Behavioural and neurochemical characteristics of phentermine and fenfluramine administered separately and as a mixture in rats

Abstract

Clinical case studies suggest that combined administration of the serotonergic agent fenfluramine (FEN) and the weak amphetamine-like anorexic agent phentermine (PHEN) may be useful in the treatment of alcohol and cocaine addictions. The present experiment examined the nature of the interaction between the two agonists using the drug discrimination paradigm. In vivo microdialysis served to examine the neurochemical profile of dopamine and serotonin release in the nucleus accumbens. In conscious rats, acute injections of FEN (1.0-2.0 mg/kg i.p.) or PHEN (1.0-2.0 mg/kg i.p.) selectively elevated levels of serotonin and dopamine in the nucleus accumbens, respectively. A mixture (1 mg/kg of each) increased levels of both amines by similar magnitudes to those observed with each individually. Three groups of Sprague-Dawley rats were trained to discriminate (1) FEN (1.0 mg/kg i.p.) alone, (2) PHEN (1.0 mg/kg i.p.) alone or a mixture (3) PHEN+FEN (1 mg/kg of each, i.p.) from saline under a fixed ratio (FR-10) schedule of food reinforcement. Rats acquired the mixture discrimination rapidly, while for the other groups the training dose had to be increased to 2.0 mg/kg to attain stimulus control. The individual components of the mixture at the training dose generalized partially to the mixture, and complete generalisation was observed following 3.0 mg/kg FEN or PHEN. Rats trained to discriminate the individual components showed respective cross-generalisation profiles. Generalisation to cocaine (0.3-10.0 mg/kg i.p.), amphetamine (0.1-3.0 mg/kg i.p.) and nicotine (0.1-0.8 mg/kg s.c.) was greatest in the MIX-trained rats, while partial or no generalisation was observed in rats trained to discriminate the individual compounds. From the present results, it may be concluded that the two drugs given as a mixture do not produce a novel cue. Rather, these aminergics appear to interact additively. Furthermore, the dual stimulation of the amines by the mixture may be the basis for the cueing effects of the FEN+PHEN drug mixture, and its effectiveness in treating drug addictions.

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.…”

“…Similar additive effects have been shown between phentermine and fenfluramine on both 5HT and dopamine levels in the nucleus accumbens. 13 In the striatum, however, evidence has been obtained for a synergistic interaction between phentermine and fenfluramine since the minimal impact of phentermine alone on striatal 5HT levels was nevertheless reported to enhance that caused by fenfluramine when the two drugs were given in combination. 16 In determining whether the interactions between phentermine and=or fenfluramine are additive, synergistic or even antagonistic, it is likely that regional differences in the sensitivity of 5HT and other systems to the drugs need to be taken into account.…”

Blunted Fenfluramine-Evoked Prolactin Secretion in Hypertensive Rats

“…24 -27 The increase in synaptic levels of serotonin in the hypothalamus stimulates the secretion of PRL. The dose of FEN used in the present study is within the reported range of doses that produce dose-dependent increases in synaptic serotonin levels 19,28 and plasma PRL levels. 20,21 The increase in plasma PRL levels after FEN is blocked either by pretreatment with serotonin receptor antagonists or reuptake inhibitors 16,17,20,21,23,29 or lesions of the raphe nuclei.…”

Comparison of the effects of sibutramine and other weight-modifying drugs on extracellular dopamine in the nucleus accumbens of freely moving rats

“…Phentermine is a structural analogue of d-amphetamine that has been used as an anti-obesity agent in the USA for over 30 years. Phentermine's weight-loss action was initially ascribed to its sympathomimetic properties involving NA and DA (Samanin et al, 1975), but in later years the dopaminergic component of phentermine has been largely overlooked (Cerulli et al, 1998;Finer, 1997); this is despite recent in vivo evidence to show that phentermine does activate the dopaminergic system Shoaib et al, 1997). d-Amphetamine was one of the first drugs to be widely employed for management of obesity, but its use is no longer recommended due to the abuse potential of the drug (Cerulli et al, 1998).…”