Elsevier

Brain Research

Volume 813, Issue 1, 30 November 1998, Pages 67-72
Brain Research

Research report
Effects of fenfluramine and phentermine (fen–phen) on dopamine and serotonin release in rat striatum: in vivo microdialysis study in conscious animals

https://doi.org/10.1016/S0006-8993(98)01003-8Get rights and content

Abstract

We measured the effects of acute or chronic administration of fenfluramine and phentermine, alone or in combination, on brain dopamine and serotonin release into striatal dialysates of freely moving rats. Samples collected every 30 min were assayed in a single run by high-pressure liquid chromatography. Acute or chronic administration of fenfluramine (1 mg/kg, i.p.) did not significantly change dopamine concentrations in rat striatal dialysates, but increased those of serotonin by 182% (acute) and 124% (chronic). Phentermine (2 mg/kg, i.p.), on the other hand, significantly increased dopamine concentrations by 52% (acute) and 80% (chronic) without affecting those of serotonin. Administration of the drugs in combination (fenfluramine 1 mg/kg and phentermine 2 mg/kg) amplified the effects of each, increasing striatal dopamine concentrations by 209% (acute) and serotonin concentrations by 330% (acute) and 299% (chronic).

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.

References (36)

  • D. Van Der Kooy et al.

    Dorsal raphe cells with collateral projections to the caudate-putamen and substantia nigra: a fluorescent retrograde double labelling study in the rat

    Brain Res.

    (1980)
  • A. Balcioglu et al.

    Effects of phentermine on striatal dopamine and serotonin release in conscious rats: in vivo microdialysis study

    Int. J. Obes.

    (1998)
  • A. Balcioglu et al.

    Dexfenfluramine enhances striatal dopamine release in conscious rats via a serotoninergic mechanism

    J. Pharm. Exp. Ther.

    (1998)
  • M.H. Bauman et al.

    Combined phentermine/fenfluramine administration and central serotonin neurons

    Synapse

    (1998)
  • A.H. Beckett et al.

    The microsomal N-oxidation of phentermine

    J. Pharm. Pharmacol.

    (1976)
  • S. Benloucif et al.

    Serotonin-facilitated dopamine release in vivo. Pharmacological characterization

    J. Pharmacol. Exp. Ther.

    (1993)
  • H. Benveniste et al.

    Regional cerebral glucose phosphorylation and blood flow after insertion of a microdialysis fibre through the dorsal hippocampus in the rat

    J. Neurochem.

    (1987)
  • S. Dobrzanski et al.

    The effect of propranolol, phentolamine and pimozide on drug-induced anorexia in the mouse

    Psychopharmacology

    (1979)
  • Cited by (34)

    • Serotonin regulation of striatal function

      2020, Handbook of Behavioral Neuroscience
    • Sex differences in the ACTH and cortisol response to pharmacological probes are stressor-specific and occur regardless of alcohol dependence history

      2018, Psychoneuroendocrinology
      Citation Excerpt :

      It is also important to note that the 5-HT releaser, fenfluramine, and the SSRI, citalopram – while both primarily targeting the 5-HT transporter, have different mechanisms of action to enhance 5-HTergic tone. Fenfluramine promotes 5-HT transport out of neurons while also blocking reuptake (Balcioglu and Wurtman, 1998), while citalopram selectively blocks reuptake. Moreover, fenfluramine’s active metabolite, norfenfluramine, works as a 5-HT2C agonist (Balcioglu and Wurtman, 1998), and our prior work has demonstrated that the breakdown of fenfluramine to norfenfluramine is induced by tobacco smoking which is commonly associated with AD (Anthenelli and Maxwell, 2000).

    • Systemic inflammation alters central 5-HT function as determined by pharmacological MRI

      2013, NeuroImage
      Citation Excerpt :

      Candidate excitatory 5-HT receptor subtypes in NAc that would not be blocked by MDL100907 include 5-HT2C, 5-HT4 and 5-HT6 receptors. Previous studies have detected non-5-HT-mediated changes in Fos response to fenfluramine in the caudate nucleus (Javed et al., 1998), and other studies report that fenfluramine releases catecholamines at higher doses (Balcioglu and Wurtman, 1998). Thus, although fenfluramine may primarily release 5-HT, a minor contribution from other transmitters is possible in the NAc.

    View all citing articles on Scopus
    View full text