Evaluation of the conditioned reinforcing effects of phentermine and fenfluramine in the rat: Concordance with clinical studies

Abstract

An unbiased place-preference conditioning procedure was used to characterize the conditioned reinforcing effects of phentermine (PHEN), fenfluramine (FEN), and their combination (PHEN/FEN) in previously drug-naive rats. Animals exhibited marked preferences for an environment previously associated with the administration of phentermine. The minimum dose producing a significant effect was 3.0 mg/kg. In contrast, FEN produced dose-related place aversions. In animals which received a subthreshold dose of FEN in combination with a dose of PHEN that produced a conditioned place preference, no preference or aversion for the drug-paired place was seen. Similarly, no significant conditioning in response to administration of PHEN (3.0 mg/kg) and FEN (3.0 mg/kg) was seen. The failure of PHEN/FEN to produce conditioned reinforcing effects is in line with recent clinical studies, and suggests that PHEN/FEN and drug combinations sharing the same neurochemical mechanisms of action will have low potential for abuse.

Balance between Dopamine and Serotonin Release Modulates Behavioral Effects of Amphetamine‐Type Drugs

“…Additionally, fenfluramine antagonizes locomotor and rewarding actions of DA releasers 19,30,35 . Studies using co‐administered phentermine and fenfluramine show that drug treatments producing simultaneous elevations in extracellular DA and 5‐HT produce minimal motor activity, 30 are not rewarding, 36 and are not reinforcing 37 . Unfortunately, interpreting the effects of fenfluramine is hampered by the complex pharmacology of the drug, and N ‐dealkylation produces a bioactive metabolite with potent agonist activity at 5‐HT 2C receptors (for review, see Ref.…”

Persistent Antagonism of Methamphetamine-Induced Dopamine Release in Rats Pretreated with GBR12909 Decanoate

“…It is well accepted that pharmacological treatments leading to increased synaptic 5-HT are not reinforcing. For example, increased serotonergic transmission decreases brain stimulation reward (Harrison and Markou, 2001), produces conditioned place aversions (Marona-Lewicka et al, 1996), and reduces the positive reward value of stimulants both in animals and humans (Brauer et al, 1996;Rea et al, 1998). Thus, in the presence of GBR-type compounds, illicit stimulants such as methamphetamine become very effective 5-HTreleasing agents that lack positive reinforcing qualities.…”

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

“…Other studies show that fenfluramine can oppose the positive reinforcing effects of phentermine. Rea et al (1998) found that phentermine produces a positive CPP, whereas fenfluramine produces a conditioned place aversion. Surprisingly, administration of a subeffective dose of fenfluramine eliminated the phentermine-evoked CPP.…”