Comparison of either norepinephrine-uptake inhibitors or phentermine combined with serotonergic agents on food intake in rats.
BACKGROUND
We have shown previously that the anorectic effects of the catecholamine-releasing agent phentermine (PHEN) and the serotonin (5-HT)-releasing agent dexfenfluramine (DFEN) are greater than additive in rats. In the present study, we examined whether the norepinephrine-uptake inhibitors desmethylimipramine (DMI) and thionisoxetine (TNIX) have additive effects with either DFEN or with the 5-HT-uptake inhibitor fluoxetine (FLX). We also examined whether PHEN interacts with a postsynaptically acting 5-HT agonist.


METHODS
Undeprived rats were trained to eat a daily sweet-milk dessert and on test days were systemically administered single or combination drugs and the intakes recorded.


RESULTS
Both DMI and TNIX produced dose-related suppressions of food intake. However, by isobolographic analysis, they did not enhance the anorectic actions of either DFEN or FLX. In contrast, confirming and extending our previous work, PHEN had a greater potentiating effect on the anorectic actions of DFEN and FLX than TNIX. Further, the anorectic action of the 5-HT2c receptor agonist TFMPP was enhanced by PHEN.


CONCLUSIONS
These and other data are consistent with the idea that 5-HT agents may work "upstream" of critical catecholaminergic synapses in the production of anorexia, and explain the diminished efficacy of norepinephrine-uptake inhibitors relative to PHEN. The implications for clinically useful anorectic agents are discussed briefly.
Rowland
N E
NE
Department of Psychology, University of Florida, Gainesville 32611-2250, USA. rowland@psych.ufl.edu
Marshall
M
M
Roth
J D
JD
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D003891:Desipramine / Q000494:pharmacology; D020372:Dexfenfluramine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004435:Eating / Q000187:drug effects*; D005260:Female; D005473:Fluoxetine / Q000031:analogs & derivatives / Q000494:pharmacology; D009638:Norepinephrine / Q000037:antagonists & inhibitors*; D010645:Phentermine / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D018490:Serotonin Agents / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013997:Time Factors
D018759:Adrenergic Uptake Inhibitors; D003891:Desipramine; D020372:Dexfenfluramine; D005473:Fluoxetine; D009638:Norepinephrine; D010645:Phentermine; D010879:Piperazines; D018490:Serotonin Agents; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; C018406:1-(3-trifluoromethylphenyl)piperazine; C093518:thionisoxetine