The MCH System as a New Target for the Management of Tourette Syndrome

Grant Type
Basic
Grant Year
2011-2012
Institution Location
CA
Institution Organization Name
University of California
Investigators Name
Civelli, Oliver, PhD

A leading hypothesis in the etiology of Tourette syndrome (TS) is that it is caused by an increase in dopamine system activity. This is underscored by results from nuclear imaging protocols, cerebrospinal fluid, and post-mortem studies. But, most notably, the dopamine system’s importance in TS pathophysiology is reflected by the fact that many people with TS respond to dopamine D2 receptor antagonists. Unfortunately these drugs can have deleterious side effects due to the broad range of D2 receptor expression and action. We propose to determine whether a different neurotransmitter system, the melanin-concentrating hormone (MCH) system, could be used as a target to manage TS without traditional side effects. Our proposal is based on the finding that the MCH receptor is highly expressed in the mesocorticolimbic but not in the nigrostriatal dopaminergic system. The mesocorticolimbic system is thought to be involved in the etiology of TS while the nigrostriatal system is implicated in many of the side effects of the D2 antagonist drugs. Furthermore, because the MCH system can modulate the dopaminergic tone, it may modulate prepulse inhibition (PPI), an assay commonly used in therapies aimed at schizophrenia and TS. Consequently, we will test the role of the MCH system on PPI in mice subjected to a treatment known to relate to TS and also in rats that have been bred over several generations to model some aspects of TS. We expect to show that by blocking the MCH system we will be able to reduce some of the TS-like symptoms in these animals. On the other hand, since MCH1R is practically absent in the nigrostriatal pathway, we propose that there will be fewer locomotor side effects. If our hypothesis proves to be correct, then we would promote inhibition of the MCH system as a possible target for new TS drug therapies. Olivier Civelli, Ph.D., Mark Geyer, Ph.D., Gerard Martens, Ph.D. University of California School of Medicine, Irvine, CA Award: $70,520 Commentary: Tourette syndrome (TS) is often treated with a class of medications called dopamine D2 antagonists. These medications (also referred to as antipsychotics) often have deleterious side effects because they act not only on the intended nerve-cell pathway, but also on other brain pathways that results in the unwanted side effects. These investigators propose to target TS symptoms by taking advantage of a different nerve-cell system – the MCH system. This system is present in the pathways associated with TS but not in the pathways involved in side effects. The researchers will use rats and mice to determine whether blocking the MCH system could reduce TS-like symptoms without causing serious side effects. Tourette Association of America Inc. – Research Grant Award 2011-2012