Title

Investigation Into Select Isoquinolines as a Putative Causal Agent of Ethanol Addiction in Mammals

Date of Award

2009

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry and Biochemistry

First Advisor

Robert C. Bateman, Jr.

Advisor Department

Chemistry and Biochemistry

Abstract

Alcohol is the most abused drug in America today. The neurological root of the problem is still a much debated subject and many differing views exist on the nature of alcoholism, be it a social dysfunction or a neurochemical imbalance. Some researchers have proposed that a skewed metabolism of dopamine that results in the formation of tetrahydroisoquinoline (THIQ) alkaloids plays a major role in the neurochemical acquisition and maintenance of alcohol addiction. In an effort to better understand the relationship of THIQ's to alcohol addiction, a series of experiments have been conducted. The chiral separation via high pressure liquid chromatography (HPLC) of various salsolinol (SAL) and salsolinol-derived compounds using a macrocyclic substituted sugar, sulfated β-cyclodextrin, as a chiral mobile phase additive was investigated. These HPLC separations yield data on a cheap and effective method for resolving enantiomers of simple catecholamines. The second set of experiments involved measuring the ethanol intake of rats given intracerebroventricular (ICV) injections of racemic tetrahydropapaveroline (THP) and R-(+)-THP. A similar experiment was conducted with tetrahydroberbine (THB). Finally, rats were administered ethanol solutions via gavage and the local cerebrospinal fluid (CSF) in the lateral ventricle of the rats' brains was sampled via microdialysis. These dialysate solutions were assayed for THP concentration using high pressure liquid chromatography with electrochemical detection (HPLC-ECD). The results of our experiments indicate that THP is formed in vivo in the rat brain and THP levels increase in response to ethanol ingestion. This finding appears to support the hypothesis that THP plays an important role in the etiology or symptoms of alcoholism in humans.