agonists and SERT blockers. Adult female Sprague-Dawley rats received unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB) to deplete DA neurons. Thereafter they received 2 weeks of L-DOPA treatment until they developed stable abnormal involuntary movement (AIMs) akin to LID. Rats were also assessed for motor performance with the forepaw adjusting steps (FAS) test. Results revealed that Vilazodone and Vortioxetine significantly reduced AIMs and maintained L-DOPA beneficial prokinetic effects. In contrast, YL-0919 unexpectedly had no effect on LID though it did maintain L-DOPA motor performance. Overall, these findings support pharmacological targets within the 5-HT system that reduce LID. They also provide evidence for unique features of Vilazodone and Vortioxetine, both FDA approved compounds, as potential adjunct therapeutics for LID management in PD patients.https://orb.binghamton.edu/research_days_posters_2021/1090/thumbnail.jp

Broad Serotonergic Actions of Vortioxetine as a Promising Avenue for the Treatment of L-DOPA-Induced Dyskinesia

Parkinson\u27s Disease (PD) is a neurodegenerative disorder characterized by motor symptoms that result from loss of nigrostriatal dopamine (DA) cells. While L-DOPA provides symptom alleviation, its chronic use often results in the development of L-DOPA-induced dyskinesia (LID). Evidence suggests that neuroplasticity within the serotonin (5-HT) system contributes to LID onset, persistence, and severity. This has been supported by research showing 5-HT compounds targeting 5-HT receptors and/or the 5-HT transporter (SERT) can reduce LID. Recently, vortioxetine, a multimodal 5-HT compound developed for depression, demonstrated acute anti-dyskinetic effects. However, the durability and underlying pharmacology of vortioxetine\u27s anti-dyskinetic actions have yet to be delineated. To address these gaps, we used hemiparkinsonian rats in Experiment 1, examining the effects of sub-chronic vortioxetine on established LID and motor performance. In Experiment 2, we applied the 5-HT antagonist WAY-100635 or 5-HT antagonist SB-224289 in conjunction with L-DOPA and vortioxetine to determine the contributions of each receptor to vortioxetine\u27s effects. The results revealed that vortioxetine consistently and dose-dependently attenuated LID while independently, 5-HT and 5-HT receptors each partially reversed vortioxetine\u27s effects. Such findings further support the promise of pharmacological strategies, such as vortioxetine, and indicate that broad 5-HT actions may provide durable responses without significant side effects

\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