Reducing tic-like behavior in D1CT-7 mouse models of Tourette syndrome through isoallopregnanolone
Abstract Tourette Syndrome (TS) is a semi-voluntary neuropsychiatric condition typified by motor and vocal manifestations known as tics. These tic episodes are generally provoked by stress exposures, although the exact mechanism is not well known. Acute stress has recently been shown to increase tic-like behavior through the well-established D1CT-7 mouse model of TS. This effect is promoted by neurosteroid synthesis of allopregnanolone (AP). Expanding on these findings, suppression of stress-induced tic-like behavior was seen as a result of AP synthesis inhibition through finasteride (FIN), while administration of AP showed profound increases in tic-like behavior. Because AP works primarily as a positive allosteric modulator at GABAA receptors, we aimed to show that either stress or AP induced increases in tic-like behavior could be mitigated by antagonizing AP binding of GABAA receptors with isoallopregnanolone (isoAP). We found that isoAP reduced tic-like behavior of D1CT-7 mice in a dose-dependent manner, and that this outcome was similar to those seen in both haloperidol, a hallmark TS therapy, and FIN. We also found AP induced tic-like behavior was successfully countered by isoAP. Because isoAP already has valid safety and tolerability profiles, our findings support its potential value in the TS armamentarium.
Very interesting what causes some of the Tics and that it can be managed somewhat. Some animals at the zoos seem to have behaviors like this due to stress.
Cole, nicely done. Tic disorders can be so devastating for the individuals experiencing them, that identification of novel treatments is desperately needed. I was curious how you measured tic behaviors in the mice, and also catalepsy?
Very promising results, Cole. If you were going to design the next trial to evaluate this treatment how would you go about it?
Great job on your poster and all the research that went into it. Seems like from your conclusion/discussion with its safety and tolerability it would be a positive hopeful to these patients. Sure excited you’ll be finishing soon! Congratulations.
Cole, nice job. this is complex neuropharmacology.
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