Dopamine's role as a major central neurotransmitter, and its involvement in motor activity, were confirmed when it was found that one area of the brain in particular, the caudate nucleus, contained the highest concentration of DA of any tissue in the body (Bertler and Rosengren, 1959; Sano et al., 1959). This brain area was already known to mediate the extrapyramidal side effects of several drugs, and the experiments of Vander Eecken et al. (1960) and Adams et al. (1964) showed that patients with movement disorders had loss of tissue in the caudate nucleus. It was also discovered from post-mortem samples that there were much lower levels of DA in the caudate/putamen (striatum) as well as the cell bodies of the substantia nigra (SN) in Parkinson's patients than in these same brain areas from normal individuals (Ehringer and Hornykiewicz, 1960). Within two years the efficacy of using L-DOPA to alleviate the symptoms of Parkinson's disease was reported by Birkmayer and Hornykiewicz (1961) and Barbeau et al. (1962). Interestingly, within a few years it was found that cigarette smokers had a reduced risk of developing Parkinson's disease (Nefzger et al. (1968). This negative correlation between cigarette smoking and Parkinson's disease has now been confirmed in a number of studies (reviewed by Baron, 1986; Morens et al., 1995).
The elucidation of dopamine's role in mesolimbic neurons has an equally interesting history. The neurochemical basis of reinforcement made a major advance with the discovery by Olds and Milner (1954) that there were specific areas of the brain where electrodes could be placed such that animals would work to obtain electrical stimulation by means of lever pressing. In these studies, response rates of thousands per hour were obtained, and animals would forego most other activities, including eating and drinking, to obtain stimulation (Olds and Olds, 1963). Pharmacological experiments indicated that increased catecholamine concentrations were responsible for the self-stimulation behavior since amphetamine (which was known to elevate catecholamine levels) enhanced self-stimulation whereas reserpine (which was found to deplete catecholamines in the brain) decreased this activity (Stein, 1962). The specific catecholamine involved was subsequently determined to be DA since selective DA receptor antagonists blocked the self-stimulation in animals induced by amphetamine and cocaine, whereas noradrenergic antagonists did not (Risner and Jones, 1976, 1980; deWit and Wise, 1977). Comparable experiments were conducted in human subjects (Gunne et al., 1972) showing that DA was similarly involved in the rewarding effects of amphetamine and cocaine. The dopaminergic pathway was later identified by the use of neurotoxins to originate in the ventral tegmental area (VTA) with projections to the nucleus accumbens (NAc), amygdala, olfactory tubercle and the frontal cortex (Lyness et al., 1979; Roberts and Koob, 1982; Bozarth and Wise, 1986).
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