Dynamic changes in sensitivity occur during the acute response to cocaine and methylphenidate

Abstract 

Rationale: We have previously shown that during the acute response to amphetamine, a stimulant that released dopamine, behavioral sensitivity to the drug undergoes dynamic changes, as evident in the altered behavioral profile expressed to the subsequent administration of a low dose of the drug. Objective: The present studies were designed to determine if these dynamic changes in sensitivity occur with amphetamine-like stimulants that act primarily by blocking dopamine uptake. Methods: Groups of animals were primed with 40 mg/kg cocaine or 30 mg/kg methylphenidate, then during the acute response, a low, locomotor-stimulant dose of amphetamine (1.5 mg/kg) was administered to probe for changes in sensitivity. Conversely, to determine whether the manifestation of the increased responsivity is idiosyncratic to amphetamine, animals were also primed with amphetamine (4 mg/kg), then probed with low doses of cocaine (10 and 20 mg/kg) or methylphenidate (10 mg/kg). Parallel microdialysis studies were performed to assess the caudate-putamen and nucleus accumbens extracellular dopamine responses. Results: Priming with the uptake blockers each resulted in a stereotypy response to the subsequent low-dose amphetamine probe. Likewise, after priming with amphetamine, the uptake blockers each induced a pronounced stereotypy response. In each case, these changes in behavioral responsivity were expressed in the absence of corresponding changes in the probe-induced regional dopamine responses. Conclusions: Dynamic changes in behavioral sensitivity during the response to acute stimulant administration are a characteristic common to both dopamine releasers and uptake blockers. These rapid changes in sensitivity may contribute to the behaviors associated with binge patterns of drug abuse.