Vol. 291, Issue 1, 19-30, October 1999

Escalating Dose-Binge Treatment with Methylphenidate: Role of Serotonin in the Emergent Behavioral Profile

David S. Segal and Ronald Kuczenski

Department of Psychiatry, School of Medicine, University of California at San Diego, La Jolla, California

Our previous studies indicate that exposure of rats to an escalating-dose, multibinge pattern of amphetamine or methamphetamine administration results in a unique emergent behavioral profile and concomitant regionally specific dopamine response patterns in the nucleus accumbens and caudate-putamen. In the present study, we explored the generality of these effects by using an escalating-dose, multibinge treatment with methylphenidate (MP), a stimulant that, unlike the amphetamines, produces no increase in serotonin transmission. Furthermore, MP exerts many of its effects through dopamine uptake blockade, in contrast to the amphetamines that primarily release dopamine. The results showed that MP administered according to an escalating-dose, multibinge regimen produced the expression of the emergent behavioral profile. This pattern of behavior was also evident in these animals in response to 2.5 mg/kg acute amphetamine after the last MP binge exposure. Consistent with previous evidence, neither acute nor multibinge MP treatment produced a significant serotonin response. In contrast, a regionally specific dopamine response alteration was observed during the course of this treatment. Caudate-putamen dopamine exhibited a pattern of increasing response during an acute MP binge but pronounced tolerance developed to this effect after multiple binges. By contrast, the nucleus accumbens dopamine response did not significantly change during the acute binge and exhibited a slight incremental pattern to the injections of the final binge. These findings, along with the effects of other stimulants, are discussed in terms of a possible role for serotonin and for the differential changes in the caudate-putamen and nucleus accumbens dopamine responses in the emergent behavioral profile. The similarity between the effects of MP and the amphetamines provides further support for the multibinge-induced behavioral profile as a possible animal model for stimulant-induced psychosis.