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

Abstract

Combined administration of the amphetamine analogs phentermine and fenfluramine (PHEN/FEN) has been used in the treatment of obesity. While these medications are thought to modulate monoamine transmission, the precise neurochemical effects of the PHEN/FEN mixture have not been extensively studied. To assess the mechanism of PHEN/FEN action, in vivo microdialysis studies were performed in the nucleus accumbens of conscious freely moving rats. A series of amphetamine derivatives including phentermine, chlorphentermine, fenfluramine, and PHEN/FEN (1:1 ratio), were infused locally into the accumbens via reverse-dialysis (1, 10, 100 microM) 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 DA, whereas fenfluramine selectively increased extracellular 5-HT. Local administration of chlorphentermine or the PHEN/FEN mixture caused parallel elevations of both transmitters. Analogous results were obtained when the drugs were injected systemically. Phentermine stimulated robust locomotor activity in mice, whereas chlorphentermine and fenfluramine did not. PHEN/FEN caused modest locomotor stimulation after a low dose, but had no effect at the highest dose. Accumulating evidence suggests that chronic drug and alcohol abuse is associated with deficits in both DA and 5-HT neuronal function. Thus, dual activation of DA and 5-HT neurotransmission with monoamine releasing agents may be an effective treatment strategy for substance use disorders, as well as for obesity. Synapse 36:102-113, 2000. Published 2000 Wiley-Liss, Inc.

Additive effects on rat brain 5HT release of combining phentermine with dexfenfluramine

“…10 The potent 5HT-releasing action of fenfluramines noted in the hypothalamus (Gundlah et al 5 and present data), the striatum 16 and in the nucleus accumbens 13,15 has also been demonstrated using blood platelets. 22,23 This could provide a peripheral source of 5HT that is sufficient to play a role in the genesis of valvulopathy.…”

“…5,13 -16 Phentermine produces a significant increase of hypothalamic 5HT efflux in vivo at a pharmacologically relevant dose and is, therefore, not a catecholamine-selective agent. 15 Whilst the rapid onset of this phentermine-induced increase in 5HT efflux is consistent with that of a releasing agent 5 (albeit a weak one), phentermine did not evoke release of radiolabelled 5HT from in vitro slices of hypothalamus. It is therefore likely that the ability of Drugs or saline were injected at time 0.…”

Antisense Knockdown of the Shaker-like Kv1.1 Gene Abolishes the Central Stimulatory Effects of Amphetamines in Mice and Rats

“…The observation that aODN pretreatment substantially reduces the AMPH-induced DA efflux in rat microdialysis experiments, while also impairing the central activity of TYR and PHE (both substrate-type releasers that share the phenylaethylamine skeleton with AMPH), reinforces the view that Shaker-like Kv1.1 subtypes are primarily involved in these effects. Conversely, the failure of the aODN to reduce the anorectic effect of d-FEN could be explained with the observation that this preferential serotoninergic agent (Baumann et al, 2000) may block channel subtypes different from Kv1.1 (such as Kv1.5 or Kv2.1), as proposed for the activity of this compound in rat taste cells (Hu et al, 1998).…”

Monoamine oxidase inhibition is unlikely to be relevant to the risks associated with phentermine and fenfluramine: a comparison with their abilities to evoke monoamine release

“…Whilst the pathobiology of both events remains uncertain, a link with elevated plasma serotonin (5HT) has been proposed on more than one occasion 3 -6 and for valvulopathy, 5HT receptor mechanisms on valve tissue are also postulated to be relevant. 7 Aside from the known ability of phentermine to promote dopamine release in the brain, 8,9 recent discussion on its mode of action has centred on a proposal that phentermine may inhibit monoamine oxidase (MAO). 10 Within this proposal, the authors not only inferred that such an action could boost free 5HT concentrations in plasma beyond those evoked by 5HT-releasing agents such as fenfluramine and S( þ )-fenfluramine, but for the same reason they also warned against the possible combined use of phentermine with selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine.…”