Chronic Clonidine and Alpha-2 Modulation of Central Noradrenergic Function: Implications for Tourette Syndrome

Grant Type
Grant Year
Institution Location
Institution Organization Name
University of Pittsburgh
Investigators Name
Mana, Michael, PhD

Clonidine is a medication which mimics the action of the neurotransmitter norepinephrine (NE) at a particular type of norepinephrine receptor in the central nervous system, the alpha-2 receptor. The fact that clonidine is an effective treatment for the symptoms of Tourette Syndrome (TS) has led to the hypothesis that a dysfunction of norepineprine’s function in the brain is involved in the development of this disorder. This idea is supported by the fact that stress, which often exacerbates the symptoms of TS, is also known to increase the activity of norepinephrine-containing neurons in a particular area of the brain called the locus coeruleus (LC). Because the norepinephrine-containing neurons of the LC send projections to many different parts of the brain, this stress-induced increase in their activity is reflected in a widespread increase in NE release throughout much of the central nervous system. The proposed experiments are based upon the hypothesis that clonidine’s therapeutic efficacy in the treatment of TS is due to this drug’s ability to alter the activity of norepinephrine-containing neurons in the LC under stressful conditions. Our research will employ electrophysiological recording techniques to examine the effect of chronic clonidine on two aspects of central noradrenergic function: 1) the basal and stress-evoked electrophysiological activity of NE-containing neurons in the LC; and 2) the modulatory effect of NE on the activity of neurons in prefrontal cortex, a forebrain area relevant to TS in which stress-related alterations in noradrenergic function have also been reported. The first project will examine chronic clonidine’s effects on the basal and evoked electrophysiological activity of single norepinephrine-containing neurons in the LC, to determine whether an alteration in the response of LC cells to stressful stimuli might contribute to clonidine’s therapeutic effect on the symptoms associated with TS. The second project will examine chronic clonidine’s effect on the sensitivity of neurons in the prefrontal cortex to the modulatory effects of norepinephrine. These experiments will help to determine whether an alteration in the effect of NE on cells that receive norepinephrine-containing projections from neurons in the LC might contribute to clonidine’s therapeutic effect on TS. Together, the proposed experiments will provide new insights into the effects of chronic clonidine on noradrenergic function in the central nervous system — insights that may be relevant to both the treatment of TS as well as to its underlying physiological bases. Michael J. Mana, Ph.D., Anthony A. Grace, Ph.D., University of Pittsburgh, Pittsburgh, PA Award $22,000 Tourette Association of America Inc. – Research Grant Award 1994