Methamphetamine discrimination and in vivo microdialysis in squirrel monkeys

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.

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.

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 i.m. 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.

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.

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.