Differential Effects of Saikosaponins A, B2, B4, C and D on Alcohol and Chocolate Self-Administration in Rats.

AIMS: Treatment with saikosaponin A (SSA)-an ingredient of the medicinal herb, Bupleurum falcatum-has been reported to suppress several addictive-like behaviors, including morphine, cocaine, alcohol and chocolate self-administration in male rats. The aim of this investigation was to investigate whether saikosaponins of B. falcatum other than SSA affect alcohol and chocolate self-administration in rats. METHODS: Ovariectomized female Sardinian alcohol-preferring (sP) and Wistar rats were trained to self-administer alcohol (15%, v/v) and a chocolate solution [5% (w/v) Nesquik® in water], respectively, under fixed ratio schedules of reinforcement. The following saikosaponins were compared to SSA: saikosaponin D (SSD; epimer of SSA), saikosaponin C (SSC), saikosaponin B2 (SSB2) and saikosaponin B4 (SSB4). All saikosaponins were tested acutely at the doses of 0, 0.25, 0.5 and 1 mg/kg (i.p.). RESULTS: Treatment with SSA and SSD resulted in highly similar, marked reductions in alcohol self-administration; SSC failed to alter lever-responding for alcohol, while SSB2 and SSB4 produced intermediate reductions. Only SSA and SSD reduced chocolate self-administration, with SSC, SSB2 and SSB4 being ineffective. CONCLUSIONS: The wide spectrum of efficacy of saikosaponins in reducing alcohol and chocolate self-administration suggests that even relatively small structural differences are sufficient to produce remarkable changes in their in vivo pharmacological profile. Together, these results confirm that roots of B. falcatum may be an interesting source of compounds with anti-addictive potential.

Reducing Effect of Saikosaponin A, an Active Ingredient of Bupleurum falcatum, on Intake of Highly Palatable Food in a Rat Model of Overeating.

Recent lines of experimental evidence have indicated that saikosaponin A (SSA)-a bioactive ingredient of the medicinal plant, Bupleurum falcatum L.-potently and effectively reduced operant self-administration of chocolate and reinstatement of chocolate-seeking behavior in rats. The present study was designed to assess whether the protective properties of SSA on addictive-like, food-related behaviors generalize to a rat model of overeating of palatable food. To this end, rats were habituated to feed on a standard rat chow for 3 h/day; every 4 days, the 3-h chow-feeding session was followed by a 1-h availability of highly palatable, calorie-rich Danish butter cookies or Oreo chocolate cookies. Even though fed, rats consumed large amounts of cookies; intake of calories from cookies (consumed in 1 h) was even larger than that of calories from chow (consumed in 3 h). SSA (0, 0.25, 0.5, and 1 mg/kg, i.p.) was administered 10 min before cookie presentation. Treatment with SSA resulted in a dose-related decrease in intake of both butter and chocolate cookies. Administration of the cannabinoid CB1 receptor antagonist/inverse agonist, rimonabant (0, 0.3, 1, and 3 mg/kg, i.p.; tested as reference compound), produced a similar reduction in intake of butter cookies. These results (a) contribute to the set-up and validation of a rat model of overeating, characterized by the intake of large amounts of unnecessary calories and (b) provide an additional piece of evidence to the anorectic profile of SSA in rats.

Anxiolytic effect of an extract of Salvia miltiorrhiza roots in rats.

BACKGROUND: Preparations from roots of Salvia miltiorrhiza, a herb widely used in traditional Chinese medicine, have been reported to induce a series of central effects, including sedation. In the wake of this ethnopharmacological information, the present study was designed to assess the anxiolytic potential of an extract of S. miltiorrhiza roots. METHODS: To this end, rats were acutely treated with S. miltiorrhiza extract (0, 50, and 100 mg/kg; i.g.) and exposed to the Elevated Plus Maze (EPM) test. The effect of treatment with S. miltiorrhiza extract on Stress-Induced Hyperthermia (SIH; a physiological response to stressful events) was also evaluated. RESULTS: Treatment with 100 mg/kg S. miltiorrhiza extract produced robust anxiolytic effects at the EPM test; specifically, it increased (a) percent of entries into open arms, (b) percent of time spent in open arms, (c) total number of head dips, (d) number of unprotected head dips, and (e) number of end-arm explorations in open arms, without any alteration in spontaneous locomotor activity. Treatment with 100 mg/kg S. miltiorrhiza extract also suppressed SIH response. The anxiolytic effects produced by 100 mg/kg S. miltiorrhiza extract were comparable to those exerted by acute treatment with 1.5 mg/kg (i.p.) of the reference compound, diazepam. CONCLUSION: These data demonstrate the ability of an extract of S. miltiorrhiza roots to produce anxiolysis in two different rodent models of "anxiety".

Suppressing effect of saikosaponin A, an active ingredient of Bupleurum falcatum, on chocolate self-administration and reinstatement of chocolate seeking in rats.

Recent lines of experimental evidence have indicated that saikosaponin A (SSA) - a bioactive ingredient of the medicinal plant, Bupleurum falcatum L. - suppressed alcohol, morphine, and cocaine self-administration in rats. The present paper was designed to assess whether the protective properties of SSA on addiction-related behaviors generalize to a hyperpalatable food such as a chocolate-flavored beverage (CFB). To this end, rats were initially trained to lever-respond for CFB [5% (w/v) Nesquik® powder in water] under fixed ratio (FR) 10 (FR10) schedule of reinforcement. Once lever-responding reached stable levels, rats were treated acutely with two different dose ranges of SSA (0, 0.25, 0.5, and 1mg/kg; 0, 1, 2.5, and 5mg/kg; i.p.) and exposed to the FR10 and progressive ratio (PR) schedules of reinforcement in four independent experiments. The effect of acutely administered SSA (0, 0.25, 0.5, and 1mg/kg; i.p.) on cue-induced reinstatement of seeking behavior for CFB was also assessed. Under the FR and PR schedules of reinforcement, treatment with SSA diminished lever-responding for CFB, amount of self-administered CFB, and breakpoint for CFB. All variables were virtually completely suppressed after treatment with 5mg/kg SSA. Treatment with SSA also suppressed reinstatement of CFB-seeking behavior. No dose of SSA altered rat motor-performance, evaluated exposing all rats to an inverted screen test immediately after the self-administration session. These results demonstrate that acute treatment with SSA potently suppressed several addictive-like behaviors motivated by highly hedonic nourishment. These data extend to a highly rewarding natural stimulus the anti-addictive properties of SSA recently disclosed in rats self-administering alcohol, morphine, and cocaine.

Reducing effect of saikosaponin A, an active ingredient of Bupleurum falcatum, on alcohol self-administration in rats: Possible involvement of the GABAB receptor.

Recent studies demonstrated that treatment with saikosaponin A (SSA) - an active ingredient of the medicinal herb, Bupleurum falcatum L. - selectively suppressed, likely via a GABAB receptor-mediated mechanism, intravenous self-administration of morphine and cocaine in rats [Yoon et al., 2012; 2013]. The present study was designed to investigate whether the capacity of SSA to suppress morphine and cocaine self-administration extends to oral alcohol self-administration. To this end, selectively bred Sardinian alcohol-preferring (sP) rats were trained to lever-respond on a Fixed Ratio (FR) 4 (FR4) schedule of reinforcement for alcohol (15%, v/v) in daily 30-min sessions. Once responding had stabilized, rats were tested under the FR4 (measure of alcohol reinforcing properties) and Progressive Ratio (PR; measure of alcohol motivational properties) schedules of reinforcement. The possible involvement of the GABAB receptor system was investigated testing the effect of (a) pretreatment with the GABAB receptor antagonist, SCH50911, and (b) combined treatment with the positive allosteric modulator of the GABAB receptor, GS39783. Treatment with SSA (0, 0.25, 0.5, and 1mg/kg, i.p.) markedly reduced lever-responding for alcohol, amount of self-administered alcohol, and breakpoint for alcohol (defined as the lowest response requirement not achieved in the PR experiment). Pretreatment with 2mg/kg SCH50911 (i.p.) resulted in a partial blockade of the reducing effect of 0.5mg/kg SSA on lever-responding for alcohol and amount of self-administered alcohol. Combination of per se ineffective doses of GS39783 (5mg/kg, i.g.) and SSA (0.1mg/kg, i.p.) reduced lever-responding for alcohol and amount of self-administered alcohol. These results (a) extend to alcohol self-administration the capacity of SSA to suppress morphine and cocaine self-administration in rats and (b) suggest that the GABAB receptor system is likely part of the neural substrate underlying the reducing effect of SSA on alcohol self-administration.

Risk of thiamine deficiency and Wernicke's encephalopathy after gastrointestinal surgery for cancer.

BACKGROUND: Cancer patients submitted to gastrointestinal surgery are at risk of thiamine deficiency (TD) and Wernicke's encephalopathy (WE). Although permanent neurological damage and death could be prevented by a timely replacement therapy, they often remain undiagnosed and untreated. We hypothesized that WE remains unrecognized because most cases may manifest several months after hospital discharge. METHODS: WE frequency was investigated in a sample of cancer patients who underwent gastrointestinal surgery, by using the diagnostic criteria proposed to improve diagnosis among alcoholics. Patients were evaluated at discharge through the examination of medical records and 6 months after by telephonic interview. RESULTS: Forty-five patients were selected. Signs of WE resulted in 4.4% at discharge. At 6 months, 21 patients were interviewed. Among them, 90.4% had signs of WE. The number of affected patients was significantly higher 6 months after discharge than at discharge (90.4 vs 9.5%, p < 0.0001). CONCLUSIONS: Further studies with larger samples are needed to establish the prevalence of TD and related WE in cancer patients after gastrointestinal surgery. This study suggests that the problem is understated. Even in absence of symptoms of TD, the use of prophylactic thiamine supplementation should be taken in consideration, as consequences of misdiagnosis can be severe.

Reducing effect of the Chinese medicinal herb, Salvia miltiorrhiza, on alcohol self-administration in Sardinian alcohol-preferring rats.

The dried roots of Salvia miltiorrhiza are highly valued in Chinese folk medicine for use in the prevention and treatment of a series of ailments. Previous studies have demonstrated that administration of standardized extracts of S. miltiorrhiza selectively reduced excessive alcohol drinking and relapse-like drinking in selectively bred Sardinian alcohol-preferring (sP) rats. The present study was designed to extend these findings on the "anti-alcohol" properties of S. miltiorrhiza extracts to operant procedures of oral alcohol self-administration. Two independent groups of sP rats were trained to lever-respond on an FR4 schedule of reinforcement for alcohol (15%, v/v) or sucrose (1-3%, w/v) in daily 30 min sessions. Once responding had stabilized, rats were tested under the fixed ratio 4 (FR4) schedule of reinforcement (index of alcohol reinforcing properties) and the progressive ratio (PR) schedule of reinforcement (index of alcohol motivational properties). Treatment with S. miltiorrhiza extract (0, 50, 100, and 200 mg/kg, intragastrically [i.g.]) markedly reduced lever responding for alcohol, amount of self-administered alcohol, and breakpoint for alcohol (defined as the lowest response requirement not achieved in the PR experiment). No dose of S. miltiorrhiza extract altered any parameter of sucrose self-administration. These results a) demonstrate that treatment with S. miltiorrhiza extract selectively reduced the reinforcing and motivational properties of alcohol in sP rats and b) extend to operant procedures of alcohol self-administration previous data on the "anti-alcohol" effects of S. miltiorrhiza extracts. These data strengthen the notion that novel pharmacological approaches for treatment of alcohol use disorders may stem from natural substances.

Protective effect of Panax ginseng in cisplatin-induced cachexia in rats.

AIM: This study investigated the protective effect of a standardized extract of Panax ginseng on multiple cisplatin-induced 'sickness behaviors' (model of cancer-induced cachexia) in rats. MATERIALS & METHODS: Cisplatin was administered twice weekly (1-2 mg/kg, intraperitoneal) for 5 consecutive weeks. Panax ginseng extract (0, 25 and 50 mg/kg, intragastric) was administered daily over the 5-week period of cisplatin exposure. Malaise, bodyweight and temperature, pain sensitivity, and endurance running were recorded at baseline and at 5 weekly intervals. RESULTS: Treatment with cisplatin produced severe signs of malaise, marked loss of bodyweight, hypothermia, hyperalgesia and reduction in running time. Treatment with Panax ginseng extract completely prevented all cisplatin-induced alterations. CONCLUSION: These data indicate that treatment with Panax ginseng extract exerted a protective effect in a rat model of cachexia and suggest that Panax ginseng extract may be a therapeutic promising tool for supportive care in oncology.

Reducing effect of an extract of Phaseolus vulgaris on food intake in mice--focus on highly palatable foods.

Different lines of experimental evidence indicate that treatment with extracts from and derivatives of Phaseolus vulgaris reduces intake of food, including highly palatable foods and beverages, in rats. The present study was designed to extend to mice these lines of evidence. To this end, CD1 mice were treated acutely with a standardized extract of P. vulgaris and then exposed to unlimited access to regular food pellets (Experiment 1) or 1-hour limited access to three different palatable foods/beverages, such as butter cookies (Experiment 2), a condensed-milk beverage (Experiment 3), and a chocolate-flavored beverage (Experiment 4). Treatment with P. vulgaris extract resulted in a significant reduction in the intake of regular food pellets, that was still evident 24h later, as well as of the three palatable nourishments. Together, these results (a) extend to mice several previous findings on the capacity of P. vulgaris extracts to suppress food intake in rats, (b) suggest that P. vulgaris extracts may interfere with the central mechanisms regulating appetite, food intake, palatability, and/or the rewarding and hedonic properties of food, and (c) P. vulgaris extracts may represent a potentially effective therapy for overeating, obesity, and food craving.

Reducing effect of a combination of Phaseolus vulgaris and Cynara scolymus extracts on food intake and glycemia in rats.

Extracts from Phaseolus vulgaris and Cynara scolymus may reduce food intake and/or postprandial glycemia. This study investigated the effect of standardized extracts of P. vulgaris and C. scolymus and their combination on food intake and glycemia in rats. P. vulgaris and C. scolymus extracts, and their 1:2 combination, were administered acutely to rats (a) given access to regular food and water, (b) given access to regular food, water, and a chocolate-flavored beverage, or (c) infused with a starch bolus. P. vulgaris extract and the combination produced comparable reductions in intake of regular food and chocolate-flavored beverage; conversely, C. scolymus extract was ineffective on both parameters. P. vulgaris and C. scolymus extracts additively contributed to the reducing effect of the combination on glycemic rise. These results suggest that a mixture of P. vulgaris and C. scolymus extracts is preferable over each single extract, as it combines the anorectic effect of the P. vulgaris extract with the hypoglycemic effect of both extracts. These data support the recent clinical use of the combination of P. vulgaris and C. scolymus extracts in the control of appetite, food intake, and postprandial glycemia and represent a successful example of translational research in the nutraceutical field.

Voluntary alcohol drinking enhances proopiomelanocortin gene expression in nucleus accumbens shell and hypothalamus of Sardinian alcohol-preferring rats.

BACKGROUND: Evidence obtained in humans and rodents indicates that beta-endorphin (encoded by the proopiomelanocortin [POMC] gene) is critical in the regulation of alcohol drinking behavior. However, the alcohol effect on POMC gene expression has not been studied in rodent mesolimbic regions, such as the nucleus accumbens (NAc). METHODS: In this study, we first utilized POMC-enhanced green fluorescent protein (EGFP) transgenic mice to visualize POMC neurons and found that POMC-EGFP cells were modestly distributed throughout the NAc shell and core, in addition to the hypothalamic arcuate nucleus. POMC mRNA expression in the NAc of mice and rats was confirmed using reverse transcriptase-polymerase chain reaction and solution hybridization assays. We then investigated whether there are genetically determined differences in basal mRNA levels of POMC and mu opioid receptor (MOP-r) between selectively bred Sardinian alcohol-preferring (sP) and nonpreferring (sNP) rats, and whether these mRNA levels are altered in sP rats after alcohol drinking (10%, unlimited access) for 17 days. RESULTS: Alcohol-naïve sP rats had higher basal POMC mRNA levels than sNP rats only in hypothalamus. Alcohol drinking increased POMC mRNA levels in both the NAc shell (by 100%) and the hypothalamus (by 50%) of sP rats. Although sP rats had lower basal levels of MOP-r mRNA and GTPγS binding in NAc shell than sNP rats, voluntary alcohol consumption had no effect on MOP-r mRNA levels in the NAc shell. CONCLUSIONS: Our results define the distribution of POMC-expressing neurons in the NAc of mice and rats. Higher POMC expression at basal levels in sP rats (genetically determined), along with increases after drinking (alcohol-induced) in the NAc shell and hypothalamus, suggests that the POMC systems play a role in high alcohol preference and consumption.

Reducing effect of a combination of Phaseolus vulgaris and Cynara scolymus extracts on operant self-administration of a chocolate-flavoured beverage in rats.

Treatment with a rational combination of standardized extracts of Phaseolus vulgaris and Cynara scolymus reduced food intake and glycemia in rats. The present study was designed to assess the effect of this extract combination and of each single extract in an experimental model of food craving, made up of rats displaying exaggerated seeking and taking behaviors for a chocolate-flavoured beverage. After training to lever-respond for the chocolate-flavoured beverage, rats were treated with vehicle, Phaseolus vulgaris extract alone (200 mg/kg), Cynara scolymus extract alone (400 mg/kg), or combination of Phaseolus vulgaris (200 mg/kg) and Cynara scolymus (400 mg/kg) extracts. The Phaseolus vulgaris extract and the extract combination exerted similar and substantial decrements in the number of lever-responses and amount of self-administered chocolate-flavoured beverage; conversely, the Cynara scolymus extract was totally ineffective. These results suggest that (i) the capacity of the extract combination to reduce the self-administration of the chocolate-flavoured beverage entirely relied on the Phaseolus vulgaris extract, (ii) Phaseolus vulgaris extract may interfere with the mechanisms regulating food-related addictive-like behaviors, and (iii) combinations of Phaseolus vulgaris and Cynara scolymus extracts may possess a broad spectrum of activities, from treatment of metabolic syndrome to overweight, obesity, and possibly food-related addictive disorders.

Multiple cycles of repeated treatments with a Phaseolus vulgaris dry extract reduce food intake and body weight in obese rats.

Previous lines of experimental evidence have suggested that Phaseolus vulgaris extracts reduce food intake, body weight, lipid accumulation, hedonic properties of food, carbohydrate absorption and metabolism, and glycaemia in rats. The present study was designed to assess the effect of multiple cycles of repeated treatments with a standardised P. vulgaris dry extract on daily food intake and body weight in genetically obese Zucker fa/fa rats (Expt 1). Additionally, the study tested the effect of acute treatment with P. vulgaris dry extract on postprandial glycaemia in Zucker fa/fa rats (Expt 2). In Expt 1, P. vulgaris dry extract was administered daily, at doses of 50 and 500 mg/kg, in three 5 d treatment periods followed by three 20 d off-treatment periods. Administration of P. vulgaris dry extract resulted in dose-dependent decreases in daily food intake and body weight in each treatment phase. Reductions in food intake were of comparable magnitude in each treatment phase. In Expt 2, food-deprived rats were acutely treated with 50 and 500 mg P. vulgaris dry extract per kg immediately before access to a fixed amount of a starch-enriched chow. Treatment with P. vulgaris dry extract resulted in a dose-dependent suppression of glycaemia. These results extend previous data on the anorectic and hypoglycaemic effects of the P. vulgaris dry extract to a validated animal model of obesity. Together with data published previously in the literature, these results strengthen the hypothesis that potentially effective, novel pharmacotherapies for obesity and related disorders may originate from extracts and derivatives of P. vulgaris.

Involvement of arginine vasopressin and V1b receptor in alcohol drinking in Sardinian alcohol-preferring rats.

BACKGROUND: Recent animal studies have shown that the level of stress-responsive arginine vasopressin (AVP) gene expression in the amygdala is increased during early withdrawal from long-term heroin or cocaine administration. The selective AVP V1b receptor antagonist SSR149415 (capable of exerting antidepressant-like and anxiolytic effects in animal models) also blocked stress-induced reinstatement of drug-seeking behavior. This study was undertaken to investigate the effects of alcohol and to determine whether (i) there are genetically determined differences in basal AVP mRNA levels in the medial/central amygdala (Me/CeA) and medial hypothalamus (MH) between selectively bred Sardinian alcohol-preferring (sP) and alcohol-nonpreferring (sNP) rats; (ii) the AVP mRNA levels are altered by long-term alcohol drinking in sP rats; and (iii) the V1b receptor antagonist SSR149415 alters alcohol drinking in sP rats. METHODS: In Experiment 1, AVP mRNA levels were measured in the Me/CeA and MH of alcohol-naïve sP and sNP rats, and sP rats exposed to the standard, homecage 2-bottle "alcohol versus water" choice regimen 24 h/d for 17 days. In Experiment 2, SSR149415 (0, 3, 10, or 30 mg/kg; intraperitoneal) was acutely administered 30 minutes before lights off to alcohol-experienced sP rats. Alcohol, water, and food intake were monitored 6 and 24 hours later. RESULTS: We found higher basal AVP mRNA levels in both Me/CeA and MH of alcohol-naïve sP than sNP rats; alcohol consumption decreased AVP mRNA levels in both brain regions of sP rats, suggesting genetically determined differences between the 2 rat lines and in the effects of alcohol drinking in sP rats. Acute treatment with SSR149415 significantly reduced alcohol intake of sP rats. CONCLUSION: The stress-responsive AVP/V1b receptor system is 1 component of the neural circuitry underlying high alcohol drinking in sP rats.

Methamphetamine neurotoxicity increases brain expression and alters behavioral functions of CB1 cannabinoid receptors.

Cannabis is the most common secondary illicit substance in methamphetamine (METH) users, yet the outcomes of the concurrent consumption of both substances remain elusive. Capitalizing on recent findings on the implication of CB1 cannabinoid receptors in the behavioral effects of METH, we hypothesized that METH-induced neurotoxicity may alter the brain expression of CB1, thereby affecting its role in behavioral functions. To test this possibility, we subjected rats to a well-characterized model of METH neurotoxicity (4 mg/kg, subcutaneous × 4 injections, 2 h apart), and analyzed their CB1 receptor brain expression three weeks later. METH exposure resulted in significant enhancements of CB1 receptor expression across several brain regions, including prefrontal cortex, caudate-putamen, basolateral amygdala, CA1 hippocampal region and perirhinal cortex. In parallel, a different group of METH-exposed rats was used to explore the responsiveness to the potent cannabinoid agonist WIN 55,212-2 (WIN) (0.5-1 mg/kg, intraperitoneal), within several paradigms for the assessment of emotional and cognitive functions, such as open field, object exploration and recognition, and startle reflex. WIN induced anxiolytic-like effects in METH-exposed rats and anxiogenic-like effects in saline-treated controls. Furthermore, METH-exposed animals exhibited a significantly lower impact of WIN on the attenuation of exploratory behaviors and short-term (90 min) recognition memory. Conversely, METH neurotoxicity did not significantly affect WIN-induced reductions in locomotor activity, exploration time and acoustic startle. These results suggest that METH neurotoxicity may alter the vulnerability to select behavioral effects of cannabis, by inducing distinct regional variations in the expression of CB1 receptors.

Reducing effect of a Phaseolus vulgaris dry extract on operant self-administration of a chocolate-flavoured beverage in rats.

Extracts from or derivatives of Phaseolus vulgaris beans reduce body weight and food intake, including highly palatable foods and fluids, in multiple rodent models of overeating and obesity. The present study was designed to assess whether a standardised P. vulgaris dry extract was effective in reducing also the operant self-administration of a chocolate-flavoured beverage. To this end, rats were initially trained to lever-press for a chocolate-flavoured beverage under a fixed ratio 10 schedule of reinforcement in daily 60 min sessions. Once lever-responding reached stable levels, the effect of a P. vulgaris dry extract on the number of lever-responses for the chocolate-flavoured beverage was determined. Pretreatment with 50, 200 and 500 mg (intragastric) P. vulgaris dry extract per kg produced an approximate 15, 35 and 40 % reduction, respectively, in lever-responding for the chocolate-flavoured beverage. These results indicate the capacity of a P. vulgaris preparation to reduce the reinforcing properties of a highly palatable fluid in rats.

Reducing effect of a Phaseolus vulgaris dry extract on food intake, body weight, and glycemia in rats.

Extracts of kidney beans ( Phaseolus vulgaris ) are known to reduce food intake and glycemia in rodents and humans. This study evaluated the effect of a novel extract of P. vulgaris on food (regular food pellets, starch-enriched diet, and chocolate-flavored beverage) intake, body weight, and glycemia in rats. The effect of the combination of the colecistokinin (CCK) receptor antagonist, lorglumide, and P. vulgaris dry extract on food intake was also investigated. Administration of doses of P. vulgaris dry extract devoid of any behavioral toxicity dose-dependently decreased food intake (irrespective of the diet), body weight gain, and glycemia. Pretreatment with lorglumide blocked the reducing effect of P. vulgaris dry extract on food intake. The capacity of this P. vulgaris dry extract to reduce food intake, body weight, and glycemia in rats may be due to (a) inhibition of alpha-amylase, (b) stimulation of CCK release from the intestinal brush border cells, and/or (c) interference with the central mechanism(s) regulating appetite, food intake, and food palatability.

Sleep deprivation disrupts prepulse inhibition of the startle reflex: reversal by antipsychotic drugs.

Sleep deprivation (SD) is known to induce perceptual impairments, ranging from perceptual distortion to hallucinatory states. Although this phenomenon has been extensively described in the literature, its neurobiological underpinnings remain elusive. In rodents, SD induces a series of behavioural patterns that might be reflective of psychosis and mania, such as hyperlocomotion and sensitization to psychotogenic drugs. Notably, such changes are accompanied by transitory alterations of dopaminergic signalling. Based on the hypothesis that both psychotic and manic disorders reflect gating impairments, the present study was aimed at the assessment of the impact of SD on the behavioural model of prepulse inhibition (PPI) of the startle reflex, a reliable paradigm for the study of informational filtering. Rats subjected to SD (24 h, 48 h, 72 h) exhibited a time-dependent increase in startle reflex and a dramatic deficit in PPI. Both alterations were reversed 24 h after termination of the SD period. Interestingly, PPI disruption was efficiently prevented by haloperidol (0.1 mg/kg i.p.) clozapine (5 mg/kg i.p.) and risperidone (1 mg/kg i.p.). Conversely, neither the anxiolytic diazepam (5 mg/kg i.p.) nor the antidepressant citalopram (5 mg/kg i.p) affected the PPI disruption mediated by SD, although diazepam reversed the enhancement in startle reflex magnitude induced by this manipulation. Our data suggest that SD induces gating deficits that might be relevant to the hallucinatory phenomena observed in humans, and provide a novel reliable animal model where such relationship can be studied.

Efficacy of rimonabant and other cannabinoid CB1 receptor antagonists in reducing food intake and body weight: preclinical and clinical data.

The present paper focuses on the different lines of evidence indicating that cannabinoid CB(1) receptor antagonists, including the prototype rimonabant, reduce food intake and body weight in laboratory animals. Recent clinical surveys demonstrated that rimonabant significantly reduced body weight also in overweight/obese humans. Treatment with rimonabant was associated with a beneficial effect on different metabolic parameters and cardiovascular risk factors linked to overweight. The data reviewed in this paper suggest that cannabinoid CB(1) receptor antagonists may constitute a novel class of drugs potentially effective in the treatment of obesity-related disorders.

Identification of miltirone as active ingredient of Salvia miltiorrhiza responsible for the reducing effect of root extracts on alcohol intake in rats.

BACKGROUND: Previous work found that extracts from the roots of Salvia miltiorrhiza, a Chinese medicinal herb, reduced alcohol intake in selectively bred Sardinian alcohol-preferring (sP) rats. The present study was designed to evaluate whether miltirone, one of the possible active constituents of S. miltiorrhiza, might be responsible for the reducing effect of the extracts on alcohol intake. METHODS: An initial experiment assessed the effect of 100 mg/kg (intragastric, i.g.) of 4 extracts of S. miltiorrhiza, differing in miltirone content (0, 2, 3, and 7%, respectively), on alcohol intake in alcohol-experienced sP rats exposed to the 2-bottle "alcohol (10%, volume in volume) versus water" choice regimen. Subsequently, the effect of pure miltirone (2.5-10 mg/kg, i.g., i.e., a dose range comparable to its content in the effective doses of the active extracts) on acquisition and maintenance of alcohol-drinking behavior was evaluated in alcohol-naive and alcohol-experienced sP rats exposed to the 2-bottle choice regimen. The effect of miltirone (10 mg/kg, i.g.) on blood alcohol levels was assessed after the i.g. and intraperitoneal (i.p.) administration of alcohol. Finally, the effect of miltirone (30-100 mg/kg, i.g.) on the severity of alcohol withdrawal syndrome was evaluated in Wistar rats made physically dependent on alcohol by the repeated administration of intoxicating doses of alcohol. RESULTS: The reducing effect of 4 different extracts of S. miltiorrhiza on alcohol intake was positively and significantly correlated with their miltirone content. Pure miltirone reduced alcohol intake in alcohol-experienced rats and delayed acquisition of alcohol-drinking behavior in alcohol-naive rats. Similar to S. miltiorrhiza extracts, miltirone markedly reduced blood alcohol levels when alcohol was administered i.g. but not i.p., suggesting that miltirone hampered alcohol absorption from the gastrointestinal system. Finally, miltirone failed to affect the severity of alcohol withdrawal syndrome in alcohol-dependent rats. CONCLUSIONS: The results of the present study suggest that miltirone is the likely active constituent of S. miltiorrhiza responsible for the reducing effect of its extracts on alcohol intake in different experimental models of excessive alcohol consumption.