Effects of dopamine and serotonin-releasing agents on methamphetamine discrimination and self-administration in rats

To analyze the involvement of dopamine (DA) and serotonin (5-HT) release in the stimulus properties of methamphetamine, two amphetamine analogs that s electively release either brain DA (phentermine) or 5-HT (fenfluramine) wer e tested for their ability to substitute for methamphetamine in rats discri minating methamphetamine (1.0 mg/kg) from saline. They were subsequently te sted for their ability to alter TV methamphetamine (0.06 mg/kg per injectio n) self-administration in the same species when given as a pretreatment. Th e DA releaser phentermine, like methamphetamine itself, decreased methamphe tamine self-administration (to 70% of baseline responding), but only at a d ose of 3.0 mg/kg that fully generalized to the methamphetamine stimulus in the discrimination study. The 5-HT releaser fenfluramine attenuated methamp hetamine self-administration to a much larger extent than phentermine (to 3 7% of baseline responding) at a dose of 1.8 mg/kg that did not generalize t o methamphetamine and did not decrease rate of responding in the discrimina tion study. Tolerance developed to the inhibitory effect of 1.8 mg/kg fenfl ur amine on methamphetamine self-administration when it was given repeatedl y over four consecutive daily sessions. The fenfluramine-induced decrease i n methamphetamine self-administration was also attenuated when it was given together with the small 1.0 mg/kg dose of phentermine. These results sugge st that DA release plays a dominant role in the discriminative stimulus eff ects of methamphetamine. However, stimulation of 5-HT release can strongly modify methamphetamine self-administration.