Cocaine is a habit-forming stimulant that shares with other drugs of abuse the ability to produce rewarding or """"""""reinforcing"""""""" effects. Because of the alarming rise in cocaine abuse during the last 15 years, there has been a keen interest in cocaine from both public health and basic science perspectives. Various behavior studies imply a major role of central dopamine in the expression of the pharmacological effects of cocaine, but direct biochemical support for this view is at best very sparse and inconsistent. The latter may be attributed to two important factors. First, most reports on the biochemical effect of cocaine were obtained from acute studies. Second, in the majority of these studies, the striatum and nucleus accumbens were the brain regions frequently analyzed. Therefore, certain important brain regions may have been overlooked. To correct for the above experimental flaws, we have systematically evaluated the effects of 1 to 3 weeks' chronic cocaine administration on central and peripheral biogenic amines, especially the catecholamines. The results of our investigation revealed a preferential, long-term reduction of dopamine turnover and/or metabolism in both the periphery and the brain. In the brain, the frontal cortex and the hypothalamus apparently are the areas most affected. We have concentrated our efforts in the last 12 months on understanding the mechanism by which cocaine reduces frontal cortex DA production and metabolism. One hypothesis that warrants serious consideration is the stimulation of 6-hydroxydopamine (6-OHDA) production. 6-OHDA is a very potent neurotoxin of catecholamine neurons and their terminals. Preliminary investigations indicated the presence of a 6-OHDA-like substance in the brain. This compound is elevated in a few samples after administration of cocaine and other stimulants. Except for a slightly shorter retention time, this compound shares many chromatographic characteristics with authentic 6-OHDA. We urgently need to identify this substance and follow its origin and metabolic fate, an undertaking that necessitates the use of a triple quadruple mass strectometer.
