Cross tolerance between anorectic action and induction of Fos-ir with dexfenfluramine and 5HT1B/2C agonists in rats.
BACKGROUND
We have shown that the anorectic effect of dexfenfluramine (DFEN), an agent that acutely increases synaptic availability of serotonin (5-HT), shows complete tolerance after 2-3 prior applications when using acute feeding protocols and low dosages. It is unlikely this is due to either accumulative weight loss or presynaptic 5-HT depletion. In this study, we examined the possible contribution of 5-HT1B/2C receptors to behavioral tolerance by testing for cross tolerance between DFEN and the 5-HT1B/2C receptor agonists, m-chloro- and trifluoromethyl-substituted phenylpiperazines (mCPP and TFMPP). Additionally, we sought neuronal correlates of the behavioral changes by study of the induction of Fos-like immunoreactivity (ir) in discrete brain regions.


METHODS
Sprague-Dawley rats received two or three pre-injections, at 2-day intervals, of 2 mg/kg DFEN or vehicle. The rats were then food deprived for 24 h and, 30 min prior to a 1-h feeding test, received a s.c. injection of either DFEN, TFMPP (1 mg/kg), or mCPP (2 mg/kg). Additional groups received mCPP preinjections and test injection of either DFEN or mCPP. Rats in Fos-ir studies received similar injection regimens but were not food deprived and were perfused 1.5 h after the test injection.


RESULTS
DFEN-pretreated rats showed complete anorectic tolerance to DFEN, TFMPP, and mCPP. However, rats given this regimen of mCPP pretreatment were tolerant to neither mCPP nor DFEN. Fos-ir induced by DFEN in each brain region examined was either significantly reduced or abolished by prior DFEN injections. TFMPP induced less Fos-ir in these regions than DFEN and this was attenuated by prior DFEN.


CONCLUSIONS
The behavioral data indicate that tolerance to DFEN anorexia is mediated partially or completely by functional subsensitivity at 5-HT1B and/or 5-HT2C receptors. The brain regions implicated include the paraventricular hypothalamus, medial striatum, lateral parabrachial nucleus, and nucleus of the solitary tract.
Rowland
N E
NE
Department of Psychology, University of Florida, Gainesville 32611-2250, USA. rowland@psych.ufl.edu
Robertson
K
K
Lo
J
J
Rema
E
E
D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology*; D020372:Dexfenfluramine / Q000494:pharmacology*; D004361:Drug Tolerance / Q000502:physiology*; D004435:Eating / Q000187:drug effects / Q000502:physiology; D005260:Female; D008297:Male; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044302:Receptor, Serotonin, 5-HT1B; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000096:biosynthesis*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*
D001067:Appetite Depressants; D016760:Proto-Oncogene Proteins c-fos; D044302:Receptor, Serotonin, 5-HT1B; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D020372:Dexfenfluramine