The Rate Hypothesis and Agonist Substitution Approaches to Cocaine Abuse Treatment

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A drug with slower onset of action would have less abuse liability. In principle, these two favorable characteristics could be achieved either pharmacokinetically, such as by giving the drug via a slowly absorbed route of administration or pharmacodynamically, such as by giving an analogue with slow, long-lasting binding to the site of action. Evidence in humans for the rate hypothesis of cocaine effects is largely circumstantial, based on pharmacokinetic differences among routes of administration. The agents with slow onset of effect, including possibly the abused drug itself by another route of administration, may be useful in implementing the agonist-substitution approach to treatment of cocaine abuse, consistent with the rate hypothesis of psychoactive drug effect. In this chapter several medications that bind to the presumed major site of action for cocaine's psychoactive effects have been studied as possible agonist substitution agents. These agents have some mild stimulant-like agonist properties, with little apparent human abuse potential when taken in slow-onset form. Both mazindol, an appetite suppressant, and bupropion, an antidepressant, have been ineffective in double-blind clinical trials. This may be related to dose-limiting side effects that have kept doses in the range that probably occupies less than half of brain presynaptic dopamine transporters (DAT) sites. In animal studies, it has reduced the increased brain extracellular dopamine concentration produced by cocaine administration and reduced cocaine selfadministration at doses that do not influence food intake.

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