An Animal Model of Congenital Defect of Gene Expression of Cholecystokinin (CCK)-A Receptor

Funakoshi, Akihiro; Miyasaka, Kyoko; Shinozaki, Hirotsugu; Masuda, Masao; Kawanami, Takako; Takata, Yutaka; Kono, Akira

doi:10.1006/bbrc.1995.1728

Cited by 132 publications

(85 citation statements)

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“…Although fractional islet blood flow was increased in OLETF rats compared with LETO rats at 12 weeks of age, islet blood flow did not significantly differ between the two. Previous studies indicated that OLETF rats genetically lack cholecystokinin (CCK) receptor A, a major form expressed in the rat pancreas (29,30). Because CCK stimulates pancreatic growth and increases pancreatic blood flow (31), the absence of CCK action may contribute to the small pancreas and hemodynamic changes seen in OLETF rats.…”

Section: Discussionmentioning

confidence: 99%

Islet Hyperperfusion During Prediabetic Phase in OLETF Rats, a Model of Type 2 Diabetes

Iwase

Uchizono²,

Tashiro³

et al. 2002

Diabetes

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Although it has been hypothesized that initial hyperperfusion followed by late hypoperfusion in islet circulation occurs in rodent models of type 2 diabetes, islet blood flow has not been measured during prediabetic phase. We studied islet blood flow in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of slowly progressive obese type 2 diabetes. Islet blood flow was measured by the two-color microsphere method under anesthesia at different ages. Islet blood flow was significantly higher in young OLETF rats compared with control Long-Evans Tokushima Otsuka (LETO) rats when the former were not obese or diabetic and had normal insulin secretion at 5 weeks of age (LETO 4.6 ؎ 1.1, OLETF 8.8 ؎ 1.2 ml ⅐ min ؊1 ⅐ mg ؊1 , P < 0.01). At 6 months of age, islet hyperperfusion was observed in OLETF rats, and >40% of whole pancreatic blood flow was diverted into islets in OLETF rats. Prevention of obesity by food restriction increased basal islet blood flow. On the other hand, long-term hyperglycemia induced by sucrose feeding decreased fractional islet blood flow as well as glucose-stimulated islet blood flow. Our results indicate that hyperperfusion is present during the preobese and prediabetic phase in our type 2 diabetes rats.

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Section: Discussionmentioning

confidence: 99%

Islet Hyperperfusion During Prediabetic Phase in OLETF Rats, a Model of Type 2 Diabetes

Iwase

Uchizono²,

Tashiro³

et al. 2002

Diabetes

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“…Exogenous CCK inhibits food intake in rats in a behaviourally specific manner. Loss of the CCK-1 receptor in rats due to a spontaneous mutation [218] leads to hyperphagia and subsequently to obesity [219], although obesity does not develop in CCK-1 receptor knock -1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 17 out mice [220]. The prospect of 5-HT-CCK interactions in the control of satiety was primarily based on pharmacological data.…”

Section: -Ht Interactions With Cck and Leptinmentioning

confidence: 99%

Serotonin controlling feeding and satiety

Voigt

Fink

2015

Behavioural Brain Research

257

167

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Serotonin has been implicated in the control of satiety for almost four decades. Historically, the insight that the appetite suppressant effect of fenfluramine is linked to serotonin has stimulated interest in and research into the role of this neurotransmitter in satiety. Various rodent models, including transgenic models, have been developed to identify the involved 5-HT receptor subtypes. This approach also required the availability of receptor ligands of different selectivity, and behavioural techniques had to be developed simultaneously which allow differentiating between unspecific pharmacological effects of these ligands and 'true' 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 IntroductionWhat are the behavioural and physiological mechanisms that promote satiety? How is satiety defined? Satiety can be seen as a behavioural state which arises from food consumption and suppresses the initiation of eating for a particular period of time [1]. This description alone suggests a high degree of complexity as peripheral post-ingestive and post-absorptive signals need to be relayed to the brain where they are integrated with other signals to produce (or not) the behavioural state called satiety. The state of satiety is brought about a process called satiation, where sensory, cognitive and early post-ingestive mechanisms bring feeding to a halt and thus stopping a meal. Promoting satiation alone must not necessarily lead to reduced total food intake as the frequency of meals could be increased subsequently. Many peripheral and brain mechanisms have been identified that are involved in the expression satiety and it has been suggested that serotonin accelerates satiation and prolongs satiety [2]. In the following, we will review the role of serotonin in satiety in more detail 1 . The reader will see that, despite immense progress made during the last years, the field is still far from being resolved.As serotonin (5-Hydroxytryptamine; 5-HT) is a phylogenetically old neurotransmitter, various functions had time to evolve in different phyla, but maybe also in different species. 5-HT receptors exist in animal cells for millions of years and they are as old as adrenoreceptors ore some peptide receptors, possibly even older [5,6]. Even in invertebrates such as molluscs (Aplysia californica) and annelids (Hirudo medicinalis), 5-HT might functionally be related to food intake [7]. 5-HT is involved in feeding even in the honeybee where it has separate effects in the gut and in the insect brain [8]. In general, however, 5-HT seems rather to be involved in appetitive behaviours in invertebrates whereas it has more of a satiating effect in vertebrates [9]. In general, 5-HT neurons seem to be more extensively distributed throughout the body in lower animals than in higher animals including mammals where 5-HT neurones...

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“…CCK in the periphery has also been shown to regulate mesolimbic function by what appears to be a presynaptic mechanism of action mediated by peripheral CCK-A receptors (Kariya et al 1994;Kihara et al 1993). Because of its ability to regulate mesolimbic function, the CCK-A system could contribute to mechanism underlying psychiatric disorders such as schizophrenia.Otsuka Long Evans Tokushima Fatty (OLETF) rats lack CCK-A receptors because of a spontaneous mutation (Funakoshi et al 1995). These rats have been studied extensively as a model to understand the metabolic role of peripheral CCK as they have a tendency to demonstrate diabetes-like changes after 18 weeks of age (Otsuki et al 1995).…”

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confidence: 99%

“…Otsuka Long Evans Tokushima Fatty (OLETF) rats lack CCK-A receptors because of a spontaneous mutation (Funakoshi et al 1995). These rats have been studied extensively as a model to understand the metabolic role of peripheral CCK as they have a tendency to demonstrate diabetes-like changes after 18 weeks of age (Otsuki et al 1995).…”

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Startle and Sensorimotor Gating in Rats Lacking CCK-A Receptors

Feifel

2001

Neuropsychopharmacology

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Long Evans Tokushima Fatty (OLETF) rats lack CCK-A receptors because of a genetic mutation. Previous studies have shown that CCK-A receptors seem to play a role in the regulation of prepulse inhibition (PPI) of the startle reflex, an operational measure of sensorimotor gating. This study investigated baseline and drug-disrupted PPI in OLETF rats and their non-mutant counterparts, Long Evans Tokushima Otsuka (LETO) rats. Baseline PPI did not differ significantly between the two rat genotypes but OLETF rats exhibited a higher acoustic startle response compared to LETO rats. Amphetamine (2 mg/kg), and the dizocilpine (0.1 mg/ kg), disrupted PPI in LETO rats but not in the OLETF rats. Apomorphine (0.5 mg/kg) failed to disrupt PPI in both LETO and OLETF rats, and haloperidol (0.5 Cholecystokinin (CCK), a gut-brain peptide, has been implicated in the modulation of mesolimbic dopamine transmission. CCK coexists with dopamine in a large proportion of mesolimbic neurons that terminate in the medial-posterior nucleus accumbens (mpNAC) (Hokfelt et al. 1980). CCK co-localized in mesolimbic dopamine cells appears to potentiate dopamine transmission via CCK-A receptors in the mpNAC (Crawley 1991). CCK in the periphery has also been shown to regulate mesolimbic function by what appears to be a presynaptic mechanism of action mediated by peripheral CCK-A receptors (Kariya et al. 1994;Kihara et al. 1993). Because of its ability to regulate mesolimbic function, the CCK-A system could contribute to mechanism underlying psychiatric disorders such as schizophrenia.Otsuka Long Evans Tokushima Fatty (OLETF) rats lack CCK-A receptors because of a spontaneous mutation (Funakoshi et al. 1995). These rats have been studied extensively as a model to understand the metabolic role of peripheral CCK as they have a tendency to demonstrate diabetes-like changes after 18 weeks of age (Otsuki et al. 1995). OLETF rats represent a potentially useful model to investigate the role of the endogenous CCK-A system in the regulation of mesolimbic dopamine function. A previous study found that OLETF rats exhibited decreased spontaneous locomotor activity relative to Long Evans Tokushimo Otsuka (LETO) rats, 24 , NO . 6 their control counterparts, and the authors suggested that this difference may be the result of perturbations in basal dopamine regulation in OLETF rats (Kobayashi et al. 1996). We previously reported that amphetamineinduced early gene expression, as measured by zif 268 mRNA expression in the NAC, did not differ between LETO and OLETF rats (Shilling et al. 2000).To further examine the role of the CCK-A receptor in the regulation of mesolimbic dopamine function, this study investigated prepulse inhibition (PPI) in OLETF and LETO rats. PPI is the normal suppression of the startle response when the intense startling stimulus (pulse) is preceded immediately (50-200 msecs) by a much weaker, non-startling stimulus (prepulse) such as an auditory "click". PPI was studied because it is an operational measure of sensorimotor gating and the ba...

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An Animal Model of Congenital Defect of Gene Expression of Cholecystokinin (CCK)-A Receptor

Cited by 132 publications

References 0 publications

Islet Hyperperfusion During Prediabetic Phase in OLETF Rats, a Model of Type 2 Diabetes

Islet Hyperperfusion During Prediabetic Phase in OLETF Rats, a Model of Type 2 Diabetes

Serotonin controlling feeding and satiety

Startle and Sensorimotor Gating in Rats Lacking CCK-A Receptors

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