Methamphetamine discrimination and in vivo microdialysis in squirrel monkeys

Rationale: Characterization of changes in dopamine activity associated with the discriminative-stimulus effects of methamphetamine (MA) and related stimulants will aid our understanding of the role of dopamine in mediating the subjective effects of this drug class. Objectives: Squirrel monkeys were studied to explore the relationship between discriminative-stimulus effects of psychomotor stimulant drugs and their ability to increase extracellular dopamine levels in the caudate nucleus. Methods: The ability of MA, cocaine and methylphenidate (0.01-0.32 mg/kg) to produce MA-like discriminative-stimulus effects was assessed in monkeys trained to discriminate IM injections of 0.32 mg/kg MA from saline. In addition, the effects of a range of MA doses (0.01-0.32 mg/kg) and selected doses of cocaine, methylphenidate and the GBR 12909 analog AM2517 on extracellular dopamine in the caudate nucleus were determined by microdialysis. Results: MA, cocaine and methylphenidate produced dose-related increases in responding on the MA-associated lever and fully substituted at higher doses. In microdialysis studies, doses of MA, cocaine, methylphenidate, and AM2517 that produced 100% MA-lever responding produced comparable increases in caudate dopamine (to approximately 250% of control values). However, comparable increases in extracellular dopamine also were observed following a lower dose of MA (0.1 mg/kg) that produced, on average, 42% MA-lever responding. Moreover, increases in dopamine levels following administration of 0.03 and 0.1 mg/kg MA persisted after responding on the MA-associated lever had subsided. Conclusions: Taken together, these results support a prominent role for dopamine in MA-like discriminative-stimulus effects, but are consistent with the additional involvement of other neurochemical actions.