An investigation of the mechanism responsible for fluoxetine-induced hypophagia in rats

Lightowler, S.; Wood, Martyn; Brown, Tony; Glen, A.I.M.; Blackburn, Thomas P.; Tulloch, I.F.; Kennett, Guy A.

doi:10.1016/0014-2999(95)00704-0

Cited by 32 publications

(14 citation statements)

References 26 publications

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“…Furthermore, chronic FLX treatment similarly reduced brainstem TPH-2 mRNA expression and depressive-like behaviors in the FST in CON and DEF rats. Consistent with prior rat FLX treatment studies [36,37], food intake and body weight were similarly reduced in both CON and DEF rats following chronic FLX treatment. We also found that DEF+FLX rats exhibited a significantly lower NFLX/FLX ratio compared with CON+FLX rats, suggesting that n -3 fatty acid deficiency may impair FLX metabolism.…”

Section: Discussionsupporting

confidence: 86%

Omega-3 fatty acid deficiency does not alter the effects of chronic fluoxetine treatment on central serotonin turnover or behavior in the forced swim test in female rats

McNamara¹,

Able²,

Liu³

et al. 2013

Pharmacology Biochemistry and Behavior

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While translational evidence suggests that long-chain omega-3 fatty acid status is positively associated with the efficacy of selective serotonin reuptake inhibitor drugs, the neurochemical mechanisms mediating this interaction are not known. Here we investigated the effects of dietary omega-3 (n-3) fatty acid insufficiency on the neurochemical and behavioral effects of chronic fluoxetine (FLX) treatment. Female rats were fed diets with (CON, n=56) or without (DEF, n=40) the n-3 fatty acids during peri-adolescent development (P21-P90), and one half of each group were administered FLX (10 mg/kg/d) for 30 d (P60-P90) prior to testing. In adulthood (P90), regional brain serotonin (5-HT) and 5-hydroxyindoleacetic (5-HIAA) concentrations, presynaptic markers of 5-HT neurotransmission, behavioral responses in the forced swim test (FST), and plasma FLX and norfluoxetine (NFLX) concentrations were investigated. Peri-adolescent n-3 insufficiency led to significant reductions in cortical docosahexaenoic acid (DHA, 22:6n-3) composition in DEF (−25%, p≤0.0001) and DEF+FLX (−28%, p≤0.0001) rats. Untreated DEF rats exhibited significantly lower regional 5-HIAA/5-HT ratios compared with untreated CON rats, but exhibited similar behavioral responses in the FST. In both CON and DEF rats, chronic FLX treatment similarly and significantly decreased 5-HIAA concentrations and the 5-HIAA/5-HT ratio in the hypothalamus, hippocampus, and nucleus accumbens, brainstem tryptophan hydroxylase-2 mRNA expression, and immobility in the FST. While the FLX-induced reduction in 5-HIAA concentrations in the prefrontal cortex was significantly blunted in DEF rats, the reduction in the 5-HIAA/5-HT ratio was similar to CON rats. Although plasma FLX and NFLX levels were not significantly different in DEF and CON rats, the NFLX/FLX ratio was significantly lower in DEF+FLX rats. These preclinical data demonstrate that n-3 fatty acid deficiency does not significantly reduce the effects of chronic FLX treatment on central 5-HT turnover or behavior in the FST in female rats.

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Section: Discussionsupporting

confidence: 86%

Omega-3 fatty acid deficiency does not alter the effects of chronic fluoxetine treatment on central serotonin turnover or behavior in the forced swim test in female rats

McNamara¹,

Able²,

Liu³

et al. 2013

Pharmacology Biochemistry and Behavior

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“…Consistent with these Þndings is the report by Vickers et al (1996), showing that 5-HT 1A receptors do not mediate d-fenßuramine-induced anorexia in rats. Moreover, Lightowler et al (1996) suggested that ßuoxetine-induced anorexia in the rat is not mediated by the serotonergic system.…”

Section: Discussionmentioning

confidence: 98%

Blockade of pre-and post-synaptic 5-HT 1A receptors does not modify the effect of fluoxetine or 5-hydroxytryptophan on ethanol and food intake in rats

et al. 1997

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Selective serotonin reuptake inhibitors (SSRIs) or serotonin precursors inhibit ethanol and food intake by increasing the synaptic availability of 5-HT in the central nervous system. However, these agents can also increase 5-HT levels at somatodendritic 5-HT1A autoreceptors, with negative effects on serotonergic transmission. (+)WAY100135 [N-ter-butyl 3-4-(2-methoxy-phenyl) piperazin-1-yl-2-phenylpropanamide dihydrochloride] is a selective antagonist both at pre- and post-synaptic 5-HT1A receptors. The present study investigated the effect on ethanol and food intake of (+)WAY100135, given alone or coadministered with the SSRI fluoxetine or the 5-HT precursor 5-hydroxytryptophan (5-HTP) in genetically selected alcohol-preferring rats. Blockade of presynaptic 5-HT1A receptors after injection of (+)WAY100135, 0.1 or 1 microgram/rat, into the dorsal raphe did not significantly modify ethanol, food or total fluid intake. The same doses of (+)WAY100135 did not modify the inhibition of ethanol and food intake induced by intraperitoneal (i.p.) injection of fluoxetine, 5 mg/kg. Subcutaneous (s.c.) administration of (+)WAY100135 (1 or 10 mg/kg) did not affect the 3-h, or the overnight intake of ethanol, food or total fluids. Given together with i.p. fluoxetine (5 mg/kg) or s.c. 5-HTP (100 mg/kg plus carbidopa. 12.5 mg/kg), the same s.c. doses of (+)WAY100135 did not modify their inhibitory effect on ethanol and food consumption. Present findings suggest that blockade either of pre- or of pre- and postsynaptic 5-HT1A receptors does not potentiate the inhibitory effect of fluoxetine or 5-HTP on ethanol and food intake.

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“…Fluoxetine has an anorectic effect that may lead to this decrease in weight gain observed clinically and experimentally (McGuirk and Silverstone, 1990). Fluoxetine-induced hypophagia is thought to be mediated by fluoxetine acting on the 5-HT 2C receptor (Lightowler et al, 1996). The 5-HT 2C receptor is important in feeding as 5-HT 2C receptor knockout mice have increased feeding and obesity (Tecott et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Chronic Fluoxetine Differentially Affects 5-Hydroxytryptamine_2A Receptor Signaling in Frontal Cortex, Oxytocin- and Corticotropin-Releasing Factor-Containing Neurons in Rat Paraventricular Nucleus

Damjanoska

Kar²,

Kindel³

et al. 2003

J Pharmacol Exp Ther

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Differential adaptive changes in serotonin 2A 2A ] receptor signaling during treatment may be one mechanism involved in the latency of therapeutic improvement with antidepressants, such as fluoxetine. We examined the effects of fluoxetine (2, 3, 7, 21, or 42 days) on hypothalamic 5-HT 2A receptor signaling. The hormone responses to an injection of the 5-HT 2A receptor agonist (Ϯ)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane HCl (DOI) were used as an index of hypothalamic 5-HT 2A receptor function. Treatment with fluoxetine for 21 or 42 days produced diminished adrenocorticotropic hormone (ACTH) and oxytocin (but not corticosterone) responses to DOI injections (2.5 mg/kg i.p.; 15 min postinjection). Regulators of G protein signaling 4 and G ␣q protein levels in the hypothalamic paraventricular nucleus were not altered during fluoxetine treatment. Because previous studies indicate that treatment with fluoxetine for 21 days resulted in increased hormone responses to DOI when measured at 30 min after injection, we examined the effect of fluoxetine (21 days) on DOI-induced increase hormone levels at 15, 30, and 60 min after DOI injection. Fluoxetine decreased the oxytocin response at 15 but not at 30 min post-DOI injection, and potentiated the ACTH and corticosterone responses at 30 min post-DOI injection. For comparison, we examined the effect of fluoxetine on 5-HT 2A receptor-mediated increase in phospholipase C (PLC) activity in the frontal cortex. 5-HT-stimulated, but not guanosine 5Ј-O-(3-thio)triphosphate-stimulated PLC activity was increased after 21 days of fluoxetine-treatment. Overall, these results indicate that chronic fluoxetine treatment can potentiate 5-HT 2A receptor signaling in frontal cortex but differentially alters 5-HT 2A receptor signaling in oxytocin-containing neurons and corticotropin-releasing factor-containing neurons in the paraventricular nucleus.

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An investigation of the mechanism responsible for fluoxetine-induced hypophagia in rats

Cited by 32 publications

References 26 publications

Omega-3 fatty acid deficiency does not alter the effects of chronic fluoxetine treatment on central serotonin turnover or behavior in the forced swim test in female rats

Omega-3 fatty acid deficiency does not alter the effects of chronic fluoxetine treatment on central serotonin turnover or behavior in the forced swim test in female rats

Blockade of pre-and post-synaptic 5-HT 1A receptors does not modify the effect of fluoxetine or 5-hydroxytryptophan on ethanol and food intake in rats

Chronic Fluoxetine Differentially Affects 5-Hydroxytryptamine_2A Receptor Signaling in Frontal Cortex, Oxytocin- and Corticotropin-Releasing Factor-Containing Neurons in Rat Paraventricular Nucleus

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An investigation of the mechanism responsible for fluoxetine-induced hypophagia in rats

Cited by 32 publications

References 26 publications

Omega-3 fatty acid deficiency does not alter the effects of chronic fluoxetine treatment on central serotonin turnover or behavior in the forced swim test in female rats

Omega-3 fatty acid deficiency does not alter the effects of chronic fluoxetine treatment on central serotonin turnover or behavior in the forced swim test in female rats

Blockade of pre-and post-synaptic 5-HT 1A receptors does not modify the effect of fluoxetine or 5-hydroxytryptophan on ethanol and food intake in rats

Chronic Fluoxetine Differentially Affects 5-Hydroxytryptamine2A Receptor Signaling in Frontal Cortex, Oxytocin- and Corticotropin-Releasing Factor-Containing Neurons in Rat Paraventricular Nucleus

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Chronic Fluoxetine Differentially Affects 5-Hydroxytryptamine_2A Receptor Signaling in Frontal Cortex, Oxytocin- and Corticotropin-Releasing Factor-Containing Neurons in Rat Paraventricular Nucleus