Research reportEffects of fenfluramine and phentermine (fen–phen) on dopamine and serotonin release in rat striatum: in vivo microdialysis study in conscious animals
Introduction
Fenfluramine 14, 25and phentermine [15]are substituted amphetamines which have been used alone or, more recently, in combination 35, 36to treat obesity. The anorectic properties of fenfluramine are related to enhanced serotoninergic neurotransmission 14, 27: its dextro isomer, dexfenfluramine, inhibits serotonin (5-HT) reuptake, and its metabolite dexnorfenfluramine both releases 5-HT and stimulates postsynaptic 5-HT2 receptors [30]. The levo isomer, levofenfluramine, has dopamine-antagonistic properties and, at high doses, increases dopamine (DA) concentrations in striatal dialysates [8]. Phentermine, introduced into the USA in the 1970s, was initially thought to act as a `sympathomimetic agent' [15]. That phentermine's action might also involve DA was initially suggested by the finding that its anorectic activity could be blocked by pimozide, a DA receptor antagonist [11], or by pretreatment with 6-hydroxydopamine, a toxin which damages both noradrenergic and dopaminergic brain neurons [28]. We subsequently showed that phentermine (like amphetamine) directly releases DA into striatal dialysates [1]. Others have also demonstrated that phentermine increases DA release in rat nucleus accumbens 3, 29.
In 1984, Weintraub et al. [35]proposed administering phentermine with fenfluramine in combination, hoping thereby to reduce the side effects observed when each compound was given separately. They found that the stimulant effect of phentermine and the sedative action of fenfluramine were indeed diminished when the drugs were given in combination 35, 36. Subsequently, this combination was found to be effective in treating many obese patients.
In this study, we examined the ability of certain doses of phentermine or fenfluramine, and the combination of these two drugs, to elevate DA and 5-HT concentrations in rat striatal dialysates. While some evidence suggests that these two neurotransmitters also act upon each other, studies on these interactions between DA and 5-HT have been inconsistent. Destruction of 5-HT fibers decreased DA turnover and tyrosine hydroxylase activity within the striatum [17]. On the other hand, striatal DA content was increased following the destruction of 5-HT terminals [22]. We and others observed that the local application of 5-HT agonists enhances striatal DA release in awake animals, and 5-HT antagonists block this effect of 5-HT; the receptor type(s) involved is unclear. 5-HT also increased striatal DA release in anesthetized rats, and the 5-HT1, 5-HT3 or 5-HT4 receptor subtypes were implicated in this effect 5, 6, 9, 10, 13, 23.
Our choice of striatum to investigate the interactions of phentermine or fenfluramine, in affecting DA and 5-HT release, was based in part on known effects of these two neurotransmitters in this brain region. Studies using immunohistochemical techniques have demonstrated serotonin-containing nerve terminals in the striatum, within neurons originating in the dorsal raphe nucleus 31, 33, as well as dopamine-containing striatal nerve terminals, originating in the substantia nigra. The nigra, in turn, receives serotoninergic inputs from medial raphe and dorsal raphe nuclei [34].
We now show that, given together acutely, phentermine can amplify the release of 5-HT by fenfluramine, and fenfluramine can amplify that of DA by phentermine. In addition, after chronic administration of the combination, phentermine can still amplify the release of 5-HT by fenfluramine even though the release of DA by phentermine is no longer amplified by fenfluramine.
Section snippets
Animals
Male Sprague–Dawley rats weighing 200–300 g were purchased from Taconic Farms (Germantown, NY); housed two per cage; kept on a 12:12-h light/dark cycle; and given ad libitum access to food and water.
Drug treatments
Fenfluramine and phentermine, dissolved in saline, were administered intraperitoneally. For acute administration, all pharmacological treatments were given after stabilization of DA and 5-HT levels in perfusates, usually after about 3.5 h of perfusion. For chronic administration, all pharmacological
Effect of acute administration of fenfluramine or phentermine, alone or in combination, on the release of DA and 5-HT into striatal dialysates
Baseline DA and 5-HT concentrations for fenfluramine, phentermine and combination groups were as follows (fmol/50 μl). For DA, Fenfluramine 43.5±2.3; Phentermine 59.7±2.3 and Combination 40.9±4.1. For 5-HT, Fenfluramine 2.2±0.2; Phentermine 2.5±0.1 and Combination 3±0.2. There were no statistically significant differences between the baseline values of the different treatment groups.
Administration of 1 mg/kg, i.p. fenfluramine did not affect DA concentrations in the striatal dialysates.
Discussion
These data show that when fenfluramine and phentermine are administered acutely in combination, their effects on striatal 5-HT and DA release, respectively, are amplified. In addition, 5-HT release by fenfluramine, but not DA release by phentermine, is also amplified after chronic administration of the drugs in combination.
We used a 1 mg/kg dose of fenfluramine and a 2 mg/kg dose of phentermine because, at these doses, fenfluramine significantly increases 5-HT concentrations (Fig. 1b), but not
Conclusion
In conclusion, the acute administration of a combination of fenfluramine and phentermine amplified the effect of each drug on 5-HT and DA release respectively, while chronic administration of a combination of these drugs only amplified the effect of fenfluramine on 5-HT release.
Acknowledgements
These studies were supported by a grant from the Center for Brain Sciences and Metabolism Charitable Trust.
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