Acute fluoxetine treatment potentiates amphetamine hyperactivity and amphetamine-induced nucleus accumbens dopamine release: possible pharmacokinetic interaction

Abstract

Amphetamine stimulates locomotor activity, in large part by activating central dopaminergic systems. Serotonin shares on overlapping distribution with dopamine and has been shown to modulate dopaminergic function and dopamine-mediated behaviors. The present study examined whether increasing serotonergic function, via the selective serotonin reuptake inhibitor fluoxetine, would alter the stimulatory effects of amphetamine on locomotor activity and dopamine overflow in the nucleus accumbens. In addition, the present study determined whether fluoxetine treatment would alter the metabolism of amphetamine. Results show that 5.0 mg/kg fluoxetine potentiated the locomotor activity induced by amphetamine (0.5-1.0 mg/ kg), and enhanced the increased dopamine overflow in the nucleus accumbens induced by amphetamine. Fluoxetine treatment also resulted in a higher concentration of amphetamine in the CNS. Together, these findings indicate that acute fluoxetine treatment potentiates the locomotor stimulating and dopamine activating effects of amphetamine. Further, the results indicate that fluoxetine potentiates the effects of amphetamine by decreasing the metabolism of amphetamine, probably through inhibition of cytochrome P450 isozymes.

Role of 5-HT2A and 5-HT2B/2C Receptors in the Behavioral Interactions Between Serotonin and Catecholamine Reuptake Inhibitors

“…If acute administration of fluvoxamine impedes the metabolism of mazindol via inhibition of metabolic enzymes, increased brain concentrations of mazindol could contribute to the observed hyperactivity. A similar mechanism was proposed for the facilitation of amphetamine-induced hyperactivity and DA efflux in NAc by systemic fluoxetine; in that study, increased amphetamine levels were observed in the NAc of fluoxetine-treated rats (Sills et al 1999a). Fluvoxamine has been shown to inhibit cytochrome P450 isozymes that catalyze the oxidative metabolism of certain drugs and could, therefore, increase brain levels of drugs metabolized by these isozymes (Hiemke and Hartter 2000).…”

“…The ability of cytochrome P450 isozymes to contribute to the transformation of mazindol into imidazole-3-one, its primary metabolite in the rat, is currently unknown (Dugger et al 1979). In vivo microdialysis is one strategy that could be used to determine the extent to which the observed synergism between fluoxetine and mazindol might be related to fluvoxamineevoked increases in brain concentrations of mazindol (Sills et al 1999a). However, we have recently shown that microinjections of fluvoxamine into the shell of the NAc result in an immediate enhancement of hyperactivity evoked by systemic cocaine (McMahon et al 2000), a finding difficult to reconcile with a mechanism dependent upon inhibition of metabolism.…”

“…These and similar findings generated the hypothesis that 5-HT plays an inhibitory role in DA-mediated behavior. On the other hand, systemic administration of selective serotonin reuptake inhibitors (SSRIs) potentiated hyperactivity induced by amphetamine or cocaine in rats (Herges and Taylor 1998; Sills et al 1999aSills et al , 1999b, but not in mice (Arnt et al 1984;Maj et al 1984;Reith et al 1991). The ability of SSRIs to increase 5-HT efflux is well-documented (e.g., Guan and McBride 1988;Li et al 1996), thus, these data imply a more sophisticated role for 5-HT in the control of DA-mediated behaviors than simple inhibition.…”

“…A possible pharmacokinetic interaction at the level of metabolic enzymes has been suggested to contribute to the potentiation of amphetamine-induced hyperactivity by SSRIs (Sills et al 1999a(Sills et al , 1999b. However, a role for specific 5-HT receptors is suggested by the observation that the facilitation of cocaine-induced hyperactivity by fluoxetine was attenuated by the 5-HT 1A receptor antagonist WAY 100635 and the nonselective 5-HT 2 receptor antagonist ketanserin (Herges and Taylor 1998).…”

Repeated antipsychotic treatment progressively potentiates inhibition on phencyclidine-induced hyperlocomotion, but attenuates inhibition on amphetamine-induced hyperlocomotion: Relevance to animal models of antipsychotic drugs

“…Acute fluoxetine or citalopram increases amphetamine-induced hyperlocomotion Millan et al, 2003) but has no effect on phencyclidine-induced model (Redmond et al, 1999). Repeated fluoxetine or citalopram treatment tends to enhance amphetamine-induced hyperlocomotion (Arnt et al, 1984;Sills et al, 1999Sills et al, , 2000 and phencyclidine-induced hyperlocomotion (Redmond et al, 1999). Taken together, a combination of repeated amphetamine and phencyclidine hyperlocomotion models may be utilized to distinguish anxiolytics and antidepressants from antipsychotics.…”