Early withdrawal from stimulant abuse may represent a potential window for treatment. Considerable evidence demonstrates that chronic intermittent vs. continuous cocaine dosing regimes induce residual withdrawal states, i.e., sensitization vs. tolerance. When tested on day 7 after withdrawal, a number of altered neurobiological mechanisms are differently associated with sensitization vs. tolerance to cocaine administration. Thus, the different chronic dosing regimes allow distinct separation of adapted mechanisms underlying sensitization vs. tolerance. In the literature, sensitization and tolerance have been hypothesized to contribute several conditions in cocaine abusers including withdrawal anergia, craving and compulsive drug administration behaviors as well as relapse. To some extent, during withdrawal, sensitization versus tolerance can be conceived of in terms of the old counter-adaptation or opponent process hypothesis (Koob and Bloom, 1988; Himmelsbach, 1943). The opponent process may be a within system or between system changes (Koob and Bloom, 1988). Our findings that dopamine mechanisms are in a state of dynamic flux in the 7-10 day withdrawal period is consistent with a form of the opponent process hypothesis which requires the withdrawal period for the establishment or consolidation of adaptive mechanisms. Thus, this early withdrawal period may represent a treatment opportunity to alter the consolidation of residual effects. To the extent the neuroadaptations related to sensitization/tolerance contribute to high rate of recidivism, an elucidation of means for their pharmacological reversibility will advance medication development efforts for treating cocaine addicts. The proposed hypothesis, testing, and screening model includes: 1) dosing with cocaine sensitization and tolerance regimes for 14 days; 2) treating with the candidate therapeutic drug and controls for the first 5 days of withdrawal; and 3) testing on withdrawal day 7 and laterfor reversal of sensitization/tolerance and associated mechanisms. Our current understanding of the mechanisms associated with sensitization/tolerance as well as clinical studies will guide and constrain the search for new medications for cocaine abuse.
