Psychopharmacology · 2001
Cross tolerance between anorectic action and induction of Fos-ir with dexfenfluramine and 5HT1B/2C agonists in rats.
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Rowland N E, Robertson K, Lo J, Rema E
Аннотация
RATIONALE: 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.
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.