Characterization of the serotonin transporter knockout rat: A selective change in the functioning of the serotonergic system

Homberg, Judith R.; Olivier, Jocelien; Smits, Bart M. G.; Mul, Joram D.; Mudde, Josine; Verheul, Mark; Nieuwenhuizen, O.F.M.; Cools, Alexander R.; Ronken, Eric; Cremers, Thomas; Schoffelmeer, Anton N. M.; Ellenbroek, Bart A.; Cuppen, Edwin

doi:10.1016/j.neuroscience.2007.03.030

Cited by 230 publications

(250 citation statements)

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“…This animal has a premature stopcodon (TGC>TGA) introduced at position 3924 in the third exon encoding the second extracellular loop of the SERT protein. Consistent with the absence of SERT in these rats, northern blot analysis revealed that the mutation resulted in nonsense-mediated decay of the mutant SERT transcript and showed reduced SERT mRNA transcript in the SERT heterozygous knockout (SERT +/− ) rat (Homberg et al 2007a). In addition, [ 3 H]citalopram (SSRI) binding to brain slices of SERT −/− rats is completely absent, whereas in SERT +/− rats, citalopram binding was reduced by approximately 40%.…”

Section: Introductionmentioning

confidence: 56%

“…After weaning at the age of 21 days, ear cuts were taken for genotyping. Genotyping was performed at the Hubrecht Institute (Utrecht, The Netherlands), and the procedure has been described elsewhere (Homberg et al 2007a). During the experiment, all animals were individually housed in standard Macrolon® type 3 cages (42×26×20 cm) in temperature-controlled rooms (21±1°C) with standard 12/12-h day/night cycle (lights on at 7.00 A.M.) and food (Sniff, long cut pellet, Bio Services, Uden, The Netherlands) and water available ad libitum.…”

Section: Animalsmentioning

confidence: 99%

“…In addition, [ 3 H]citalopram (SSRI) binding to brain slices of SERT −/− rats is completely absent, whereas in SERT +/− rats, citalopram binding was reduced by approximately 40%. Moreover, extracellular 5-HT levels in the hippocampus of SERT −/− are nine-fold elevated (Homberg et al 2007a;Olivier et al 2008), whereas in SERT +/− rats, extracellular 5-HT levels are similar to wildtype littermates (SERT +/+ ) (Olivier et al unpublished data). However, intracellular 5-HT levels were reduced by approximately 75-50% in SERT −/− rats and by 45-55% in SERT +/− rats in several brain areas (Homberg et al 2007a).…”

Section: Introductionmentioning

confidence: 98%

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Acute tryptophan depletion dose dependently impairs object memory in serotonin transporter knockout rats

et al. 2008

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Rationale Acute tryptophan depletion (ATD) transiently lowers central serotonin levels and can induce depressive mood states and cognitive defects. Previous studies have shown that ATD impairs object recognition in rats. Objectives As individual differences exist in central serotonin neurotransmission, the impact of ATD may vary accordingly. In this experiment, we investigated the hypothesis that male serotonin transporter knockout (SERT −/− ), rats marked by a lower SERT function, are more vulnerable to the effects of ATD in an object recognition task than male wildtype (SERT +/+ ) and heterozygous (SERT +/− ) rats. Materials and methods Twelve male SERT +/+ , SERT +/− , and SERT −/− rats were treated with standard dose and lowdose ATD using a gelatine-based protein-carbohydrate mixture lacking tryptophan. In the control treatment, Ltryptophan was added to the mixture. Four hours after treatment, the rats were subjected to the object recognition task. In addition, the effects of ATD on plasma amino acid concentrations were measured, and concentrations of 5-HT and 5-HIAA were measured in the frontal cortex and hippocampus of these rats. Results Plasma TRP levels and central 5-HT and 5-HIAA levels were decreased in all genotypes after ATD, but effects were stronger in SERT −/− rats. The standard dose of ATD impaired object recognition in all genotypes. SERT −/− and SERT +/− rats were more vulnerable to low dose of ATD in the object recognition task compared to SERT +/+ rats. Conclusions These results indicate a greater sensitivity to ATD in SERT −/− and SERT +/− rats, which may be related to stronger central depletion effects in these rats.

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Section: Introductionmentioning

confidence: 56%

Section: Animalsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Acute tryptophan depletion dose dependently impairs object memory in serotonin transporter knockout rats

et al. 2008

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“…Northern blot analysis (as described in Ref. 27) was done using a Pmch-specific radiolabeled PCR-derived probe covering the first exon of the gene. The following primers were used for probe generation: forward primer: ATTCT CCTTC GGCTT TACG; and reverse primer: TCCAG AGAAG GAGCA ACAAC.…”

Section: Animalsmentioning

confidence: 99%

Pmchexpression during early development is critical for normal energy homeostasis

Mul

Berg³

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

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Mul JD, Yi CX, van den Berg SAA, Ruiter M, Toonen PW, van der Elst MCJ, Voshol PJ, Ellenbroek BA, Kalsbeek A, la Fleur SE, Cuppen E. Pmch expression during early development is critical for normal energy homeostasis. Am J Physiol Endocrinol Metab 298: E477-E488, 2010. First published November 24, 2009 doi:10.1152/ajpendo.00154.2009.-Postnatal development and puberty are times of strong physical maturation and require large quantities of energy. The hypothalamic neuropeptide melanin-concentrating hormone (MCH) regulates nutrient intake and energy homeostasis, but the underlying mechanisms are not completely understood. Here we use a novel rat knockout model in which the MCH precursor Pmch has been inactivated to study the effects of loss of MCH on energy regulation in more detail. Pmch Ϫ/Ϫ rats are lean, hypophagic, osteoporotic, and although endocrine parameters were changed in pmch Ϫ/Ϫ rats, endocrine dynamics were normal, indicating an adaptation to new homeostatic levels rather than disturbed metabolic mechanisms. Detailed body weight growth and feeding behavior analysis revealed that Pmch expression is particularly important during early rat development and puberty, i.e., the first 8 postnatal weeks. Loss of Pmch resulted in a 20% lower set point for body weight that was determined solely during this period and remained unchanged during adulthood. Although the final body weight is diet dependent, the Pmch-deficiency effect was similar for all diets tested in this study. Loss of Pmch affected energy expenditure in both young and adult rats, although these effects seem secondary to the observed hypophagia. Our findings show an important role for Pmch in energy homeostasis determination during early development and indicate that the MCH receptor 1 system is a plausible target for childhood obesity treatment, currently a major health issue in first world countries. melanin-concentrating hormone; hypothalamus; childhood obesity; rat knockout model CHILDHOOD OBESITY IS NOW WIDELY recognized as a severe public health issue (43). Treatment with drugs aimed at neural systems involved in the determination of the energy balance could potentially result in a lower energy balance during puberty as well as later in adulthood. Therefore, neuropeptides involved in body weight regulation during early development and puberty are attractive targets for anti-childhood obesity drugs.The neuronal metabolic systems in humans and primates develop prenatally, while in rodents these systems develop during the first 3 postnatal weeks (5, 21). This results in the activation and optimization of neuronal systems during early rodent development. A second important metabolic period is puberty, a period of major growth, hormonal changes, and sexual maturation. In the rat, puberty is characterized by different responses of young-adolescent [postnatal day (PND) 40] and young-adult (PND 60) male rats to environmental cues like stress and cold (17,18). In addition to these age-dependent behavioral differences, the amount of food consumed durin...

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“…Regarding the non-serotonergic neurotransmitter systems of SERT knockout mice, no alterations have been found in the tissue concentrations of dopamine or norepinephrine in brain structures examined (Bengel et al, 1998;Kim et al, 2005), a characteristic shared by the SERT knockout rat (Homberg et al, 2007). The only reported changes to non-serotonergic systems in SERT KO mice are 5-HT uptake by dopamine transporters into neurons in the midbrain (Pan et al, 2001;Zhou et al, 2002) and decreased basal glucose utilization in most brain regions (Esaki et al, 2005).…”

Section: Discussionmentioning

confidence: 96%

Marked decrease of LSD-induced stimulus control in serotonin transporter knockout mice

Krall

Richards

Rabin

et al. 2008

Pharmacology Biochemistry and Behavior

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Rationale-Based upon extensive studies in the rat, it has been suggested that stimulus control by LSD is mediated by 5-HT 2A receptors, with serotonergic receptors of the 5-HT 1A and 5-HT 2C subtypes playing modulatory roles. In genetically modified mice lacking the serotonin transporter (SERT), 5-HT 2A receptor density is decreased and, at a functional level, the head twitch response following the administration of DOI, an index of activation of 5-HT 2A receptors, is reduced. Taken together, these studies led us to hypothesize that the efficacy of LSD in establishing stimulus control is diminished or abolished in mice lacking the serotonin transporter.Objective-Determine the efficacy of LSD for establishing stimulus control in SERT knockout (KO) mice.Methods-SERT KO mice and wildtype (WT) littermates were trained in a visual discrimination on a progressive fixed ratio (FR) water-reinforced task and subsequently trained on a FR10 schedule with LSD (0.17 or 0.30 mg/kg) or vehicle. To control for general deficiencies in drug discrimination, mice were trained with pentobarbital (15 or 30 mg/kg) or vehicle.Results-The visual stimulus exerted control in both genotypes. LSD induced stimulus control in 90% of WT mice but only 31% of SERT KO mice. In contrast, pentobarbital induced stimulus control in 80% of WT mice and 54% of knockout mice.Conclusions-Although SERT KO mice exhibited stimulus control by the non-serotonergic drug, pentobarbital, the efficacy of LSD in these animals was markedly decreased, suggesting that reduced density of 5-HT 1A and/or 5-HT 2A receptors underlies the absence of stimulus control by LSD.

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Characterization of the serotonin transporter knockout rat: A selective change in the functioning of the serotonergic system

Cited by 230 publications

References 44 publications

Acute tryptophan depletion dose dependently impairs object memory in serotonin transporter knockout rats

Acute tryptophan depletion dose dependently impairs object memory in serotonin transporter knockout rats

Pmchexpression during early development is critical for normal energy homeostasis

Marked decrease of LSD-induced stimulus control in serotonin transporter knockout mice

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