Increased Sucrose Intake Research Articles

Validation of chronic mild stress in the Wistar-Kyoto rat as an animal model of treatment-resistant depression.

A recent review proposed four criteria for an animal model of treatment-resistant depression (TRD): a phenotypic resemblance to a risk factor for depression; enhanced response to stress; nonresponse to antidepressant drugs and response to treatments effective in TRD, such as deep brain stimulation (DBS) of the prefrontal cortex or ketamine. Chronic mild stress (CMS) provides a valid model of depression; the Wistar-Kyoto (WKY) rat is considered to be nonresponsive to antidepressant drugs. Here, we applied CMS to WKY rats. WKY and Wistar rats were exposed to CMS, then treated with saline, imipramine, citalopram or venlafaxine. After 5 weeks of CMS and 3 weeks of drug treatment, all WKY groups were implanted unilaterally with DBS electrodes in the prefrontal cortex, and examined in sucrose intake, elevated plus maze (EPM; decreased entries and time in the open arms) and novel object recognition (decreased exploration) tests, following 2×2 h of DBS. CMS decreased sucrose intake, open arm entries on the EPM, and object recognition. Relative to Wistars, WKY rats showed evidence of increased emotionality in the EPM and novel object recognition tests, and a greater impact of CMS on body weight gain and open arm entries. Wistars responded to drug treatment with an increase in sucrose intake but WKY were nonresponsive to drug treatment on all three behavioural tests. With one exception, DBS reversed the anhedonic, anxiogenic and dyscognitive effects of CMS in all groups of WKY rats. In a further experiment, subacute ketamine (10 mg/kg) also normalized behaviour on all three tests. We conclude that WKY rats subjected to CMS meet all four criteria for a valid model of TRD, and provide a basis for studying the mechanism of action of DBS.

Ferulic Acid Improves Depressive-Like Behavior in Prenatally-Stressed Offspring Rats via Anti-Inflammatory Activity and HPA Axis.

Prenatal stress (PS) can increase the risk of nervous, endocrine and metabolic diseases, and immune dysfunction. Ferulic acid (FA) is a dietary phenolic acid that has pharmacological properties, including potent anti-inflammatory action. We used male, prenatally-stressed offspring rats to investigate the anti-depressive-like effects and possible anti-inflammatory mechanism of FA. We determined the animal behaviors, and the mRNA expression and concentration of inflammatory cytokines, and HPA axis. In addition, we assessed the modulation of hippocampal nuclear factor-κB (NF-κB) activation, neuronal nitric oxide synthase (nNOS) and glucocorticoid receptors (GR) expression via western blotting and immunohistochemistry. Administration of FA (12.5, 25, and 50 mg/kg/day, i.g.) for 28 days markedly increased sucrose intake, and decreased immobility time and total number of crossings, center crossings, rearing, and grooming in the male PS offspring. FA significantly reduced IL-6, IL-1β, and TNF-α concentration and increased IL-10 concentration in male, prenatally-stressed offspring, stimulated by the NF-κB pathway. In addition, FA inhibited interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α), and increased interleukin-10 (IL-10) mRNA and protein expression. Furthermore, FA markedly decreased the serum adrenocorticotropin (ACTH) and corticosterone concentration by the increase of GR protein expression. Taken together, this study revealed that FA has anti-depressive-like effects in male, prenatally-stressed offspring, partially due to its anti-inflammatory activity and hypothalamic-pituitary-adrenal (HPA) axis.

Increased sugar intake as a form of compensatory hyperphagia in patients with type 2 diabetes under dapagliflozin treatment

AimsSodium-glucose cotransporter 2 inhibitors (SGLT2i) cause substantially less weight loss than would be expected based on their caloric deficits, probably due to enhanced appetite regulation known as “compensatory hyperphagia,” which occurs to offset the negative energy balance caused by increased glycosuria. We examined whether any specific nutrients contributed to the compensatory hyperphagia in diabetic patients taking SGLT2i. MethodsSixteen patients with type 2 diabetes were newly administered dapagliflozin 5 mg daily as the experimental SGLT2i group. Sixteen age-, sex- and BMI-matched type 2 diabetes patients not receiving dapagliflozin served as controls. A brief-type self-administered diet history questionnaire (BDHQ) was undertaken just before and 3 months after study initiation to evaluate changes of energy and nutrient intakes in each group. ResultsAt 3 months, daily intakes of total calories and the proportions of the three major nutrients were not significantly increased in either group. However, daily sucrose intake was significantly increased after treatment versus the baseline value in the SGLT2i group (p = .003), but not in controls. The calculated intakes of all other nutrients were not significantly changed in either group. ConclusionsDapagliflozin treatment specifically increased sucrose intake, which might be an ideal target for nutritional approaches to attenuate compensatory hyperphagia.

Crassifoside H improve the depressive-like behavior of rats under chronic unpredictable mild stress: Possible involved mechanisms.

Crassifoside (CH) is a novel chlorine-containing compound isolated from rhizomes of Curculigo glabrescens. This study aimed to explore the antidepressant-like effect of CH and involved mechanisms. A rat depression model was established using chronic unpredictable mild stress (CUMS) paradigm. Behavioral tests including sucrose preference test (SPT), open field test (OFT) and forced swimming test (FST) were used to evaluate the antidepressant-like effect of CH. The levels of plasma corticosterone (CORT) and corticotrophin-releasing factor (CRF) in hypothalamus were measured to determine the activity of hypothalamic pituitary-adrenal (HPA) axis. Protein expression of 5-hydroxytryptamine 1A (5-HT1A) receptor, brain-derived neurotrophic factor (BDNF), as well as the total and phosphorylated extracellular signal-regulated kinase (ERK)1/2 in hippocampus were also analyzed by Western blotting. The CH administration effectively ameliorated the depressive-like behaviors of CUMS rats, as indicated by the increased sucrose intake in SPT, reduced immobility time in FST, and the increased rearing and grooming numbers, spent more time in inner zone and less time in outer zone in OFT. CH improved CUMS-induced HPA axis hyperactivity by reduced plasma CORT and CRH expression in hypothalamus. Moreover, CH reversed CUMS-induced decrease of 5-HT1A receptor expression, and up-regulated BDNF and phosphorylated-ERK1/2 levels in hippocampus. These findings suggest that CH improved depressive behaviors of CUMS rats by modulating of HPA axis dysfunction, increasing 5-HT1A receptor expression, and activating BDNF-ERK signaling pathway.

Chronic high-sucrose diet increases fibroblast growth factor 21 production and energy expenditure in mice

Excess carbohydrate intake causes obesity in humans. On the other hand, acute administration of fructose, glucose or sucrose in experimental animals has been shown to increase the plasma concentration of anti-obesity hormones such as glucagon-like peptide 1 (GLP-1) and Fibroblast growth factor 21 (FGF21), which contribute to reducing body weight. However, the secretion and action of GLP-1 and FGF21 in mice chronically fed a high-sucrose diet has not been investigated. To address the role of anti-obesity hormones in response to increased sucrose intake, we analyzed mice fed a high-sucrose diet, a high-starch diet or a normal diet for 15 weeks. Mice fed a high-sucrose diet showed resistance to body weight gain, in comparison with mice fed a high-starch diet or control diet, due to increased energy expenditure. Plasma FGF21 levels were highest among the three groups in mice fed a high-sucrose diet, whereas no significant difference in GLP-1 levels was observed. Expression levels of uncoupling protein 1 (UCP-1), FGF receptor 1c (FGFR1c) and β-klotho (KLB) mRNA in brown adipose tissue were significantly increased in high sucrose-fed mice, suggesting increases in FGF21 sensitivity and energy expenditure. Expression of carbohydrate responsive element binding protein (ChREBP) mRNA in liver and brown adipose tissue was also increased in high sucrose-fed mice. These results indicate that FGF21 production in liver and brown adipose tissue is increased in high-sucrose diet and participates in resistance to weight gain.

Possible anti-depressant effect of efavirenz and pro-depressive-like effect of voriconazole in specified doses in various experimental models of depression in mice.

Reports from experimental and clinical studies have indicated the possible relation between cholesterol and depression. Efavirenz (EFV) and Voriconazole (VRC) have been reported to affect cholesterol-24S-hydroxylase enzyme. The objective of the present study was to evaluate the effect of EFV and VRC in experimental models of depression in mice. There was a measurement of immobility time in forced swim test and tail suspension test in which mice were previously subjected to the treatment of EFV (0.09mg/kg, orally (po)) and VRC (75mg/kg, intraperitoneally (ip)) separately for 14days. Sucrose intake was measured during stress schedule of 21days in chronic mild stress model in which mice were subjected to above mentioned drug treatment for last 14days. There was an estimation of serum total cholesterol and brain serotonin levels on day 21. The results indicated that mice treated with EFV showed a significant decrease in the immobility time and increase in sucrose intake with decrease in serum total cholesterol. Mice treated with VRC showed a significant increase in the immobility time and decrease in the sucrose intake with increase in serum total cholesterol. There was a significant increase and decrease in brain serotonin levels in mice treated with EFV and VRC respectively. The results of the present study indicates the possible anti-depressant effect of EFV and pro-depressive-like effect of VRC in specified doses in mice, raising the possibility that stimulation but not inhibition of cholesterol-24S-hydroxylase may be important in the treatment of depression.

Sex-dependent effects of early life inflammatory pain on sucrose intake and sucrose-associated hippocampal Arc expression in adult rats

We hypothesize that dorsal hippocampal (dHC) neurons, which are critical for episodic memory, form a memory of a meal and inhibit the initiation of the next meal and the amount ingested during that meal. In support, we showed previously that (1) consuming a sucrose meal induces expression of the synaptic plasticity marker activity-regulated cytoskeleton-associated protein (Arc) in dHC neurons and (2) reversible inactivation of these neurons immediately following a sucrose meal accelerates the onset of the next meal and increases the size of that meal. These data suggest that hippocampal-dependent memory inhibits intake; therefore, the following experiments were conducted to determine whether hippocampal-dependent memory impairments are associated with increased intake. We reported recently that one episode of early life inflammatory pain impairs dHC-dependent memory in adult rats. The present study determined whether neonatal inflammatory pain also increases sucrose intake and attenuates sucrose-associated Arc expression. Male and female Sprague-Dawley rats were given an intraplantar injection of the inflammatory agent carrageenan (1%) on the day of birth and sucrose intake and sucrose-associated dHC Arc expression were measured in adulthood. Neonatal inflammatory pain increased sucrose intake in adult female and male rats, decreased sucrose-associated dHC Arc expression in female rats, and tended to have a similar effect on Arc expression in male rats. Neonatal inflammatory pain significantly decreased the interval between two sucrose meals in female but not in male rats. Morphine administration at the time of insult attenuated the effects of injury on sucrose intake. Collectively, these findings indicate that one brief episode of inflammatory pain on the day of birth has a long long-lasting, sex-dependent impact on intake of a palatable food in adulthood.

Stress differentially regulates brain expression of corticotropin-releasing factor in binge-like eating prone and resistant female rats

The expression of corticotropin-releasing factor (CRF), a neuropeptide that regulates endocrine and behavioral responses to stress, was assessed in the brain in rats prone or resistant to stress-induced binge-like eating of sucrose. Female Sprague-Dawley rats were subjected to unpredictable intermittent 1-h access to sucrose in non-stressful conditions or after exposure to three foot shock stress sessions. Experimental sessions were performed at metestrus, diestrus, and proestrus. The rats were assigned to the binge-like eating prone (BEP) or the binge-like eating resistant (BER) phenotypes according to the rats' persistently high or low sucrose intake following three stress sessions. The BEP rats displayed elevated consumption of sucrose in non-stressful conditions and an additional significant increase in sucrose intake in response to stress. Conversely, the BER rats showed lower sucrose intake in non-stressful conditions, and stress did not increase sucrose intake in this phenotype. The brain expression of CRF mRNA and plasma corticosterone levels were assessed 30 min after the last stress session at the diestrous phase of the estrous cycle. Stress triggered a significant increase in plasma corticosterone levels and strongly increased CRF mRNA expression in the paraventricular hypothalamic nucleus in the BER but not in the BEP rats. However, the BEP but not the BER rats demonstrated a significant increase in CRF mRNA expression in the bed nucleus of the stria terminalis (BNST) after stress. Hyporeactivity of the hypothalamic-pituitary-adrenal axis and the higher CRF expression in the BNST in BEP rats may contribute to stress-induced binge-like sucrose eating in the BEP phenotype.

Icariin reverses corticosterone-induced depression-like behavior, decrease in hippocampal brain-derived neurotrophic factor (BDNF) and metabolic network disturbances revealed by NMR-based metabonomics in rats

Previously published reports have revealed the antidepressant-like effects of icariin in a chronic mild stress model of depression and in a social defeat stress model in mice. However, the therapeutic effect of icariin in an animal model of glucocorticoid-induced depression remains unclear. This study aimed to investigate antidepressant-like effect and the possible mechanisms of icariin in a rat model of corticosterone (CORT)-induced depression by using a combination of behavioral and biochemical assessments and NMR-based metabonomics. The depression model was established by subcutaneous injections of CORT for 21 consecutive days in rats, as evidenced by reduced sucrose intake and hippocampal brain-derived neurotrophic factor (BDNF) levels, together with an increase in immobility time in a forced swim test (FST). Icariin significantly increased sucrose intake and hippocampal BDNF level and decreased the immobility time in FST in CORT-induced depressive rats, suggesting its potent antidepressant activity. Moreover, metabonomic analysis identified eight, five and three potential biomarkers associated with depression in serum, urine and brain tissue extract, respectively. These biomarkers are primarily involved in energy metabolism, lipid metabolism, amino acid metabolism and gut microbe metabolism. Icariin reversed the pathological process of CORT-induced depression, partially via regulation of the disturbed metabolic pathways. These results provide important mechanistic insights into the protective effects of icariin against CORT-induced depression and metabolic dysfunction.

Behavioral and hormonal responses to stress in binge-like eating prone female rats

Binge eating episodes are frequently stimulated by stress. We developed a model of binge eating proneness based on individual sensitivity of young female Sprague Dawley rats to significantly increase sucrose consumption in response to stress. The rats were subjected to unpredictable intermittent 1-h access to 10% sucrose. After the stabilization of sucrose intake, rats were assessed for consistency of higher (for binge-like eating prone, BEP) or lower (for binge-like eating resistant, BER) sucrose intake in response to unpredictable episodes of foot-shock stress. The objectives of this study included demonstrating face validity of the BEP model and determining if some of the features of this model were pre-existing before exposure to intermittent access to sucrose and repeated stress. The BEP rats consumed a larger (20%>BER) amount of sucrose in a discrete (1-h) period of time compared to the BER phenotype in non-stressful conditions and significantly increased sucrose intake (50%>BER) under stress. Conversely, stress did not affect sucrose intake in BER rats. BEP rats showed higher sucrose intake compared to BER rats at the beginning of darkness as well as during the light period when they were sated and not physically hungry. Analyses of the sucrose licking microstructure revealed that BEP rats had a high motivational drive to consume sucrose in non-stressful condition and an increased hedonic value of sucrose when they were exposed to stressful conditions. BEP rats consumed sucrose much more rapidly under stressful conditions compared to BER rats. Finally, BEP rats demonstrated compulsive-like intake of sucrose (assessed in the light-dark box) and a blunted stress-induced increase in plasma corticosterone levels. Body weight and chow intake were not different between the phenotypes. Before exposure to intermittent access to sucrose and repeated stress, the BEP rats showed no clear evidence for compulsive sucrose intake. However, from the first 1-h access to sucrose, the BEP rats exhibited sucrose overeating; and from the first exposure to stress before intermittent access to sucrose, the BEP rats showed a blunted increase in corticosterone plasma levels. Innate sucrose hyperconsumption and altered reactivity of the hypothalamo-pituitary adrenal (HPA) axis to stress may be involved in the development of binge-like eating. Increased perceived hedonic value of palatable food and an increased motivation to consume this food despite aversive conditions as well as deregulated reactivity of the HPA axis may contribute to stress-induced bingeing on sucrose in BEP rats.

Role of relaxin-3/RXFP3 system in stress-induced binge-like eating in female rats

Binge eating is frequently stimulated by stress. The neuropeptide relaxin-3 (RLN3) and its native receptor RXFP3 are implicated in stress and appetitive behaviors. We investigated the dynamics of the central RLN3/RXFP3 system in a newly established model of stress-induced binge eating. Female Sprague–Dawley rats were subjected to unpredictable intermittent 1-h access to 10% sucrose. When sucrose intake stabilized, rats were assessed for consistency of higher or lower sucrose intake in response to three unpredictable episodes of foot-shock stress; and assigned as binge-like eating prone (BEP) or binge-like eating resistant (BER). BEP rats displayed elevated consumption of sucrose under non-stressful conditions (30% > BER) and an additional marked increase in sucrose intake (60% > BER) in response to stress. Conversely, sucrose intake in BER rats was unaltered by stress. Chow intake was similar in both phenotypes on ‘non-stress’ days, but was significantly reduced by stress in BER, but not BEP, rats. After stress, BEP, but not BER, rats displayed a significant increase in RLN3 mRNA levels in the nucleus incertus. In addition, in response to stress, BEP, but not BER, rats had increased RXFP3 mRNA levels in the paraventricular and supraoptic nuclei of the hypothalamus. Intracerebroventricular administration of a selective RXFP3 antagonist, R3(B1-22)R, blocked the stress-induced increase in sucrose intake in BEP rats and had no effect on sucrose intake in BER rats. These results provide important evidence for a role of the central RLN3/RXFP3 system in the regulation of stress-induced binge eating in rats, and have therapeutic implications for eating disorders.

The effects of nicotine self-administration and withdrawal on concurrently available chow and sucrose intake in adult male rats

Carbohydrate intake, preference, and taste thresholds may be altered in current and former cigarette smokers, which may mediate weight gain and risk for obesity in individuals who quit smoking. Attempts to model these effects in rodents have primarily used noncontingent nicotine administration. The purpose of this research was to characterize changes in chow and sucrose intake in rats during a 23-h access model of i.v. nicotine self-administration (NSA), in which rats lever-pressed for chow, sucrose, and nicotine under concurrent fixed-ratio (FR) 1 schedules. Male rats were assigned to one of three groups that differed in food and drug availability. The Nicotine C+S group had concurrent access to nicotine, chow, and sucrose. The Saline C+S group had access to saline, chow, and sucrose. The Nicotine C-Only group had access to nicotine and chow, but not sucrose. Changes in food intake and weight gain were assessed during baseline, NSA, and nicotine withdrawal (i.e., saline extinction). Weight gain was significantly slowed during NSA and increased during withdrawal, but did not differ between the nicotine groups. NSA produced a significant decrease in both chow and sucrose intake. Gradual tolerance to nicotine's effects on sucrose, but not chow intake, occurred. During withdrawal, chow and sucrose intake increased, with a larger percent increase in sucrose intake compared to chow. The proportion of total food intake from sucrose was greater at the end of withdrawal compared to baseline, indicating a history of nicotine intake changed dietary preference. Combined, these results indicate that sucrose intake is more resistant to nicotine's appetite suppressant effects and withdrawal from nicotine produces a greater increase in sweet food intake alongside general increases in chow intake. Changes in overall food intake in current and ex-smokers may lead to increased risk for obesity and other health problems, potentially limiting the benefit of quitting smoking.

Chronic variable stress exposure in male Wistar rats affects the first step of olfactory detection

For most animal species, olfaction plays a paramount role in their perception of the environment. Odours are initially detected in neurons located in the olfactory mucosa. This tissue is regulated by several physiological signals and can be altered in pathology. A number of clinical studies suggest an association between depressive disorders and olfactory sensory loss. In rodents, depressive-like states can be observed in models of chronic stress. We tested the hypothesis that olfactory function might be altered in a rat model of depression, induced by chronic variable stress (CVS). While CVS rats exhibited several symptoms consistent with chronic stress exposure and depressive-like states (increased sucrose intake in sucrose preference test, increased immobility in forced swim test, hyperlocomotion), their odorant responses recorded at the olfactory mucosa level by electro-olfactogram were decreased. In addition we observed increased apoptosis markers in the olfactory mucosa using Western Blot. Our data are consistent with reduced olfactory capacities in a laboratory rat model of chronic stress and depression, in agreement with human clinical data; this warrants further mechanistic studies. Furthermore, this works raises the possibility that altered olfactory function might be a confounding factor in the behavioural testing of chronically stressed or depressed rats.

Antidepressant-like effect of geniposide on chronic unpredictable mild stress-induced depressive rats by regulating the hypothalamus–pituitary–adrenal axis

Geniposide as the major active component of Gardenia jasminoides Ellis has neuroprotective activity. This study elucidated the potential antidepressant-like effect of geniposide and its related mechanisms using a depression rat model induced by 3 consecutive weeks of chronic unpredictable mild stress (CUMS). Sucrose preference test, open field test (OFT) and forced swimming test (FST) were applied to evaluate the antidepressant effect of geniposide. Adrenocorticotropic hormone (ACTH) and corticosterone (CORT) serum levels, adrenal gland index and hypothalamic corticotrophin-releasing hormone (CRH) mRNA expression were measured to assess the activity of hypothalamus–pituitary–adrenal (HPA) axis. Hypothalamic glucocorticoid receptor α (GRα) mRNA expression and GRα protein expression in hypothalamic paraventricular nucleus (PVN) were also determined by real-time PCR and immunohistochemistry, respectively. We found that geniposide (25, 50, 100mg/kg) treatment reversed the CUMS-induced behavioral abnormalities, as suggested by increased sucrose intake, improved crossing and rearing behavior in OFT, shortened immobility and prolonged swimming time in FST. Additionally, geniposide treatment normalized the CUMS-induced hyperactivity of HPA axis, as evidenced by reduced CORT serum level, adrenal gland index and hypothalamic CRH mRNA expression, with no significant effect on ACTH serum level. Moreover, geniposide treatment upregulated the hypothalamic GRα mRNA level and GRα protein expression in PVN, suggesting geniposide could recover the impaired GRα negative feedback on CRH expression and HPA axis. These aforementioned therapeutic effects of geniposide were essentially similar to fluoxetine. Our results indicated that geniposide possessed potent antidepressant-like properties that may be mediated by its effects on the HPA axis.

Antidepressant effects of abscisic acid mediated by the downregulation of corticotrophin-releasing hormone gene expression in rats.

Background:Corticotrophin-releasing hormone (CRH) is considered to be the central driving force of the hypothalamic-pituitary-adrenal axis, which plays a key role in the stress response and depression. Clinical reports have suggested that excess retinoic acid (RA) is associated with depression. Abscisic acid (ABA) and RA are direct derivatives of carotenoids and share a similar molecular structure. Here, we proposed that ABA also plays a role in the regulation of CRH activity sharing with the RA signaling pathway.Methods:[3H]-ABA radioimmunoassay demonstrated that the hypothalamus of rats shows the highest concentration of ABA compared with the cortex and the hippocampus under basal conditions.Results:Under acute stress, ABA concentrations increased in the serum, but decreased in the hypothalamus and were accompanied by increased corticosterone in the serum and c-fos expression in the hypothalamus. Moreover, chronic ABA administration increased sucrose intake and decreased the mRNA expression of CRH and retinoic acid receptor alpha (RARα) in the hypothalamus of rats. Furthermore, ABA improved the symptom of chronic unpredictable mild stress in model rats, as indicated by increased sucrose intake, increased swimming in the forced swim test, and reduced mRNA expression of CRH and RARα in the rat hypothalamus. In vitro, CRH expression decreased after ABA treatment across different neural cells. In BE(2)-C cells, ABA inhibited a series of retinoid receptor expression, including RARα, a receptor that could facilitate CRH expression directly.Conclusions:These results suggest that ABA may play a role in the pathogenesis of depression by downregulating CRH mRNA expression shared with the RA signaling pathway.

Alteration in the expression of exon IIC transcripts of brain-derived neurotrophic factor gene by simvastatin [correction of simvastain] in chronic mild stress in mice: a possible link with dopaminergic pathway.

We have investigated the influence of dopaminergic agents on the expression of brain-derived neurotrophic factor (BDNF) gene in relation with lipid levels in chronic mild stress (CMS). Mice subjected to CMS were treated with simvastatin (10 mg/kg, per os (orally)) along with bromocriptine (2 mg/kg, intraperitoneally (ip)), levodopa (200 mg/kg, ip), or haloperidol (0.1 mg/kg, ip) for 14 days. CMS produced a decrease in sucrose intake and an increase in serum cholesterol and triglycerides levels with a decrease in high-density lipoprotein cholesterol, which were prevented by simvastatin. This was greater when it was combined with bromocriptine or levodopa. Haloperidol significantly prevented the simvastatin-induced increase in sucrose intake but not the alterations in lipids. There was an upregulation in the expression of BDNF exon-IIA and -IIB transcripts by CMS but not the exon-IIC transcripts. Simvastatin could increase expression of exon-IIC transcripts in stressed mice. This was partially increased by bromocriptine. Haloperidol significantly prevented simvastatin-induced increase in expression of BDNF exon-IIC transcripts. The results showed a positive correlation between expression of BDNF exon-IIC transcripts and sucrose intake. In conclusion, our data suggest the involvement of lipid levels and BDNF exon-IIC transcripts in CMS-induced behaviour in mice, possibly through the dopaminergic system.

Inhibition in the lateral septum increases sucrose intake and decreases anorectic effects of stress.

Sucrose-overeating rats with decreased anorectic response to stress showed lower stress-induced activation of c-fos expression in the lateral septum (LS). The present study tested a hypothesis that neuronal inhibition in the LS is important for the development and maintenance of the sucrose-overeating phenotype. Sucrose overeating was developed with weekly episodes of food restriction (21 h per day, 4 days per week) followed by 1-h access to sucrose. The anorectic effects of stress on 1-h sucrose intake were estimated using weekly foot shock stress sessions. The development of the sucrose-overeating phenotype was accompanied by a decrease in the anorectic effects of stress and by an increase in LS mRNA expression of a γ-aminobutyric acid (GABA) synthesising enzyme, glutamic acid decarboxylase 67 in stressed rats. Direct recordings of neuronal firing in the LS in rats submitted to repeated weekly cycles of food restriction, sucrose refeeding and stress showed that the development of sucrose overeating increased the percentage of LS neurons inhibited during anticipation and at the start of clusters (CS) of sucrose licking. In addition, the CS-excited LS neurons showed a decrease in responsiveness to sucrose during the development of sucrose overeating. Direct injection of baclofen, an agonist of the GABAB receptor, into the LS decreased the anorectic effects of stress and increased sucrose intake. These results suggest that an increase in inhibitory effects in the LS is important for the development of sucrose overeating and the decreased anorectic effects of stress.

The Kv7 potassium channel activator retigabine decreases alcohol consumption in rats

Background: Activation of Kv7 potassium channels may decrease the reactivity of mesolimbic dopaminergic neurons that are implicated in mediating the reinforcing effects of ethanol. Objectives: The objective of this study was to determine whether the administration of the Kv7 potassium channel opener retigabine would decrease ethanol intake in Long Evans rats. Methods: A limited access two-bottle choice model of alcohol (10% solution) consumption was used in this study. A separate group of animals was tested to evaluate the actions of retigabine on sucrose (5% solution) consumption to determine whether this drug might produce non-selective impairment of the ability of rats to drink liquids. Animals were treated with either vehicle or increasing doses (2.5–7.5 mg/kg SC) of retigabine administered over a 3-day period. Results: Compared to vehicle, retigabine at a dose of 7.5 mg/kg produced a reduction in the amount of ethanol consumed. These effects did not occur in association with significant changes in water consumption. A significant time effect was found for the actions of retigabine in sucrose-drinking rats with a trend for an increase in sucrose intake with the highest dose of retigabine administered. Conclusions: These results indicate that the administration of retigabine may produce a decrease in ethanol consumption by rats at doses that do not significantly reduce the drinking of either water or a sucrose solution. These findings are consistent with the hypothesis that activation of Kv7 channels facilitates the reduction of alcohol consumption in the rat.

Little Evidence of a Role for the α1GABAA Subunit‐Containing Receptor in a Rhesus Monkey Model of Alcohol Drinking

Alcohol potentiates GABAergic neurotransmission via action at the GABAA receptor. α1 subunit-containing GABAA receptors have been implicated as mediators, in part, of the behavioral and abuse-related effects of alcohol in rodents. We systematically investigated the effects of 1 α1-preferring benzodiazepine agonist, zolpidem, and 2 antagonists, β-carboline-3-carboxylate-tert-butyl ester (βCCT) and 3-propoxy-β-carboline hydrochloride (3-PBC), on oral self-administration of alcohol (2% w/v) or sucrose solution and observable behavior in rhesus macaques. We compared these effects to those of the nonselective benzodiazepine agonist triazolam, antagonist flumazenil, and inverse agonist β-carboline carboxylate (βCCE). Alcohol and sucrose solutions maintained reliable baseline drinking behavior across the study. The α1-preferring compounds did not affect intake, number of sipper extensions, or blood alcohol levels (BALs) at any of the doses tested. Zolpidem, βCCT, and 3-PBC increased latency to first sipper extension in animals self-administering alcohol, but not sucrose, solution. Triazolam exerted biphasic effects on alcohol-drinking behavior, increasing intake at low doses but decreasing BAL and increasing latency at higher doses. At doses higher than those effective in alcohol-drinking animals, triazolam increased sucrose intake and latency. Flumazenil nonsystematically increased number of extensions for alcohol but decreased BAL, with no effects on sucrose drinking. βCCE decreased sipper extensions for alcohol and increased latency for first sucrose sipper extension, but full dose-effect relationships could not be determined due to seizures at higher doses. Alcohol-drinking animals appeared more sensitive to the effects of GABAergic compounds on drinking behavior. However, these results do not support a strong contribution of α1GABAA receptors to the reinforcing effects of alcohol in primates.

Paradoxical surrogate markers of dental injury-induced pain in the mouse

Dental pain, including toothache, is one of the most prevalent types of orofacial pain, causing severe, persistent pain that has a significant negative effect on quality of life, including eating disturbances, mood changes, and sleep disruption. As the primary cause of toothache pain is injury to the uniquely innervated dental pulp, rodent models of this injury provide the opportunity to study neurobiological mechanisms of tissue injury-induced persistent pain. Here we evaluated behavioral changes in mice with a dental pulp injury (DPI) produced by mechanically exposing the pulp to the oral environment. We monitored the daily life behaviors of mice with DPI, including measures of eating, drinking, and movement. During the first 48hours, the only parameter affected by DPI was locomotion, which was reduced. There was also a significant short-term decrease in the amount of weight gained by DPI animals that was not related to food consumption. As cold allodynia is frequently observed in individuals experiencing toothache pain, we tested whether mice with DPI demonstrate an aversion to drinking cold liquids using a cold-sucrose consumption test. Surprisingly, mice with DPI increased their consumption of sucrose solution, to over 150% of baseline, regardless of temperature. Both the weight loss and increased sucrose intake in the first 2days of injury were reversed by administration of indomethacin. These findings indicate that enhanced sucrose consumption may be a reliable measure of orofacial pain in rodents, and suggest that alterations in energy expenditure and motivational behaviors are under-recognized outcomes of tooth injury.