Effects of phentermine and fenfluramine on extracellular dopamine and serotonin in rat nucleus accumbens: Therapeutic implications

Combined administration of the amphetamine analogs phentermine and fenflura mine (PHEN/FEN) has been used in the treatment of obesity. While these medi cations are thought to modulate monoamine transmission, the precise neuroch emical effects of the PHEN/FEN mixture have not been extensively studied. T o assess the mechanism of PHEN/FEN action, in vivo microdialysis studies we re performed in the nucleus accumbens of conscious freely moving rats. A se ries of amphetamine derivatives including phentermine, chlorphentermine, fe nfluramine, and PHEN/FEN (1:1 ratio), were infused locally into the accumbe ns via reverse-dialysis (1, 10, 100 mu M) or injected systemically (1 mg/kg , ip). Dialysate samples were assayed for dopamine (DA) and serotonin (5-HT ) by high-performance Liquid chromatography with electrochemical detection. When infused locally, phentermine preferentially increased extracellular D A, whereas fenfluramine selectively increased extracellular 5-HT. Local adm inistration of chlorphentermine or the PHEN/FEN mixture caused parallel ele vations of both transmitters. Analogous results were obtained when the drug s were injected systemically. Phentermine stimulated robust locomotor activ ity in mice, whereas chlorphentermine and fenfluramine did not. PHEN/FEN ca used modest locomotor stimulation after a low dose, but had no effect at th e highest dose. Accumulating evidence suggests that chronic drug and alcoho l abuse is associated with deficits in both DA and 5-HT neuronal function. Thus, dual activation of DA and 5-HT neurotransmission with monoamine relea sing agents may be an effective treatment strategy for substance use disord ers, as well as for obesity. Published 2000 Wiley-Liss, Inc.