Suppression of alcohol and saccharin preference in rats by a novel Ca2+ channel inhibitor,Goe 5438

The effect of the novel 1,4-dihydronaphthyridine Ca²⁺ channel inhibitor Goe 5438 (CI-951) on voluntary ethanol consumption was examined in selectively bred alcohol-preferring (P) rats in a free choice two bottle preference test versus water. Intraperitoneally injected Goe 5438 dose-dependently (5, 10 or 20 µmol/kg, twice daily) inhibited ethanol and increased water intake over the 24 h period (injection day). The drug decreased ethanol preference, originally above 90%, by 6%, 19% and 45% at respective doses, on the injection day. That inhibitory effect of the highest dose of Goe 5438 on ethanol preference remained significant also on days 2 and 3 after injections (–51% and –18%, respectively). Goe 5438, in the highest dose, also tended to decrease granulated chow consumption during the injection day only. To further test whether the inhibition of ethanol preference is secondary to decrease in reinforcing properties of ethanol and not due to interference with satiety mechanisms, we compared the effect of two higher doses (10 and 20 µmol/kg, intraperitoneally, twice daily) of Goe 5438 on spontaneous preference for a non-caloric 0.04% saccharin solution in Sprague-Dawley rats. We observed a dose-dependent suppression of preference (by 44% and 58%, respectively) during the injection day, but not the subsequent 24 h period. However, Goe 5438 also significantly alleviated food pellet intake on the injection day. In conclusion, Goe 5438 produces potent and long-lasting inhibition of voluntary ethanol consumption, which may be secondary to attenuation of reinforcing properties of ethanol. Additionally, this particular Ca²⁺ channel inhibitor appears to have mild anorectic properties which may be conducive to acute suppression of alcohol intake.     

Effects of central amygdaloid nucleus lesions on ingestion, taste reactivity, exploration and taste aversion.

Central amygdaloid nucleus lesions in rats had no effect on recovery of preoperative body weight and food consumption levels. The brain damaged rats also recovered preoperative levels of water consumption as rapidly as control rats but then developed a mild but persistent hypodipsia. The experimental rats also drank less than control rats when food deprived and showed marginally reliable decreases in 0.1% quinine solution consumption and latency to consume a novel food. There was no detectable lesion effect on 0.1% saccharin solution consumption, exploration of a novel environment or formation of a learned taste aversion. It is suggested that the central amygdaloid nucleus has a role in mediating the relationship between food and water intake and in some taste mediated consummatory behavior.     

Behavioral correlates of oral and postingestive satiety in the rat

Hungry rats display the characteristic "satiety sequence" after drinking a glucose solution: The end of ingestion is accompanied by grooming and exploring, followed by resting. With saccharin solutions over a range of concentrations, however, ingestion is accompanied and followed by persistent grooming and exploring; resting rarely occurs. Gastric preloads of glucose solution promote resting to reinstate the "satiety sequence" after a bout of saccharin ingestion. Therefore, the systemic effects of glucose are sufficient to promote resting. In the absence of postingestive factors, the "satiety sequence" is incomplete following saccharin ingestion as it is after sham-feeding.     

Differential role of dopamine in drug- and lithium-conditioned saccharin avoidance

Rats learn to avoid palatable saccharin solutions that predict the systemic administration of reinforcing drugs as well as malaise-inducing lithium chloride (conditioned saccharin avoidance, CSA). In the present study the involvement of dopamine (DA) transmission in the acquisition of morphine, nicotine and lithium-conditioned CSA was investigated in a two-bottle choice paradigm. Nicotine tartrate (0.2 and 0.4 mg/kg s.c.) administered 15 min after saccharin presentation induced CSA, with a maximum effect at 0.4 mg/kg. The DA D1 receptor antagonist, SCH 39166 (0.1 mg/kg s.c.) and the DA D2 receptor antagonist raclopride (0.3 mg/kg s.c.), administered immediately after saccharin, prevented CSA induced by the lower but not by the higher dose of nicotine. However, combined administration of the two antagonists prevented CSA induced by the higher dose of nicotine. SCH 39166 prevented CSA induced by all morphine doses while raclopride prevented only CSA induced by the lowest dose of morphine (1.75 mg/kg). CSA induced by different doses of lithium given by the same schedule of drug-CSA (i.e. two pairings, 15 min after saccharin) was not affected by SCH 39166. However SCH 39166 impaired the acquisition of lithium-CSA when lithium was given 60 min after saccharin. In contrast, raclopride failed to affect lithium-CSA independently from the delay between saccharin and lithium. These results suggest that DA can play different roles in drug- and in lithium-CSA and are consistent with a different mechanism of drug- as compared to lithium-CSA.     

Central mediation of the conditioned taste aversion induced in rats by harmaline

The assumption that drugs used as unconditioned stimuli in conditioned taste aversion (CTA) studies act centrally was tested by comparing the effects of systemic and intracerebral injections of harmaline hydrochloride (H) in 340 rats. Intraperitoneal injection of 5–20 mg/kg but not of 2.5 mg/kg H administered 5 min after 15-min saccharin (0.1%) drinking decreased saccharin-water preference in a two-choice retention test, performed 48 h later, from 55% to 20%. Since CTA was not diminished when H (10 mg/kg) was injected into rats anesthetised immediately after saccharin drinking by pentobarbital (40 mg/kg), H (1.7–50 g) was administered intracerebrally to anesthetised rats fixed in the stereotaxic apparatus. Injection of 3–6 g H into the inferior olive elicited CTA comparable to that of systemic injection of 10 mg/kg H. Injections of 6 and 50 g H into cerebellum and bulbar reticular formation elicited weaker CTA while neocortical, hypothalamic and mesencephalic applications were ineffective. CTA could also be elicited when 50 g but not 6 g H was injected into the inferior olive 1 or 2 h after saccharin drinking. This delay-dependent effect and failure of non-contingent H administration to change saccharin preference indicates that the H-induced CTA is not contaminated by a non-specific increase in neophobia. It is concluded that H probably elicits CTA by activation of caudal bulbar structures, including the nucleus of the solitary tract, area postrema and lateral reticular formation.     

Antihyperglycaemic effect of saccharin in diabetic ob/ob mice

1. The effect of chronic saccharin (benzosulphimide) consumption on glucose homeostasis was examined in normal lean +/+ mice and genetically obese hyperglycaemic insulin-resistant ob/ob mice.
2. Consumption of a 5% (w/v) sodium saccharin solution for 7 weeks prevented the development of hyperglycaemia, improved glucose tolerance (area under curve decreased by 51%), reduced the extent of hyperinsulinaemia (by 21%), and reduced excessive weight gain (by 18%) in ob/ob mice.
3. Consumption of 5% (w/v) sodium saccharin temporarily decreased hyperphagia at the beginning of treatment, decreased hepatic glycogen content (by 47%), increased abdominal muscle glycogen content (by 82%), but did not significantly alter the hypoglycaemic response to exogenous insulin in ob/ob mice.
4. Consumption of a 1% (w/v) sodium saccharin solution did not prevent the development of hyperglycaemia in ob/ob mice.
5. Normal lean +/+ mice consuming 5% (w/v) sodium saccharin solution showed a marginal decrease (by 8%) in glycaemia, and glucose tolerance was improved (area under curve decreased by 30%) without a significant change in the insulin response to glucose or the hypoglycaemic effect of exogenous insulin.
6. The results suggest that chronic consumption of saccharin can defer the development of hyperglycaemia and improve glucose homeostasis in insulin-resistant ob/ob mice through a mechanism that is independent of insulin.

     

Morphine-induced suppression of saccharin intake is correlated with elevated corticosterone levels

Rats suppress intake of a saccharin conditioned stimulus (CS) when paired with a drug of abuse. This phenomenon, however, is not uniform across all subjects and is greater following exposure to stress and in animals that more readily self-administer drugs of abuse. The present study was designed to examine these individual differences in intake suppression following seven saccharin-morphine pairings. Plasma corticosterone also was evaluated both before and after conditioning in order to determine whether the magnitude of CS suppression is, or is not, related to circulating corticosterone levels. The findings indicated that, while all rats were exposed to the same number of saccharin-morphine pairings, only half of these animals actually suppressed intake of the saccharin CS. Moreover, the results showed that greater suppression of CS intake was associated with higher corticosterone levels at test (r=-0.84, P<0.0001). Taken together, the results demonstrate that individual differences affect not only the reduction in CS intake following taste-drug pairings, but also the associated cue-induced elevation in circulating corticosterone.     

Localization of Genes Affecting Alcohol Drinking in Mice

The genomic map locations of specific genes controlling behaviors can be identified by studying a panel of recombinant inbred (RI) mouse strains. The progenitor C57BL/6J (B6) and DBA/2J (D2) strains, and 19 of the BXD RI strains derived from an F2 cross of these progenitors, were tested for 3% and 10% ethanol (EtOH) intake. The test sequence began with two-bottle free choice between tap water and unsweetened ethanol, and ended with free choice between water and saccharin-sweetened ethanol. Saccharin preference was also measured. Correlational analyses indicated that 59% of the genetic variance in 10% ethanol and sweetened 10% ethanol consumption was held in common, 24% of the genetic variance in saccharin and sweetened 10% ethanol consumption was held in common, and only 7% of the genetic variance in saccharin and unsweetened 10% ethanol consumption was held in common. These percentages for 3% ethanol solutions were 21%, 36%, and 14%. In addition, the severity of handling-induced convulsions during ethanol withdrawal was found to be significantly associated with the amount of ethanol consumed from the sweetened ethanol drinking tubes, suggesting that genetic differences in avidity for ethanol could lead to the development of physical dependence. Quantitative trait loci (QTL) analyses revealed that several genetic markers were associated with ethanol consumption levels, including markers for the D2 dopamine receptor. QTL analyses of saccharin and sweetened ethanol consumption identified the sac locus, thought to determine the ability to detect saccharin. In general, our results suggest that saccharin and ethanol consumption are determined by the actions of multiple genes (QTL), some in common, and suggest specific map locations of several such QTL on the mouse genome.     

甲醇沉淀-高效液相色谱法同时测定奶茶中5种添加剂

目的 建立甲醇沉淀-高效液相色谱同时测定奶茶中安赛蜜、苯甲酸、糖精钠、山梨酸和咖啡因的方法.方法 样品加甲醇沉淀旋涡混合提取后,离心分离,取上清液,过0.22 μm滤膜,高效液相色谱检测.色谱条件:使用Agilent Poroshell 120 EC-C18(3 mm×150 mm,2.7 μm)色谱柱,以甲醇和0.0...     

Alteration of voluntary ethanol and saccharin consumption by the neurosteroid allopregnanolone in mice

RATIONALE: The neurosteroid 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone, ALLOP) is a positive modulator of gamma-aminobutyric acid type A (GABA(A)) receptors. Recent findings indicate that ethanol (EtOH) and ALLOP share common mechanisms of action and that ALLOP may modulate some of EtOH's abuse-related effects. OBJECTIVES: The present studies investigated whether ALLOP pretreatment altered voluntary EtOH consumption in male and female C57BL/6J mice, and voluntary saccharin and quinine consumption in male C57BL/6J mice. METHODS: Mice had access to two drinking tubes containing water versus 5% or 10% (v/v) EtOH or a tastant for 2 h each day at the beginning of the dark cycle. Following establishment of stable consumption, animals received 2 days of vehicle followed by 3 days of ALLOP injections (0, 3.2, 10, or 17 mg/kg, IP), immediately prior to EtOH or tastant access. RESULTS: Prior to injection, the 2-h baseline dose of the 10% EtOH solution consumed was 1.31 g/kg (expt 1) or 2.46 g/kg (expt 3) for male and 2.21 g/kg (expt 2) for female mice. Baseline intake of the 5% EtOH solution was 0.60 g/kg for males and 0.75 g/kg for females (expt 5). In males, ALLOP administration significantly and dose-dependently increased consumption of both EtOH solutions during the first hour of availability without affecting water intake. In females, ALLOP did not significantly alter EtOH consumption. Lastly, ALLOP significantly increased saccharin, but not quinine, consumption in males (females were not tested). CONCLUSIONS: ALLOP may increase voluntary EtOH consumption in male mice by altering its reinforcing effects. The lack of significant effect on quinine and water consumption suggests that ALLOP does not simply increase consumption of all fluids.