The abuse of psychomotor stimulants such as cocaine and methamphetamine is a continuing and very serious problem worldwide for which there is no accepted medication. Numerous lines of investigation indicate that elevation of dopamine (DA) in the nucleus accumbens (NAC) is largely responsible for the reinforcing (rewarding) effects of many classes of drugs including cocaine and methamphetamine. Although the precise mechanism of DA elevation in the NAC differs among drug classes, medications that suppress or deplete such elevation of DA may thus be useful in the treatment and prevention of diverse, destructive self-administration behaviors including excessive eating. We have pursued the chemical synthesis and identification of biogenic amine agonists and their antagonists as research tools and potential medications. In one example, we developed a practical nonchromatographic chemical synthesis of the 5-HT2A receptor antagonist MDL100,907 that is enabling numerous studies requiring this critical research tool. We have also studied the discriminative stimulus effects of MDL100,907 and several other drugs in order to gain further insight into their 5-HT receptor subtype(s) selectivity and the possible receptor role in certain neuropsychiatric disorders. In 1992, we introduced the selective sigma-1 receptor (Sig-1R) antagonist BD-1063 that has become a valuable research tool in the study of the Sig1R. Based on results from a number of laboratories, the Sig-1R has been proposed as a novel therapeutic target for drug and alcohol addiction. Earlier, we showed Sig-1R agonists facilitate the reinforcing effects of ethanol and induce binge-like drinking, while Sig-1R antagonists block excessive drinking in genetic and environmental models of alcoholism. Even though significant progress has been made in understanding the function of Sig-1R in alcohol reinforcement, its role in the early and late stage of alcohol addiction remains unclear. We have now shown that administration of BD-1063 dramatically reduced the acquisition of alcohol drinking behavior as well as the preference for alcohol in genetically selected TSRI Sardinian alcohol preferring (Scr:sP) rats. We observed that the treatment had no effect on total fluid intake, food intake or body weight gain, indicating selectivity of action. Furthermore, BD-1063 dose-dependently decreased alcohol-seeking behavior in rats trained under a second-order schedule of reinforcement, in which responding is maintained by contingent presentation of a conditioned reinforcer. Finally, an innate elevation in Sig-1R protein levels was found in the nucleus accumbens of alcohol-preferring Scr:sP rats, compared to outbred Wistar rats, alteration which was normalized by chronic, voluntary alcohol drinking. Taken together these findings demonstrate that Sig-1R blockade reduces the propensity to both acquire alcohol drinking and to seek alcohol, and point to the nucleus accumbens as a potential key region for the effects observed. Our data suggest that Sig-1R antagonists may have therapeutic potential in multiple stages of alcohol addiction.
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