Salsolinol in the Pathophysiology of Alcohol Dependence and Parkinson's Disease

Chung, In Won; Jeong, Seong Hoon; Kim, Jin Young

Abstract

Salsolinol, a dopamine-derived tetrahydroisoquinoline, is one of the endogenous alkaloids structurally related to morphine. It has been implicated in the pathophysiology of alcohol dependence and Parkinson's disease since it's first discovery in 1970's. Salsolinol is involved in many neurophysiological processes, including modulation of dopamine activity, facilitation of prolactin release and reinforcement of additive substance craving. In addition, salsolinol exerts highly neurotoxic effects on dopaminergic neurons ultimately leading to apoptosis, which is mediated by inhibition of endogenous antioxidants and, thereby, production of reactive oxygen species (ROS). These properties are considerably based in alcohol dependence and several neurodegenerative disorders including Parkinson's disease. Salsolinol is synthesized by the condensation of dopamine with acetaldehyde or pyruvate through enzymatic or non-enzymatic processes in the dopamine-rich neurons. Acute alcohol ingestion increase the level of acetaldehyde and salsolinol is structurally related to endogenous opioids. Therefore, it has been suggested that salsolinol may be the missing link between alcohol ingestion and the activation of reward pathway in the mesolimbic brain. The reinforcing effect of both alcohol and salsolinol in self-administration setting also strongly supports this hypothesis. N-methylsalsolinol, the major metabolite of salsolinol, is highly neurotoxic and responsible for the selective destruction of dopaminergic neurons in Parkinson's disease. In contrast to this, several structural analogs of salsolinol act as endogenous anti-parkinsonism substances. Delicate structural differences may underlie this peculiar properties. It may become possible to introduce fine structural modifications, even stereo-specific manipulations, to develop entirely newer kinds of antiparkinsonism drugs. Although the implication of salsolinol in the pathophysiology of alcohol dependence had been suggested long ago, the progression of the related research was at most very limited up to now. Even now, this important chemical, deeply involved in a wide range of essential neurophysiological processes, still is relatively neglected by psychiatric researchers. However, it is expected that the accumulating knowledge of salsolinol's neuromodulatory and neurotoxic effects will give new insights into the many dopamine related psychiatric disorders including substance dependence, parkinsonism and schizophrenia. We expect that many psychiatrists will give proper attention to this highly promising research subject.