Serotonin1A-receptor antagonism blocks psychostimulant properties of diethylpropion in marmosets (Callithrix penicillata).

Abstract

Diethylpropion (1-phenyl-2-diethylamine-1-propanone hydrochloride) is a stimulant drug with reinforcing properties that is used to treat obesity in humans. While the anorectic properties of diethylpropion are mediated by a noradrenergic mechanism, stimulant properties depend on its effects on the serotonergic (5-HT) and/or dopaminergic systems. In this study we investigated the role of the 5-HT1A-receptor in the acute behavioral effects of diethylpropion in marmosets (Callithrix penicillata). Animals were pretreated with the selective 5-HT1A-receptor antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclohexane-carboxamide trihydrochloride (WAY 100635; 0.2, 0.4, 0.8 mg/kg, i.p.) or saline (i.p.) and received a treatment with diethylpropion (10 mg/kg, i.p) or saline (i.p.). Diethylpropion induced an increase in locomotor activity in 60% of the monkeys, which were classified as diethylpropion sensitive, but did not affect locomotion in 40% of the monkeys (diethylpropion insensitive). Sensitivity analysis revealed two types of responders to diethylpropion. In the sensitive animals (type A) diethylpropion increased locomotor activity and anxiogenic-like behavior, but decreased bodycare activities. In the insensitive animals (type B) diethylpropion did not affect locomotor and bodycare activity after diethylpropion, but led to a strong increase in anxiogenic-like behavioral responses. Selective 5-HT1A-receptor antagonism modulated the acute diethylpropion effects responder type specifically. In the sensitive (type A) monkeys WAY 100635 blocked the diethylpropion-induced increase in locomotor activity, while not affecting anxiogenic-like behavioral responses or the suppression of bodycare activities. In the insensitive monkeys, WAY 100635 had no effect on locomotor activity after diethylpropion, but blocked diethylpropion effects on some anxiogenic-like behavioral responses. In conclusion, these results suggest an essential contribution of the 5-HT1A-receptor to the stimulant effects of diethylpropion, which is responder type specific. It also suggests the 5-HT1A-receptor to be a source of the interindividual variance in the acute behavioral response to the stimulant diethylpropion in monkeys.

• Authors: Eldon L Mello Jr, Rafael S Maior, Robert J Carey, Joseph P Huston, Carlos Tomaz, Christian P Müller
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 511 Issue 1 Pg. 43-52 (Mar 21 2005) ISSN: 0014-2999 [Print] Netherlands
• PMID: 15777778 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Appetite Depressants
• Piperazines
• Pyridines
• Serotonin Antagonists
• Receptor, Serotonin, 5-HT1A
• N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide
• Diethylpropion

Topics

• Analysis of Variance
• Animals
• Appetite Depressants (pharmacology)
• Behavior, Animal (drug effects)
• Callithrix
• Diethylpropion (pharmacology)
• Female
• Injections, Intraperitoneal
• Male
• Maze Learning (drug effects)
• Motor Activity (drug effects)
• Piperazines (pharmacology)
• Pyridines (pharmacology)
• Receptor, Serotonin, 5-HT1A (physiology)
• Serotonin Antagonists (pharmacology)
• Time Factors