Saccharin Intake Research Articles

Ceftriaxone attenuates acquisition and facilitates extinction of cocaine-induced suppression of saccharin intake in C57BL/6J mice

Growing evidence implicates glutamate homeostasis in a number of behaviors observed in addiction such as acquisition of drug taking, motivation, and reinstatement. To date, however, the role of glutamate homeostasis in the avoidance of natural rewards due to exposure to drugs of abuse has received little attention. The aim of the current study was to evaluate the beta-lactam antibiotic, ceftriaxone, which has been shown to normalize disrupted glutamate homeostasis associated with exposure to drugs of abuse, in cocaine-induced suppression of saccharin intake in C57BL/6J mice. Briefly, C57BL/6J mice received daily injections of either 200mg/kg ceftriaxone or saline. Mice were then given access to 0.15% saccharin for 1h and immediately injected intraperitoneally with either saline or 30mg/kg cocaine; taste–drug pairings occurred every 24h for 5 trials followed by a final CS only trial. One week following taste–drug pairings, extinction was evaluated in a series of one- and two-bottle saccharin intake tests. Individual differences in cocaine-induced suppression were observed (i.e., low and high suppressors) with differential effects of ceftriaxone. Ceftriaxone delayed suppression of saccharin intake in high suppressors but prevented suppression in low suppressors. In addition, ceftriaxone history facilitated extinction in the high suppressors. These data suggest that changes in glutamate homeostasis may be involved in the formation and expression of cocaine-induced suppression of saccharin intake in mice.

Striatal-enriched protein tyrosine phosphatase controls responses to aversive stimuli: implication for ethanol drinking.

The STriatal-Enriched protein tyrosine Phosphatase (STEP) is a brain-specific phosphatase whose dysregulation in expression and/or activity is associated with several neuropsychiatric disorders. We recently showed that long-term excessive consumption of ethanol induces a sustained inhibition of STEP activity in the dorsomedial striatum (DMS) of mice. We further showed that down-regulation of STEP expression in the DMS, and not in the adjacent dorsolateral striatum, increases ethanol intake, suggesting that the inactivation of STEP in the DMS contributes to the development of ethanol drinking behaviors. Here, we compared the consequence of global deletion of the STEP gene on voluntary ethanol intake to the consumption of an appetitive rewarding substance (saccharin) or an aversive solution (quinine or denatonium). Whereas saccharin intake was similar in STEP knockout (KO) and wild type (WT) littermate mice, the consumption of ethanol as well as quinine and denatonium was increased in STEP KO mice. These results suggested that the aversive taste of these substances was masked upon deletion of the STEP gene. We therefore hypothesized that STEP contributes to the physiological avoidance towards aversive stimuli. To further test this hypothesis, we measured the responses of STEP KO and WT mice to lithium-induced conditioned place aversion (CPA) and found that whereas WT mice developed lithium place aversion, STEP KO mice did not. In contrast, conditioned place preference (CPP) to ethanol was similar in both genotypes. Together, our results indicate that STEP contributes, at least in part, to the protection against the ingestion of aversive agents.

Dopamine D1 and opioid receptor antagonist-induced reductions of fructose and saccharin intake in BALB/c and SWR inbred mice

Sugar and fat intake in rodents are mediated in part by brain dopamine (DA) and opioid neurotransmitter systems although important strain differences exist. Thus, whereas sucrose intake of BALB/c and SWR mice was reduced by DA D1 (SCH23390: SCH) receptor antagonism, opioid (naltrexone: NTX) receptor antagonism reduced intake only in BALB/c mice. Both SCH and NTX reduced fat (Intralipid) intake in SWR, but not BALB/c mice. The present study extended this pharmacological analysis to caloric and non-caloric sweeteners by examining whether fructose (8%) or saccharin (0.2%) intakes were differentially suppressed in BALB/c and SWR mice by SCH (50–1600nmol/kg) or NTX (0.01–5mg/kg) over a 5- to 120-min time course. SCH significantly reduced fructose (200–1600nmol/kg) and saccharin (50–1600nmol/kg) intakes in both strains as did NTX (0.1–5mg/kg). Antagonist ID40 potencies were <50nmol/kg for SCH and 0.9mg/kg for NTX in inhibiting saccharin intake, and 1234nmol/kg for SCH and 5mg/kg for NTX in inhibiting fructose intake in BALB/c mice. For SWR mice, the ID40 potencies were <50nmol/kg for SCH and 0.02mg/kg for NTX in inhibiting saccharin intake, and 298nmol/kg for SCH and 2.6mg/kg for NTX in inhibiting fructose intake. Thus, saccharin intake was similarly reduced by SCH and NTX in BALB/c and SWR mice, but greater potencies of opioid (1.9-fold) and DA D1 (4-fold) receptor antagonism of fructose intake were observed in SWR relative to BALB/c mice, indicating strong strain differences.

Risk Assessments of Cyclamate, Saccharin, Neohesperidine DC, Steviol Glycosides and Neotamefrom Soft Drinks, “Saft” and Nectar

The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM), Panel on Food Additives, Flavourings, Processing Aids, Materials in Contact with Food and Cosmetics, has at the request of the Norwegian Food Safety Authority (Mattilsynet) conducted a risk assessment of the intense sweeteners cyclamate, saccharin, neohesperidine DC, steviol glycosides and neotame in soft drinks, “saft” and nectar. The risk assessment includes exposure assessments and the calculated exposures are compared to the acceptable daily intake (ADI) for the respective sweeteners. VKM was also requested to compare the current calculated intake of saccharin and cyclamate to the calculated intake reported by VKM in 2007 (the VKM report «Impact on health when sugar is replaced with intense sweeteners in soft drinks, “saft” and nectar») when Grey Literature Steffensen et al.; EJNFS, 5(1): 72-74, 2015; Article no.EJNFS.2015.004 73 possible (VKM, 2007). Six different intake scenarios with varying concentrations of added sweeteners (either the average concentration or the highest reported concentration for the respective sweetener) and varying consumption of beverages with sweeteners (either the actual reported consumption of beverages added sweetener or the assumption that all reported beverages were added sweeteners) were used for the exposure calculations. • Scenario 1 gives the best estimate of the current situation in the population (average content of sweeteners, actual reported consumption). • Scenario 2 is based on the average content of sweeteners and that all consumed beverages contain sweeteners. • Scenario 3 is based on the highest reported content of sweeteners and the actual reported consumption. • Scenario 4 is based on the highest reported content of sweeteners and that all consumed beverages contain sweeteners. Scenarios 5 and 6 are based on the maximum allowed amounts of sweeteners within a category in accordance with the Regulation on food additives, within the categories soft drinks, “saft” and nectar in Norway (Regulation No 668 of 6 June 2011 on food additives, 2011). • In scenario 5 the consumption of beverages with added sweeteners or sugar reported in dietary surveys were used for the calculations. • In scenario 6 it was assumed that all consumed soft drinks, “saft” and nectar contained sweeteners (no sugar). In the current risk assessment, the intake of the sweeteners was calculated for 2-year-old children and 18-70 year old men and women. Due to lack of new dietary surveys, the other age groups of children and adolescents were not included. For all age groups in all scenarios, the intake of the sweeteners cyclamate, saccharin, neohesperidine DC, steviol glycosides and neotame was below their respective established ADI values. Due to possible differences in the calculation, it was not possible to compare the current calculated intake of saccharin and cyclamate to the calculated intake reported by VKM in 2007. VKM concludes that there is no major health concern related to the intake of the sweeteners cyclamate, saccharin, neohesperidine DC, steviol glycosides and neotame from the beverage categories included in this risk assessment per today. VKM further concludes that among young women who are high consumers of beverages with cyclamate, and 2-year-old children who are high consumers of beverages with steviol glycosides, the estimated intake approaches the ADI values. The high intakes approaching ADI are considered conservative estimates, as the highest reported content of sweetener or the maximum allowed amounts is used. Thus, these estimates are only relevant for the part of the population that are both loyal to beverages with sweeteners and a particular brand of sweetened beverage. It should be noted that intake of sweeteners from other foods or from tabletop sweeteners is not included in the intake estimates, and that a considerable contribution from these sources cannot be excluded.

Intracranial self-stimulation reward thresholds during morphine withdrawal in rats bred for high (HiS) and low (LoS) saccharin intake

RationaleSweet preference is a marker of vulnerability to substance use disorders, and rats selectively bred for high (HiS) vs. low saccharin (LoS) intake display potentiated drug-seeking behaviors. Recent work indicated that LoS rats were more responsive to the negative effects of drugs in several assays. ObjectiveThe current study used the intracranial self-stimulation (ICSS) procedure to investigate the anhedonic component of morphine withdrawal in male HiS and LoS rats. MethodsRats were administered morphine (10mg/kg) or saline for 8 days. To evaluate withdrawal effects, reward thresholds were measured 24 and 28h following the 8th morphine injection (spontaneous withdrawal) and again for 4 days following daily acute morphine and naloxone (1mg/kg) administration (precipitated withdrawal). Results24h following the final morphine injection, reward thresholds in LoS rats were significantly elevated compared to reward thresholds in LoS controls, indicating spontaneous withdrawal. This effect was not observed in HiS rats. LoS rats also showed greater elevations of reward thresholds on several days during naloxone-precipitated withdrawal compared to their HiS counterparts. ConclusionsLoS rats were more sensitive to morphine withdrawal-mediated elevations in ICSS thresholds than HiS rats. While these differences were generally modest, our data suggest that severity of the negative affective component of opiate withdrawal may be influenced by genotypes related to addiction vulnerability.

Change in the hedonic value of an aversive stimulus in the presence of a pre-exposed odor

Rats exhibit a sensitive period from the time of birth until postnatal day 10 during which they develop preferences for odors even if those odors are paired with a moderately aversive stimulus. It is still unknown whether pre-exposure to an odor produces alterations on intake responses of basic tastants, and on other patterns that indicate a change in the hedonic value of reward, such as nipple grasping behavior. The current study assessed the effect of pre-exposure to an odor immediately after birth on intake responses of appetitive and aversive tastants. The objectives were to assess if 3-hour-old rats adjust their behaviors to obtain different values of appetitive and aversive rewards in the presence of a familiar odor. Specifically we wanted to determine whether the intake of saccharin or quinine, administered through the artificial nipple, increases in the presence of the familiar odor. Results showed that 3-hour-old rats differentially respond to two different concentrations of saccharin and two concentrations of quinine. In the presence of the pre-exposed odor newborn rats increased intake and grasp responses to the artificial nipple containing quinine. This effect disappeared with a higher concentration of quinine. These results suggest that the pre-exposed odor generated a change in the hedonic value of the aversive reward.

Bidirectional enantioselective effects of the GABAB receptor agonist baclofen in two mouse models of excessive ethanol consumption

The GABAB receptor agonist baclofen has been studied extensively in preclinical models of alcohol-use disorders, yet results on its efficacy have been uncertain. Racemic baclofen, which is used clinically, can be broken down into separate enantiomers of the drug. Baclofen has been shown to produce enantioselective effects in behavioral assays, including those modeling reflexive and sexual behavior. The current studies sought to characterize the enantioselective effects of baclofen in two separate models of ethanol consumption. The first was a Drinking-in-the-Dark procedure that provides “binge-like” ethanol access to mice by restricting access to a 2-h period, 3 h into the dark cycle. The second was a two-bottle choice procedure that utilized selectively bred High Alcohol Preferring 1 (HAP1) mice to model chronic ethanol access. HAP1 mice are selectively bred to consume pharmacologically relevant amounts of ethanol in a 24-h two-bottle choice paradigm. The results showed that baclofen yields enantioselective effects on ethanol intake in both models, and that these effects are bidirectional. Total ethanol intake was decreased by R(+)-baclofen, while total intake was increased by S(−)-baclofen in the binge-like and chronic drinking models. Whereas overall binge-like saccharin intake was significantly reduced by R(+)-baclofen, chronic intake was not significantly altered. S(−)-baclofen did not significantly alter saccharin intake. Neither enantiomer significantly affected locomotion during binge-like reinforcer consumption. Collectively, these results demonstrate that baclofen produces enantioselective effects on ethanol consumption. More importantly, the modulation of consumption is bidirectional. The opposing enantioselective effects may explain some of the variance seen in published baclofen literature.

Cocaine withdrawal in rats selectively bred for low (LoS) versus high (HiS) saccharin intake

Cocaine use results in anhedonia during withdrawal, but it is not clear how this emotional state interacts with an individual's vulnerability for addiction. Rats selectively bred for high (HiS) or low (LoS) saccharin intake are a well-established model of drug abuse vulnerability, with HiS rats being more likely to consume sweets and drugs of abuse such as cocaine and heroin (Carroll et al., 2002) than LoS rats. This study examined whether the motivational consequences of cocaine withdrawal are differentially expressed in HiS and LoS rats. HiS and LoS rats were trained to respond for a sucrose reward on a progressive ratio (PR) schedule of reinforcement and breakpoints were measured during and after chronic, continuous exposure to cocaine (30mg/kg/day). Cocaine, but not saline, treatment resulted in lower breakpoints for sucrose during withdrawal in LoS rats only. These results suggest anhedonia during withdrawal is more pronounced in the less vulnerable LoS rats. Fewer motivational deficits during withdrawal may contribute to greater drug vulnerability in the HiS line.

Cocaine-induced suppression of saccharin intake and morphine modulation of Ca2 + channel currents in sensory neurons of OPRM1 A118G mice

Several studies have shown that human carriers of the single nucleotide polymorphism of the μ-opioid receptor, OPRM1 A118G, exhibit greater drug and alcohol use, increased sensitivity to pain, and reduced sensitivity to the antinociceptive effects of opiates. In the present study, we employed a ‘humanized’ mouse model containing the wild-type (118AA) or variant (118GG) allele to examine behavior in our model of drug-induced suppression of a natural reward cue and to compare the morphine pharmacological profile in acutely isolated sensory neurons. Compared with 118AA mice, our results demonstrate that homozygous 118GG mice exhibit greater avoidance of the cocaine-paired saccharin cue, a behavior linked to an aversive withdrawal-like state. Electrophysiological recordings confirmed the reduced modulation of Ca2+ channels by morphine in trigeminal ganglion (TG) neurons from 118GG mice compared to the 118AA control cells. However, repeated cocaine exposure in 118GG mice led to a leftward shift of the morphine concentration–response relationship when compared with 118GG control mice, while a rightward shift was observed in 118AA mice. These results suggest that cocaine exposure of mice carrying the 118G allele leads to a heightened sensitivity of the reward system and a blunted modulation of Ca2+ channels by morphine in sensory neurons.

Effects of treadmill exercise on the LiCl-induced conditioned taste aversion in rats

Studies have shown that exercise can enhance learning and memory. Conditioned taste aversion (CTA) is an avoidance behavior induced by associative memory of the taste sensation for something pleasant or neutral with a negative visceral reaction caused by the coincident action of a toxic substance that is tasteless or administered systemically. We sought to measure the effects of treadmill exercise on CTA in rats by investigating the effects of exercise on acquisition, extinction and spontaneous recovery of CTA. We made two groups of rats: an exercise group that ran on a treadmill, and a control group that did not have structured exercise periods. To condition rats to disfavor a sweet taste, consumption of a 0.1% saccharin solution in place of drinking water was paired with 0.15M LiCl (2% body weight, i.p.) to induce visceral discomfort. We measured changes of saccharin consumption during acquisition and extinction of CTA. The exercise and no-exercise groups both acquired CTA to similar levels and showed maximum extinction of CTA around 6days after acquisition. This result indicates that exercise affects neither acquisition nor extinction of CTA. However, in testing for preservation of CTA after much longer extinction periods that included exercise or not during the intervening period, exercising animals showed a significantly lower saccharin intake, irrespective of having exercised or not during the conditioning phase of the trial. This result suggests that exercise may help to preserve aversive memory (taste aversion in this example) as evidence by the significant spontaneous recovery of aversion in exercising animals.

Individual differences in anhedonic and accumbal dopamine responses to chronic social stress and their link to cocaine self-administration in female rats.

Women are twice as likely as men to develop major depressive disorder. Exposure to chronic stress can induce depression in some vulnerable individuals, while others are resistant to depressive-like symptoms after equivalent levels of chronic stress. In female rats, individual differences in saccharin intake during chronic social defeat stress may predict subsequent cocaine self-administration, and may be attributed to alterations in mesolimbic dopamine activity. Female rats were exposed to 21 days of chronic social defeat stress, during which they were evaluated for their anhedonia-like responses in the form of saccharin intake. After chronic social defeat stress, the rats were tested for behavioral cross-sensitization to cocaine and escalated cocaine self-administration in a 24-h "binge." A separate group of animals underwent in vivo microdialysis of the nucleus accumbens (NAc) shell to assess dopamine (DA) in response to acute cocaine challenge. Cluster analysis revealed two phenotypes among the stressed female rats based on their saccharin intake while being exposed to stress, termed stress-resistant (SR, 28 %) and stress-sensitive (SS, 72 %). The amount of cocaine self-administered during the 24-h "binge" was positively correlated with preceding saccharin intake. The NAc DA response to a cocaine challenge was significantly lower in SR rats than in the SS and non-stressed control rats. No other significant differences were observed in behavioral cross-sensitization or cocaine self-administration prior to the "binge." Female rats showed individual differences in their anhedonic-like response to chronic social defeat stress, and these differences were reliably associated with subsequent cocaine-taking behavior.

Functional relationship between oxytocin and appetite for carbohydrates versus saccharin.

Centrally acting oxytocin (OT) inhibits feeding. Recent evidence suggests a link between OT and control of carbohydrate and saccharin intake, but it is unclear whether OT affects appetite for only carbohydrates, especially sweet ones, or sweet tastants irrespective of their carbohydrate content. Therefore, a blood-brain barrier penetrant OT receptor antagonist, L-368,899, was administered in mice and intake of liquid diets containing carbohydrates sucrose, glucose, fructose, polycose, or cornstarch (CS) or the noncarbohydrate, noncaloric sweetener saccharin was studied in episodic intake paradigms: one in which only one tastant was available and the other in which a choice between a carbohydrate (sucrose, glucose, or fructose) and saccharin was provided. We also used real-time PCR to examine hypothalamic Ot mRNA levels in mice provided short-term access to sucrose, CS, or saccharin. In the no-choice paradigm, L-368,899 increased the intake of all carbohydrates, whereas its effect on saccharin consumption showed only a trend. A 10 times lower dose (0.3 mg/kg) stimulated intake of sucrose than other carbohydrates. In the choice test, a very low 0.1 mg/kg dose of L-368,899 doubled the proportion of sucrose consumption relative to saccharin, but did not affect fructose or glucose preference. Ot gene expression increased after sucrose and CS, but not saccharin exposure compared with the controls; however, a higher level of significance was detected in the sucrose group. We conclude that OT inhibits appetite for carbohydrates. Sucrose consumption considerably enhances Ot gene expression and is particularly sensitive to OT receptor blockade, suggesting a special functional relationship between OT and sugar intake.

Delta-opioid receptor blockade in the ventral pallidum increases perceived palatability and consumption of saccharin solution in rats

The ventral pallidum (VP) is involved in ingestive behaviour. It receives dense GABAergic projections from the nucleus accumbens. GABAergic terminals in the VP co-express enkephalin, an endogenous ligand of delta-opioid receptors. The role of the delta-opioid receptors in the VP in the context of ingestive behaviour remains unclear, in contrast to the well-understood involvement of the mu-opioid receptors. We used the single-bottle test to examine the effects of VP microinjections of the delta-opioid receptor antagonist naltrindole on consumption of a saccharin solution. Naltrindole injections significantly increased the intake of saccharin, but not water, during a 2-h test session. We also investigated perceived palatability of saccharin using a taste reactivity test. The drug treatments increased ingestive responses to intraorally infused saccharin. Further experimentation explored the role of VP delta-opioid receptors in behavioural responses to saccharin that were previously paired with malaise upon the retrieval of conditioned taste aversion (CTA). Naltrindole-injected rats exhibited longer latency for the first occurrence of aversive responses than vehicle-injected control rats. However, there was no between-group difference in total aversive responses. These results suggest that naltrindole injections into the VP induce an enhancement of perceived palatability of a normally preferred saccharin solution, and thereby facilitate consumption of the solution. On the other hand, delayed aversive responses to the conditioned aversive saccharin suggest that the delta-opioid receptors in the VP mediate the initiation of aversive taste reactivity responses to the conditioned stimulus upon CTA retrieval.

Prior exposure to repeated immobilization or chronic unpredictable stress protects from some negative sequels of an acute immobilization

Exposure to chronic unpredictable stress (CUS) is gaining acceptance as a putative animal model of depression. However, there is evidence that chronic exposure to stress can offer non-specific stress protection from some effects of acute superimposed stressors. We then compared in adult male rats the protection afforded by prior exposure to CUS with the one offered by repeated immobilization on boards (IMO) regarding some of the negative consequences of an acute exposure to IMO. Repeated exposure to IMO protected from the negative consequences of an acute IMO on activity in an open-field, saccharin intake and body weight gain. Active coping during IMO (struggling) was markedly reduced by repeated exposure to the same stressor, but it was not affected by a prior history of CUS, suggesting that our CUS protocol does not appear to impair active coping responses. CUS exposure itself caused a strong reduction of activity in the open-field but appeared to protect from the hypo-activity induced by acute IMO. Moreover, prior CUS offered partial protection from acute IMO-induced reduction of saccharin intake and body weight gain. It can be concluded that a prior history of CUS protects from some of the negative consequences of exposure to a novel severe stressor, suggesting the development of partial cross-adaptation whose precise mechanisms remain to be studied.

Evaluation of saccharin intake and expression of fructose-conditioned flavor preferences following opioid receptor antagonism in the medial prefrontal cortex, amygdala or lateral hypothalamus in rats

In prior studies, systemic opioid receptor antagonism with naltrexone (NTX) failed to block flavor preference conditioning by the sweet taste or post-oral actions of sugar despite reducing overall flavored saccharin intake. Further, NTX microinjections into the nucleus accumbens (NAc) shell or core failed to alter the expression of preferences conditioned by the sweet taste or post-oral actions of sugars. In contrast, fructose-conditioned flavor preferences (CFP) were reduced or eliminated by systemic or intracerebral administration of dopamine (DA) D1 or D2 antagonists in the NAc, medial prefrontal cortex (mPFC), amygdala (AMY) or lateral hypothalamus (LH). The present study examined whether NTX microinjections into the mPFC, AMY or LH would alter expression of fructose-CFP and total flavored saccharin intake. Food-restricted rats with bilateral cannulae aimed at the mPFC, AMY or LH were trained to drink a fructose (8%)+saccharin (0.2%) solution mixed with one flavor (CS+, e.g., cherry) and a 0.2% saccharin solution mixed with another flavor (CS−, e.g., grape) during 10 one-bottle sessions. Two-bottle tests with the cherry and grape flavors in 0.2% saccharin solutions occurred 10min following total bilateral NTX doses of 0, 1, 25 and 50μg administered into the mPFC, AMY or LH. Rats preferred the CS+ over CS− flavor following vehicle and all NTX doses administered into either the mPFC or LH. CS+ intake was significantly greater than CS− intake following vehicle and the low NTX dose in the AMY; however, at the 25 and 50μg AMY NTX doses, CS+ intakes did not significantly exceed CS− intakes. Total flavored saccharin intake was significantly reduced by all three LH NTX doses (20–35%), by the 25 (14%) and 50 (22%)μg AMY NTX doses, but not by mPFC NTX. Thus, opioid antagonism in the AMY, but not the mPFC or LH attenuated, but did not block the expression of fructose-CFP, and LH and AMY, but not mPFC, NTX significantly reduced total saccharin intake. Therefore, whereas opioid antagonism in the LH and AMY reduces sweet intake, they appear less effective in altering fructose-CFP.

Altered Neurogranin Phosphorylation and Protein Levels Are Associated with Anxiety- and Depression-Like Behaviors in Rats Following Forced Swim Stress

Here we tested the hypothesis that stress-induced alterations in Neurogranin (Ng) synthesis and/ or utilization might underlie stress-related depression and anxiety. Rats were randomly divided into five conditions: chronic swim stress (CS), acute swim stress (AS), and three control groups. The CS group was exposed to daily swim stress (5 min/day) for 14 consecutive days, the AS group received a single swim stress, and control groups were maintained in a stress-free condition. Both before and after swim stress, rats were tested for body weight gain, open-field locomotor activity, and saccharine preference. Ng and phospho-Ng (P-Ng) levels in the hippocampus and prefrontal cortex were determined by Western blot analysis. Compared to controls, CS animals displayed significantly decreased body weight gain, ambulation, and saccharine intake, and increased grooming behavior. CS animals had decreased Ng levels in the hippocampus and prefrontal cortex. In CS animals, Ng levels were positively correlated with saccharine intake and ambulation, and inversely correlated with grooming behavior. Compared to controls, AS increased immobility behavior and P-Ng and Ng levels in the hippocampus and prefrontal cortex. In AS animals, immobility behavior was positively correlated with the P-Ng in the prefrontal cortex. Thus, CS and AS produced opposing effects on Ng and P-Ng levels in the hippocampus and prefrontal cortex. Low Ng levels in the hippocampus were associated with anhedonic behavior in CS animals, whereas high P-Ng levels in the prefrontal cortex were associated with anxiety-like behavior in AS animals. Thus, Ng dysfunction might contribute to the neural mechanisms underlying stress-induced depression and anxiety.

Behavioral Characteristics of Pharmacologically Selected Lines of Rats: Relevance to Depression

This brief review discusses the behavioral consequences of two pharmacologically selected lines of rats. Flinders Sensitive (FSL) and Flinders Resistant (FRL) Lines of rats were selected on the basis of differential hypothermic and behavioral responses to the anticholinesterase, diisopropylfluorophosphate (DFP). FSL rats are more sensitive to the hypothermic effects of cholinergic, serotonergic, and dopaminergic agonists but less sensitive to the locomotor or stereotypic effects of dopamine agonists. FSL rats exhibit greater immobility in the forced swim test and reduced social interaction compared with FRL rats, but do not differ in saccharin intake, behavior in the elevated plus maze, or responses for rewarding brain self-stimulation. The exaggerated immobility and reduced social interaction are counteracted by chronic treatment with antidepressants. Because FSL rats were more sensitive to 5-HT1A receptor agonists, high (HDS) and low (LDS) 8-OH-DPATsensitive lines were selectively bred for differential hypothermic responses to the 5-HT1A receptor agonist, 8-hydroxy-2-(di-N-propylamino)tetralin (8-OH-DPAT). HDS rats were also more sensitive to the hypothermic effects of oxotremorine, a cholinergic agonist, but selection for this response did not diverge with later selection. HDS rats exhibited greater immobility in the forced swim test than LDS rats and this correlated response could be seen early in selection (generation 3). HDS rats also showed reduced social interaction compared to LDS rats, but did not differ in behavior in the elevated plus maze. These findings confirm that selection for hypothermic responses to pharmacological agents do have behavioral consequences, notably the production of depressive-like phenotypes, which can be counteracted by chronic antidepressant treatment. Because increased 5-HT1A receptor sensitivity was common to both selected lines (FSL and HDS), neurobiological processes dependent on this receptor could contribute to the abnormal behaviors that manifest in these rat lines and thus suggesting a mechanism underlying depressive behaviors in humans. However, available human data are inconsistent with this hypothesis and suggest that other mechanisms underlie these behavioral abnormalities in HDS and FSL rats. These mechanisms as well as additional behavioral testing in these rat lines will be discussed.

Central effects of ethanol interact with endogenous mu-opioid activity to control isolation-induced analgesia in maternally separated infant rats

Endogenous opioid activity plays an important role in ethanol consumption and reinforcement in infant rats. Opioid systems are also involved in mediation and regulation of stress responses. Social isolation is a stressful experience for preweanling rats and changes the effects of ethanol through opioid-dependent mechanisms. The present study assessed effects of intracisternal (i.c.) administration of a selective mu-opioid antagonist (CTOP) and i.p. administration of a nonspecific opioid antagonist (naloxone) on voluntary intake and behavior in socially isolated 12-day-old (P12) pups treated with 0.5g/kg ethanol. Voluntary intake of 0.1% saccharin or water, locomotion, rearing activity, paw licking and grooming were assessed during short-term isolation from littermates (STSI; 8-min duration). Thermal nociceptive reactivity was measured before and after this intake test, with normalized differences between pre- and post-test latencies of paw withdrawal from a hot plate (49°C) used as an index of isolation-induced analgesia (IIA).Results indicated several effects of social isolation and ethanol mediated through the mu-opioid system. Effects of low dose ethanol (0.5g/kg) and voluntary consumption of saccharin interacted with endogenous mu-opioid activity associated with STSI. Blockade of mu-opioid receptors on saccharin consumption and paw licking-grooming affected intoxicated animals. Low dose ethanol and ingestion of saccharin blunted effects of CTOP on rearing behavior and nociceptive reactivity. Central injections of CTOP stimulated paw licking and grooming dependent on ethanol dose and type of fluid ingested. Ethanol selectively increased saccharin intake during STSI in females, naloxone and CTOP blocked ethanol-mediated enhancement of saccharin intake. We suggest that enhancement of saccharin intake by ethanol during STSI is the product of synergism between isolation-induced mu-opioid activity that increases the pup's sensitivity to appetitive taste stimulation and the anxiolytic effects of 0.5g/kg ethanol that decreases behaviors otherwise competing with independent ingestive activity.

“Jello® Shots” and Cocktails as Ethanol Vehicles: Parametric Studies with High- and Low-Saccharin-Consuming Rats

Naïve humans and rats voluntarily consume little ethanol at concentrations above ~6% due to its aversive flavor. Developing procedures that boost intake of ethanol or ethanol-paired flavors facilitates research on neural mechanisms of ethanol-associated behaviors and helps identify variables that modulate ethanol intake outside of the lab. The present study explored the impact on consumption of ethanol and ethanol-paired flavors of nutritionally significant parametric variations: ethanol vehicle (gelatin or solution, with or without polycose); ethanol concentration (4% or 10%); and feeding status (chow deprived or ad lib.) during flavor conditioning and flavor preference testing. Individual differences were modeled by testing rats of lines selectively bred for high (HiS) or low (LoS) saccharin intake. A previously reported preference for ethanol-paired flavors was replicated when ethanol had been drunk during conditioning. However, indifference or aversion to ethanol-paired flavors generally obtained when ethanol had been eaten in gelatin during conditioning, regardless of ethanol concentration, feeding status, or caloric value of the vehicle. Modest sex and line variations occurred. Engaging different behavioral systems when eating gelatin, rather than drinking solution, may account for these findings. Implications for parameter selection in future neurobiological research and for understanding conditions that influence ethanol intake outside of the lab are discussed.

식품 중 삭카린나트륨과 수크랄로스의 사용실태 파악 및 한국인의 삭카린나트륨과 수크랄로스의 섭취 수준 평가

This study sought to evaluate the daily intakes of sodium saccharin and sucralose for individuals in Korea with average and high levels of consumption of both these substances. The estimated daily intake of both sweeteners was determined from analytical data and dietary intake data collected as part of the Korean National Health and Nutrition Survey. Analysis of the data showed that sodium saccharin was found in 53 (15.6%) of 339 processed foods analyzed, whereas sucralose was found in 141 (23.9%) of 590 processed foods analyzed. The average intake of sodium saccharin was 1.18% of the acceptable daily intake (ADI) defined by the Joint FAO/WHO Expert committee on Food Additives (JECFA). The average intake of sucralose was 0.55% of ADI. The 95th percentile intakes of sodium saccharin and sucralose were 5.29% and 15.66% of ADI, respectively. Children 6 years old and younger consumed more sodium saccharin and sucralose than did children from any of the other age groups tested. In conclusion, the average daily intakes of sodium saccharin and sucralose within members of the Korean population fall within safe levels.