The α6 GABAA Receptor Positive Allosteric Modulator DK-I-56-1 Reduces Tic-Related Behaviors in Mouse Models of Tourette Syndrome

Tourette syndrome (TS) is a disabling neurodevelopmental disorder characterized by multiple, recurrent tics. The pharmacological treatment of TS is currently based on dopaminergic antagonists; however, these drugs are associated with extrapyramidal symptoms and other serious adverse events. Recent evidence suggests that positive allosteric modulators (PAMs) of GABA(A) receptors containing oc6 subunits (alpha 6 GABA(A) Rs) oppose the behavioral effects of dopamine. Building on this evidence, in the present study, we tested the efficacy of DK-I-56-1, a highly selective PAM for alpha 6 GABA(A) Rs, in mouse models of TS exhibiting tic-related responses. DK-I-56-1 significantly reduced tic-like jerks and prepulse inhibition (PPI) deficits in D1CT-7 transgenic mice, a well-documented mouse model of TS. DK-I-56-1 also prevented the exacerbation of spontaneous eyeblink reflex induced by the potent dopamine D-1 receptor agonist SKF 82958, a proxy for tic-like responses. We also showed that both systemic and prefrontal cortical administration of DK-I-56-1 countered the PPI disruption caused by SKF 82958. Although the effects of DK-I-56-1 were akin to those elicited by dopaminergic antagonists, this drug did not elicit extrapyramidal effects, as measured by catalepsy. These results point to alpha 6 GABA(A)R PAMs as promising TS therapies with a better safety profile than dopaminergic antagonists.

Automated summary

This study found that a novel drug targeting GABA(A) receptors, DK-I-56-1, effectively reduced tic-like jerks and PPI deficits in mouse models of Tourette syndrome, and prevented the adverse effects of dopamine. The drug showed similar effects to dopaminergic antagonists but did not elicit extrapyramidal symptoms.