The following is a synopsis of the discussions and con- tive diseases. As it turned out, the situation wasn’t quite so simple. clusions from the meeting “Neuronal Degeneration and Novel Therapeutic Approaches in Parkinson’s Disease” While L-dopa is a remarkably effective treatment, after 5 to 10 or 15 years of treatment, L-dopa becomes less that was convened at the Juan March Center for International Meetings on Biology Workshops in Madrid. The effective in a manner that is quite distinct from typical drug-induced tolerance. For instance, patients experiorganizers were CW Olanow (Mt. Sinai Medical Center, NY), Jose A. Obeso (University of Navarra, Pamplona), ence severe fluctuations in the drug effect. The so-called “OFF” phenomenon describes the time when the drug and Rosario Moratalla (Instituto Cajal, Madrid). The organizers and the Instituto Juan March brought together somehow becomes ineffective for the patient. At such times, the patient freezes up momentarily and loses a strong group of clinicians and basic scientists, and in doing so, they hosted a scientifically as well as medically mobility. The “ON” times are when the drug works and the patient gains mobility. However, both the ON and relevant state-of-the-art workshop on brain systems function and new therapeutic strategies that are relevant OFF times may be unfavorable. Symptoms can fluctuate wildly with L-dopa treatment or analog drugs, in effect to Parkinson’s disease. In addition to providing a review of some of the specific discussions and presentations resulting in problems during both the ON and OFF times. During OFF times, freezing, rigidity, and an inability to from the meeting (due to space restrictions, it is not possible to review all of the presentations), this report initiate movement is further compounded by side effects during ON times, such as involuntary movements generis intended to serve the general reader with an overview of this rapidly developing field. ated by the drug. These hyperactive movements and dystonia (abnormal muscle tension and postures) are Without pharmacological treatment, a typical person afflicted with Parkinson’s disease displays a stiff posture very debilitating. Since the ON-OFF phenomena in Parkinson’s disease are so debilitating, some neurosurand slightly unstable gait, with trembling hands and arms, and moves laboriously with short steps. The lack geons and neurologists have returned to brain surgery as a means to restrain these symptoms. Likewise, deepof movement control, tremors, instability in their posture, gait disturbance, masked face, muscle rigidity, vocal brain electrical stimulation (DBS) of the subthalamic nucleus has also been shown to alleviate some of the diminution, oradditionalautonomicreactionsarephysically as well as emotionally incapacitating, and many movement disorders of Parkinson’s disease (Benabid, 2003; Lozano et al., 2002; Welter et al., 2004). patients with Parkinson’s disease experience emotional difficulties in dealing with the disease, although their What accounts for the loss of the effectiveness of L-dopa therapy and what are the neurobiological mechcognitive functions are largely unaffected. This surprising range of symptoms is caused by the relatively selec- anisms that underlie the ON-OFF phenomena? It is reasonable to assume that one of the reasons L-dopa tive loss of a small population of approximately 500,000 dopaminergic neurons in the brain. These cells are situ- becomes less effective is that it cannot be taken up by the depleted number of surviving dopaminergic neuated deep in the midbrain in a region called the substantia nigra (literally meaning “black substance”) whose rons. If indeed …