Studies have been conducted to better document the behavioral pharmacology of drugs acting on dopaminergic systems. These studies have concentrated on the antagonism of dopamine-receptor subtype specific agonists with antagonists. These studies indicate that: (1) the D2 antagonist, sulpiride, is an effective antagonist of the behavioral effects of the D2 agonist, quinpirole in primates; (2) the D2 antagonist, haloperidol was no better antagonist of quinpirole than was a D1 antagonist. These results suggest important differences between antagonist effectiveness. (3) the Dl agonist, SKF 38393, is not well antagonized by Dl antagonists, whereas other Dl agonists are. These results indicate that much of the behavioral effects often attributed to Dl agonist activity of SKF 38393 are likely a result of activation of other mechanisms. (4) D2 agonists produce a unique scratching behavior in primates. This effect of these agonists is pharmacologically specific (drugs acting by other mechanisms do not produce this effect), there is stereospecificity (the active enantiomers of D2 agonists have the activity, whereas their racemates do not) it is antagonized by D2 antagonists but not Dl antagonists, and that antagonism shows stereospecificity. This behavior will be useful in documenting the D2 agonist activity of novel compounds. In addition, it may be used to characterize the D2 agonist sensitivity of primates with various exposures to cocaine, or those that may be acutely sensitive to the effects of drugs of abuse. The pharmacology of drugs binding irreversibly to the dopamine transporter has been pursued. One compound, para-isothiocyanato-benzyolecgonine methyl ester (para-isococaine), has been administered into the nucleus accumbens in rats and specifically antagonized the behavioral effects of cocaine 24 hours after this treatment. Several studies have indicated that this effect, at high doses, is due to non-specific neurotoxic actions. We are currently in the process of documenting the effects of lower non-toxic doses of para-isococaine.
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