Neuropharmacology Laboratory

Raymon Durso, MD, Director

Description: Parkinson disease (PD) is a disorder characterized by severe reductions in striatal brain concentrations of the neurotransmitter dopamine (DA). The most effective form of therapy involves administering levodopa (LD), the immediate precursor of DA. While such therapy often relieves the major PD signs, there remain complications and less than optimal responsesnot readily explained by current understanding. One very important area which has not been adequately investigated involves LD catabolism. Specifically, in addition to LD being metabolized to DA, further metabolism of DA to a second neurotransmitter norepinephrine (NE) readily occurs after administration of LD. Production of NE from an LD dose, or lack thereof, may very well be the crucial piece of information missing to explain complications and variable response to LD and yet the issue has never been adequately studied in vivo. We use a labeling technique for LD which employs the stable isotope 13C. Currently, there are no other existing technologies that can adequately address the issue of how LD conversion to NE might affect treatment in PD. The fundamental strength of our stable isotope labeling technique relates to the virtual absence of toxicity associated with this 13C label. Stable isotope labeled LD is not a radioisotope and is not radioactive. Thus, we can administer a full pharmacologic dose which is completely labeled. This capability allows for the first time the accurate quantitation of labeled LD metabolites (including NE). We can mimic the clinical setting almost exactly. Use of radioisotopes, on the other hand, due to inherent toxicity is limited to administration of tiny tracer doses of labeled drug. It is extremely difficult to accurately quantitate a drug’s metabolism using tiny tracer doses. In this research we investigate three important issues which may be mediated through LD metabolism to NE:

1) whether diminished NE production from an administered LD dose plays a role in the PD complication of gait freezing,

2) whether enhanced production of NE from an administered LD dose exacerbates LD-induced dyskinesia and

3) whether systemic production of NE protects against LD-induced hypotension. Our use of infused stable isotope labeled LD represents the only existing current methodology which can address these important issues in patients themselves.

Approximately 80% of patients with Parkinson’s Disease (PD) develop age-related and clinically significant cognitive and affective dysfunction as the disease progresses. “Executive cognitive functions” (such as planning, insight, cognitive fluency, set-shifting and attention) mediated by prefrontal sites are the most seriously affected cognitive fimctions and depression is the most frequently reported affective dysfunction. It is not known what causes these disorders in PD or how best to treat them. Although levodopa (LD) appears to ameliorate some of these cognitive and affective impairments in PD it is not known whether LD’s beneficial effect is mediated by dopaminergic or noradrenergic mechanisms. Understanding the separate contributions of each of these catecholaminergic transmitters to cognitive and affective deficits in PD is a vitally important step in developing effective pharmacologic therapies for treatment. We attempt to quantify the separate contributions of each of these catecholaminergic transmitters to cognitive and affective deficits in PD by using a new labeling technique for LD based on stable isotopes. Stable isotopes are not radioactive so the experimenter can administer a full pharmacologic dose of LD which is completely labeled. With isotope labeling all quantitation of metabolites (e.g,, CSF HVA and CSF MHPG) represent actual amounts produced from an administered dose of LD and is not subject to errors related to estimation based on tiny radioactive tracer doses. This stable isotope methodology allow us to accurately quantify the acute effects of levodopa on dopaminergic and noradrenergic activity and these results can then be correlated with cognitive and affective performance in PD patients. Research Faculty Names and Rank: Raymon Durso, MD (Associate Professor of Neurology) Patrick McNamara, PhD (Assistant Professor of Neurology) Representative Publications: Raymon Durso MD

1) Durso R, Evans JE, Josephs E, Szabo G, Handler J, Jennings D, Browne TR. Central levodopa metabolism in Parkinson’s disease after stable isotope labeled levodopa. Ann Neurol 42:300-304, 1997.

2) Durso R. Biotransformation and excretion: quantitative studies of tissue metabolism. In TR Browne (ed.) Stable Isotopes in Pharmaceutical Research. Elssevier, Amsterdam, pp.315-335, 1997.

3) Durso R, Evans JE, Josephs E, Szabo G, Evans B, Fernandez HH,Browne TR. Variable absorption of carbidopa affects both peripheral and central levodopa metabolism. J Clin Pharm 40:854-861, 2000. Patrick McNamara, PhD

1) McNamara P, Von Harscher H, Scioli T, Krueger M, Lawson D, Durso R. The sense of self after brain damage: evidence from aphasics and individuals with Parkinson’s disease. J Cog Rehab Nov/Dec 16-23, 1995.

2) McNamara P, Clark J, Krueger M, Durso R. Sentence Comprehension and grammaticality judgements in Parkinson’s disease: a comparison with Broca’s aphasia. Internat J Neurosci 86:151-166, 1996.

3) McNamara P and Durso R. Language functions in Parkinson’s disease: evidence for a neurochemistry of language. In: Obler L and Connor LT (eds.) Neurobehavior of Language and Cognition: Studies of Normal Aging and Brain Damage. NY Kluer Academic Publishers, 1999.

Primary teaching affiliate
of BU School of Medicine