Alcohol drinking in rats treated with 5,7-dihydroxytryptamine: Effect of 8-OH-DPAT and tropisetron (ICS 205-930)

5,7-Dihydroxytryptamine (5,7-DHT) was administered ICV to Wistar male rats. Lesioned rats displayed higher preference for ETOH than sham-lesioned animals. Among 5,7-DHT-pretreated rats 38% became high-preferring, while only 22% of sham-lesioned rats displayed this behavioural pattern (p < 0.05). Both 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; the agonist of serotonin 5-HT_1A receptors) and tropisetron (ICS 205-930, the antagonist of 5-HT₃ receptors) reduced ETOH consumption in high-preferring, sham-lesioned rats. However, in 5,7-DHT rats the effect of 8-OH-DPAT was completely abolished, while tropisetron retained its antipreference activity. Therefore, it seems that 5-HT_1A autoreceptors are critically involved in 8-OH-DPAT action, while 5-HT₃ receptor sites responsible for tropisetron action are located beyond the 5-HT system.     

Evidence that the amygdala is involved in the inhibitory effects of 5-HT3 receptor antagonists on alcohol drinking in rats

Two 5-HT₃ receptor antagonists, tropisetron (1 and 10 ng) and ondansetron (10 and 100 ng) were tested for effects on ethanol drinking in Wistar male rats after bilateral microinjection into the amygdala. The animals had limited access (2 h/day) to the 10% (v/v) ethanol solution, food and water were available ad lib during the scheduled access period. Both drugs caused a decrease in ethanol drinking. Tropisetron (1 and 10 ng) decreased ethanol intake during the first hour of access. The lower dose (10 ng) of ondansetron was more effective than the higher (100 ng) dose. The finding implicates amygdaloid 5-HT₃ receptors in the mechanism of ethanol intake in Wistar rats.     

Involvement of the serotonergic system in ethanol intake in the rat

A two-bottle, free-choice paradigm was used to investigate the influence of the serotonergic (5-HT) system on ethanol intake in genetically heterogeneous Wistar rats. Systemic administration of the 5-HT_1A agonist ipsapirone (1.25–5.0 mg/kg) caused a dose-dependent decrease in ethanol preference and intake, while the 5-HT₂ antagonist ritanserin (1.25–5.0 mg/kg) and the 5-HT₃ antagonists ondansetron (0.01–1.0 mg/kg) and granisetron (0.5–1.0 mg/kg) failed to alter ethanol consumption. The effect of ipsapirone treatment on ethanol intake was more pronounced in high-preferring animals than in low-preferring. A closer look at the microstructure of the rat's drinking behaviour by means of a microcomputer-controlled data acquisition system showed that ipsapirone treatment caused a significant decrease in the number of licks recorded at the ethanol-containing bottle and a decrease in the time spent at this bottle. Furthermore, ipsapirone treatment caused a significant increase in the number of breaks in licking behaviour recorded at this bottle. The drinking behaviour at the water-containing bottle was not affected by the ipsapirone treatment. Neither was the rat's eating behaviour altered by this treatment. These findings support the hypothesis that the 5-HT system is involved in the regulation of ethanol intake, with special emphasis on the involvement of the 5-HT_1A receptor subtype, and may indicate that central reward-mediating mechanisms are influenced.     

The 5-HT1A receptor agonist 8-OH-DPAT reduces ethanol intake and maintained behavior in female Sprague-Dawley rats

Agents affecting serotonergic (5-hydroxytryptamine, 5-HT) function influence ethanol consumption in rats and primates. In the present study female Sprague-Dawley rats were trained to orally self-administer 8% ethanol (v/v) in a large operant chamber in a 60-min test period by a prandial drinking technique. The number of responses, ethanol reinforcers (dipper deliveries), and ethanol consumption (g/kg) were measured following administration of the 5-HT_1A agonist 8-OH-DPAT (0.001–1.0 mg/kg, ip) 30 min prior to testing. Locomotor activity (LMA) was also measured to assess activity changes induced by 8-OH-DPAT. 8-OH-DPAT selectively reduced ethanol ingestion from 17.1±3.2 dipper deliveries under vehicle conditions to 6.6±3 at a dose of 0.1 mg/kg. Higher doses of 8-OH-DPAT (0.5 and 1.0 mg/kg) significantly reduced both ethanol ingestion and LMA. Lower doses of 0.001–0.01 mg/kg of 8-OH-DPAT were without effect on ethanol intake and maintained behavior. These results demonstrate that, under the present experimental conditions, the 5-HT_1A receptor agonist 8-OH-DPAT reduced ethanol self-administration in the rat, and support a role for 5-HT_1A receptors in the mediation of ethanol reinforcement.     

Sensitization to 5-HT1C receptor agonist in rats observed following withdrawal from chronic ethanol

Anxiogenic action of m-chlorophenylpiperazine (mCPP), a 5-HT_1C receptor agonist, was studied in naive rats and in ethanol-tolerant rats following withdrawal from chronic ethanol administration. The purpose of this investigation was to determine whether a sensitization to mCPP develops during withdrawal from chronic ethanol. Male Long-Evans hooded rats were fed a liquid diet containing 4.5% ethanol or dextrin (as control) for four days. Twelve hours (acute withdrawal) or 4 days (protracted withdrawal) after the last dose of ethanol, rats were injected with saline or mCPP (0.08–5.0 mg/kg) and were tested in the elevated plus-maze 15 min postinjection. A reduction in percent open-arm activity, indicative of anxiogenic behavior, was observed in ethanol-treated rats injected with saline. Administration of mCPP further reduced the percent open-arm entries and time in ethanol-withdrawn rats. An eightfold reduction in maximum effective dose of mCPP was observed during acute ethanol withdrawal as compared to that in naive rats. During protracted ethanol withdrawal the maximum effective dose of mCPP was reduced by 75%. A shift of the mCPP dose-response curve to the left following withdrawal from chronic ethanol may indicate that 5-HT_1C receptor sites are more sensitive to the activation by an agonist. This effect may be exploited in developing specific 5-HT_1C receptor antagonists for the treatment of ethanol withdrawal symptoms.     

An Investigation Into the Effects of 5-HT Agonists and Receptor Antagonists on Ethanol Self-Administration in the Rat

Pharmacological manipulation leading to altered 5-HT function has been widely demonstrated to reduce ethanol intake in free choice tests. The aim of the present study was to examine the effects of a range of compounds known to influence 5-HT neurotransmission, including selective 5-HT receptor agonists and antagonists, on ethanol ingestion and maintained behaviour in an operant self-administration paradigm. Female Sprague–Dawley rats were trained to respond for 8% ethanol (v/v) in a 60-min test by a previously described technique. The number of responses and ethanol reinforcers (dipper deliveries), ethanol consumption (g/kg of body weight), and locomotor activity (LMA) were measured following administration of 5-HT agonists (5-HT, d-fenfluramine, fluoxetine, buspirone, TFMPP, and DOI) and antagonists (metergoline, ritanserin, and ondansetron) 30 min prior to testing. d-Fenfluramine, fluoxetine, buspirone, TFMPP, and DOI all produced a reduction in ethanol ingestion and maintained behaviour at doses that failed to reduce LMA. Conversely, metergoline and ritanserin only reduced ethanol self-administration at doses that concomitantly reduced LMA. 5-HT and ondansetron were without effect on any measure. These results demonstrate that, under the present experimental conditions, activation of central 5-HT_1A, 5-HT_1B, and 5-HT₂ receptors reduced ethanol intake and reinforced behaviour in an operant paradigm.     

5-HT1A receptor agonists reduce ethanol-induced locomotor activity in mice

Animal studies as well as clinical studies have suggested that the brain 5-HT system is important for the regulation of voluntary ethanol intake and preference. Previous studies have suggested that 5-HT_1A receptor agonists may reduce ethanol preference in rats. In the present study on mice, the 5-HT_1A receptor agonists (8-OH-DPAT), ipsapirone, and buspirone all antagonized the locomotor activity (LMA) stimulatory effect of ethanol (2.5 g/kg). The present results provide further support for the notion that the LMA-increasing effect of ethanol may be homologous to its reinforcing properties and that 5-HT_1A receptor agonists may counteract these properties as well.     

Differential efficacy of serotonergic drugs FG5974, FG5893, and amperozide in reducing alcohol drinking in P rats

Amperozide (FG5606), a 5-HT₂ receptor antagonist, is well known to suppress alcohol consumption in different rat models of drinking. The present study compared the efficacy of three drugs, FG5974, FG5893, and amperozide, which have differential affinities for 5-HT_1A and 5-HT_2A receptors, on alcohol drinking in the genetic alcohol-preferring (P) rat. After preference for alcohol vs. water was determined over 10 days when concentrations of alcohol were increased from 3% to 30%, the maximal concentration of alcohol preferred by each animal was selected for drug testing. A 4-day predrug preference test was followed by SC injection of the saline control vehicle or doses of 1.0 and 2.5 mg/kg FG5974, FG5893, or amperozide given at 1600 and 2200 h for 4 days. Alcohol preference testing concluded with a final 4-day interval. A total daily dose of 5.0 mg/kg FG5974 reduced absolute g/kg intake of alcohol and proportional intakes of the P rats significantly; the lower dose of FG5974 also reduced alcohol drinking significantly following treatment. The mixed 5-HT_1A agonist/5-HT_2A antagonist, FG5893, which suppresses drinking in cyanamide-treated rats, was without effect on alcohol ingested by the P rats. However, amperozide caused a dose-dependent decline in both absolute intakes and proportion of alcohol that was more intense than that of FG5974. The control vehicle failed to alter alcohol drinking and, like the FG compounds, did not affect food intake or body weight. Although the inhibition of alcohol drinking by amperozide corresponds precisely with previous findings, the effect of FG5974 contrasts to results obtained with a structurally analogous drug FG5893. Thus, the genetic strain of rat as well as the nature of the chemical characteristics of a 5-HT agonist/antagonist will determine the differential efficacy of a drug in influencing the volitional drinking of alcohol.     

Effects of 5-HT-1A receptor agonists on ethanol preference in the rat.

Pharmacological manipulation of brain serotonin (5-HT) neurons has recently become recognized as an important approach in the treatment of ethanol (ET-OH) dependence. In the present study, we observed the effects of three agonists of 5-HT-1A receptor subtype, 8-OHDPAT, buspirone, and NDO-008, on ET-OH preference in Wistar male rats. Animals received ET-OH intragastrically during the first week of the experiment, and then during 2 consecutive weeks, the only source of fluid (23 h/d) was 5% and 8% wt/vol ET-OH solution, respectively. Then the animals were presented with a free-choice between water and 8% ET-OH solution for a 1-week period. Based on the baseline recordings, two groups of rats were formed: a high preference group (ET-OH intake greater than 50% of total daily fluid intake) and a low preference group of rats (ET-OH intake less than 20%). During week 5 of the experiment, animals were treated with 5-HT receptor agonists (subcutaneous injections twice daily for 4 days). The treatment caused a significant reduction of ET-OH intake in the high preference group, but caused no change in the remaining groups. The effect of highly selective 5-HT-1A receptor agonist, 8-OHDPAT, on ET-OH consumption in the high preference group was antagonized by cyanopindolol, a nonselective antagonist of 5-HT-1 receptor subtype. Our results support the hypothesis that activation of 5-HT-1A receptors reduces ET-OH preference.     

Overexpression of 5-HT1B mRNA in nucleus accumbens shell projection neurons differentially affects microarchitecture of initiation and maintenance of ethanol consumption

Serotonin 1B (5-HT_1B) heteroreceptors on nucleus accumbens shell (NAcSh) projection neurons have been shown to enhance the voluntary consumption of alcohol by rats, presumably by modulating the activity of the mesolimbic reward pathway. The present study examined whether increasing 5-HT_1B receptors expressed on NAcSh projection neurons by means of virus-mediated gene transfer enhances ethanol consumption during the initiation or maintenance phase of drinking and alters the temporal pattern of drinking behavior. Animals received stereotaxic injections of viral vectors expressing either 5-HT_1B receptor and green fluorescent protein (GFP) or GFP alone. Home cages equipped with a three-bottle (water and 6 and 12% ethanol) lickometer system recorded animals’ drinking behaviors continuously, capturing either initiation or maintenance of drinking behavior patterns. Overexpression of 5-HT_1B receptors during initiation increased consumption of 12% ethanol during both forced-access and free-choice consumption. There was a shift in drinking pattern for 6% ethanol with an increase in number of drinking bouts per day, although the total number of drinking bouts for 12% ethanol was not different. Finally, increased 5-HT_1B expression induced more bouts with very high-frequency licking from the ethanol bottle sippers. During the maintenance phase of drinking, there were no differences between groups in total volume of ethanol consumed; however, there was a shift toward drinking bouts of longer duration, especially for 12% ethanol. This suggests that during maintenance drinking, increased 5-HT_1B receptors facilitate longer drinking bouts of more modest volumes. Taken together, these results indicate that 5-HT_1B receptors expressed on NAcSh projection neurons facilitate ethanol drinking, with different effects during initiation and maintenance of ethanol-drinking behavior.     

Serotonin3 Receptor Antagonism of Alcohol Intake: Effects of Drinking Conditions

McKINZIE, D. L., R. EHA, R. COX, R. B. STEWART, W. DYR, J. M. MURPHY, W. J. McBRIDE, L. LUMENGAND T.-K. LI. Serotonin₃ receptor antagonism of alcohol intake: Effects of drinking conditions. ALCOHOL 15(4) 291–298, 1998.—The effects of 5-HT₃ receptor antagonists on ethanol intake were examined in the selectively bred alcohol-preferring P line of rats under continuous and limited access to 10% (v/v) ethanol with food and water ad lib. Single daily injections of either MDL 72222 (MDL) or ICS 205-930 (ICS) (0.01–3.0 mg/kg, SC) given 60 min before a 4-h scheduled access period for 4 consecutive days failed at all doses to alter the intake of a 10% (v/v) ethanol solution by P rats. However, multiple daily injections of either MDL (1–3 mg/kg, SC) or ICS (3.0 and 5.0 mg/kg, SC), given three times daily at 4-h intervals, significantly reduced ethanol intake under 24-h free-choice conditions on the first treatment day. Additionally, a single administration of 1.0 mg/kg MDL reduced 24-h free-choice ethanol intake by approximately 50% of control values and had no effect on 24-h saccharin intake. The effects of MDL were further examined in a 2-h schedule access paradigm in which rats received the access period at the same time every day (Fixed) or randomly during the dark cycle (Variable). Although 1.0 mg/kg MDL had little effect on ethanol drinking in the Fixed group, ethanol intake was reduced by 55% of control levels in the Variable group. Overall, the data indicate that drinking conditions influence the effectiveness of 5-HT₃ antagonists to reduce ethanol consumption. Furthermore, the results suggest that conditions, associated with limited access ethanol drinking, markedly reduce the actions of 5-HT₃ antagonists on ethanol intake.     

Acute effect of ethanol on renal electrolyte excretion in rats

The purpose of this study was to investigate the renal handling of sodium and potassium in rats during an acute ethanol (ETOH) administration and to relate any observed changes to alterations in renin-aldosterone secretion. Eight male Wistar rats, 7 to 8 weeks of age, were injected intraperitoneally (IP) with 1.0 g/kg body wt. ETOH (15% v/v, 95% ETOH in saline, pH 6.98, osmolality 284 mOsm/kg). Blood ETOH levels were 159 +/- 16 (Mean +/- SEM) and 120 +/- 12 mg/dl, 10 and 30 min after the ETOH injection respectively (p less than 0.05). Control animals were given either an equal volume (1.77 ml/100 g body wt.) of 0.9% saline (n = 6) or 5% dextrose solution (n = 4) with similar pH and osmolality. Following ETOH administration blood pH, urine pH, plasma bicarbonate (HCO3) concentration declined significantly (p less than 0.01) while glomerular filtration rate (GFR) and hematocrit (Hct) remained unchanged (p = 0.1). Mean fractional sodium excretion (FENa), fractional potassium excretion (FEK), and osmolar clearance (Cosm) fell significantly despite an increase in plasma sodium (p less than 0.01), potassium (p less than 0.05) and osmolality concentrations (p less than 0.05). There was no significant change in plasma aldosterone concentration (PA) or plasma renin activity (PRA) following the ETOH administration. No difference in GFR, FENa, FEK, Cosm, blood pH, urine pH, plasma electrolytes, PA, or PRA was observed following the saline or dextrose injections. In conclusion, acute ETOH administration in rats alters renal sodium and potassium excretion independent of changes in GFR, PA, PRA or plasma volume as reflected by Hct.     

The mixed 5-HT1A2A receptor drug FG5938 suppresses alcohol drinking while enhancing feeding in P rats

The neurotransmitter serotonin (5-HT) has long been implicated in the etiology of aberrant consumption of alcohol. Several compounds thought to possess a potential therapeutic value to counteract drinking have high affinities for 5-HT_1A and 5-HT_2A receptors in the brain. For example, amperoxide and FG5865 significantly reduce the volitional intake of alcohol, without altering food intake, both in rats genetically predisposed or chemically induced to drink alcohol. The present study was undertaken in the alcohol-preferring (P) rat to determine whether an amperozide-like drug. FG5938 (1-[4-(p-fluorophenyl)butyl]-4-(6-methyl-2-pyridinyl)-piperazine fumarate), exerts an action on the volitional drinking of alcohol as well as on the intakes of food and water. In 11 male P rats, the pattern of preference for different concentrations of alcohol was determined by an 11-day test for water vs. 3 to 30% alcohol solutions. After maximally preferred alcohol concentrations, i.e., 9 to 15%, had stabilized for 4 days, saline of FG5938 was injected subcutaneously at 1600 and 2200 h in a dose of 2.5, 5.0, or 10.0 mg/kg over 4 consecutive days. Following treatment, preference testing for the same concentrations of alcohol was continued for 5 additional days. FG5938 caused a significant suppression in alcohol drinking in terms of both absolute g/kg and proportion to total fluid intake. During its administration, FG5938 also enhanced the ingestion of food and water of the P animals significantly, with the largest intake occurring on the initial day, while body weights increased. After FG5938 injections, food and water intakes returned to predrug levels. The saline control vehicle had no significant effect on the intakes of alcohol, food, or water of the P rats. Overall, these results show that FG5938 acts to attenuate alcohol preference while simultaneously increasing the ingestion of food paradoxically. To our knowledge, this is the first known drug to possess this unique property. Finally, these findings support the view that a compound having affinities to both 5-HT_1A and 5-HT_2A receptors may be useful as a therapeutic agent in the treatment of alcoholism.     

Volitional consumption of ethanol by fawn-hooded rats: Effects of alternative solutions and drug treatments

Behavioral and neurochemical measures of brain 5-hydroxytryptamine (5-HT) function in the Fawn-Hooded rat are abnormal relative to outbred strains of rats. Fawn-Hooded rats freely drink large amounts of 10% ethanol in the presence of water and have been proposed to be an animal model for studies related to alcoholism. In this study, Fawn-Hooded rats were given solutions of ethanol increasing in concentration from 3% to 30% (w/v in tap water) over 10 days with tap water in a second drinking tube and a third tube left empty. The solutions of ethanol that produced maximal drinking with a preference (ml ethanol/ml total fluid) near 50% ranged from 5% to 13%, which became: the fixed individual concentrations for each rat. After a 5-day baseline period the rats were offered a solution in the third drinking tube of either 0.5% aspartame or chocolate Ultra SlimFast (diluted with water 2: 1). The chocolate drink, but not aspartame, significantly reduced the consumption of alcohol by 73%. For the drug experiments, the rats were given successive 4-day periods of: baseline drinking; drug or saline injections b.i.d.; and a posttreatment period. Neither ipsapirone, a 5-HT_1a partial agonist, nor naltrexone injected inhibited the intakes of ethanol solutions. Treatment with 2.5 mg/kg of amperozide, a 5-HT₂ antagonist, decreased the consumption of ethanol by 38%, but also caused a decrease in consumption of food. These results show a pattern of drinking of increasing concentrations of ethanol different than other strains of rats. Because ethanol intakes of the Fawn-Hooded rat decline precipitously when offered palatable chocolate drink and fail to respond to drugs known to decrease human ethanol intake, this strain may not be a valid model for testing the effects of centrally acting drugs on the consumption of ethanol.     

Serotonin-3 receptors in the posterior ventral tegmental area regulate ethanol self-administration of alcohol-preferring (P) rats

Several studies indicated the involvement of serotonin-3 ([5-hydroxy tryptamine] 5-HT₃) receptors in regulating alcohol-drinking behavior. The objective of this study was to determine the involvement of 5-HT₃ receptors within the ventral tegmental area (VTA) in regulating ethanol self-administration by alcohol-preferring (P) rats. Standard two-lever operant chambers (Coulbourn Instruments, Allentown, PA) were used to examine the effects of seven consecutive bilateral microinfusions of ICS 205-930 (ICS), a 5-HT₃ receptor antagonist, directly into the posterior VTA on the acquisition and maintenance of 15% (vol/vol) ethanol self-administration. P rats readily acquired ethanol self-administration by the fourth session. The three highest doses (0.125, 0.25, and 1.25 μg) of ICS prevented acquisition of ethanol self-administration. During the acquisition postinjection period, all rats treated with ICS demonstrated higher responding on the ethanol lever, with the highest dose producing the greatest effect. In contrast, during the maintenance phase, the three highest doses (0.75, 1.0, and 1.25 μg) of ICS significantly increased responding on the ethanol lever; after the 7-day dosing regimen, responding on the ethanol lever returned to control levels. Microinfusion of ICS into the posterior VTA did not alter the low responding on the water lever and did not alter saccharin (0.0125% wt/v) self-administration. Microinfusion of ICS into the anterior VTA did not alter ethanol self-administration. Overall, the results of this study suggest that 5-HT₃ receptors in the posterior VTA of the P rat may be involved in regulating ethanol self-administration. In addition, chronic operant ethanol self-administration and/or repeated treatments with a 5-HT₃ receptor antagonist may alter neuronal circuitry within the posterior VTA.     

Body temperature influences ethanol and ethanol/pentobarbital lethality in mice

The effect of body temperature on ethanol (ETOH) or ethanol plus pentobarbital (ETOH/PB) lethality was investigated in C57BL/6J mice. Decreasing ambient temperatures from 35-20 degrees C, decreased rectal temperatures from 38-20 degrees C and increased 8-hour survival from 0-93% for ETOH-treated and from 0-100% for ETOH/PB-treated mice. ETOH and ETOH/PB animals with no hypothermia (body temperatures = 38 degrees C) had the highest lethality. Those with body temperatures between 30-32 degrees C had the highest 24-hour survival. These results suggest that controlled hypothermia may be useful in reducing lethality from ethanol or ethanol/combination overdoses.     

Comparison of the action of the 5-HT2 antagonists amperozide and trazodone on preference for alcohol in rats

Previous studies in the rat demonstrated that the 5-hydroxytryptamine₂ (5-HT₂) antagonist amperozide attenuates the volitional intake of both alcohol and cocaine solutions in a free-choice situation. However, another 5-HT₂ antagonist, ritanserin, has not been found to reduce alcohol drinking consistently in the rat. In this study, trazodone was compared to amperozide for its effect on the volitional consumption of alcohol because, like amperozide, trazodone is a potent 5-HT₂ receptor antagonist but a weak inhibitor of 5-HT reuptake. Male Sprague-Dawley rats were induced to drink alcohol by 10 mg/kg cyanamide injected for 3 days b.i.d. One week later the rats were offered a choice of water and increasing concentrations of alcohol solutions ranging from 3% to 30% v/v in a three-bottle two-choice paradigm. After the concentration of alcohol that produced maximal daily intake was determined for each rat, trazodone or amperozide was injected b.i.d. SC in doses of 1.0 mg/kg or 2.5 mg/kg for three days. Whereas the higher dose of amperozide produced a significant, 55.6% decrease from pretreatment baseline of alcohol intake, trazodone did not alter alcohol preference at either the 1.0- or 2.5-mg/kg dose. These results are discussed in terms of whether the antagonism of 5-HT₂ receptors by amperozide is critical to its attenuating effect on preference for alcohol solutions.     

Effect of a high-protein diet on insulin and glucagon secretion in ventromedial hypothalamic (VMH) lesioned rats

The effects of a high-protein diet on insulin and glucagon secretion in ventromedial hypothalamic (VMH) lesioned and sham-operated (sham) rats were studied in vivo as well as in perfusate from isolated pancreas. Two weeks after VMH destruction or sham operation, the rats were given either a balanced diet (protein 27%, carbohydrate 61%, fat 12%) or a high-protein diet (protein 55%, carbohydrate 30%, fat 15%) for the following 2 weeks. The calorie intake and body weight changes after the commencement of the diets were almost the same in the groups of VMH lesioned rats, but these were much greater than those in the two sham-operated groups. Fasting blood glucose, plasma insulin, and plasma glucagon concentrations were also similar between the two VMH groups, but in the sham-operated rats fasting blood glucose and plasma insulin concentrations of those rats on high-protein diet were significantly increased when compared to those on balanced diet. In the isolated, perfused pancreas, an arginine-induced excess insulin and glucagon secretion was not significantly different between the VMH lesioned rats. An arginine-induced rise in insulin concentration in the sham-operated rats on high-protein diet was significantly higher than for rats on balanced diet. We therefore suggest that hyperinsulinemia already produced in the VMH lesioned rats may not be influenced by the change in the composition of the dietary protein and carbohydrate.     

The Impact of 5-HT3RA Use on Cost and Utilization in Patients with Chemotherapy-Induced Nausea and Vomiting: Systematic Review of the Literature

Background

Individual studies have assessed the impact of standard prophylactic therapy with 5-hydroxytryptamine receptor antagonists (5-HT₃RAs) for chemotherapy-induced nausea and vomiting (CINV) on cost and utilization, but no synthesis of the findings exists.

Objective

To systematically review published literature on costs and utilization associated with CINV prophylaxis with palonosetron and other 5-HT₃RAs.

Methods

PubMed and the National Institute for Health Research Centre for Reviews and Dissemination databases, conferences of 4 organizations (ie, Academy of Managed Care Pharmacy, American Society of Clinical Oncology, International Society for Pharmacoeconomics and Outcomes Research, and Multinational Association of Supportive Care in Cancer), and the bibliographies of relevant articles were queried for the medical subject headings and key terms of “ondansetron,” “granisetron,” “palonosetron,” “dolasetron mesylate,” “costs,” “cost analysis,” and “economics.” We included records published (full-length articles after 1997 and conference presentations after 2010) in English and with human patients, reporting data on cost and utilization (rescue medication, outpatient and inpatient services) associated with the use of 5-HT₃RAs for the treatment or prevention of CINV.

Results

Of the 434 identified studies, 32 are included in the current analysis: 7 studies report costs, 18 report utilization, and 7 studies report both. The costs are reported in US dollars (7 studies), in Euros (5 studies), and in Canadian dollars (2 studies). The studies vary in designs, patients, 5-HT₃RA regimens, and the definition of outcomes. The US studies report higher drug costs for CINV prophylaxis with palonosetron compared with ondansetron, lower medical outpatient and inpatient costs for palonosetron versus other 5-HT₃RAs, and higher acquisition costs for palonosetron versus ondansetron or other 5-HT₃RAs. Fewer patients receiving palonosetron versus with ondansetron or other 5-HT₃RAs required rescue medication or used outpatient or inpatient care. In Europe and in Canada, the total pharmacy costs and use of rescue medications reported are lower for patients receiving prophylaxis with palonosetron.

Conclusions

This analysis shows that prophylaxis with palonosetron for the treatment of CINV is associated with higher acquisition treatment costs, but also with lower use of rescue medications and outpatient and inpatient services compared with ondansetron or other 5-HT₃RAs in the United States. Therefore, the use of palonosetron as a standard treatment may lead to reduced service utilization for CINV.Chemotherapy-induced nausea and vomiting (CINV) is an adverse effect of cancer treatment. It may occur within a few minutes of or up to 24 hours after the administration of chemotherapy (ie, acute CINV), or it may occur more than 24 hours after treatment (ie, delayed CINV). CINV may last up to 7 days.1–7Although there are several patient-specific factors that place patients at an increased risk for developing CINV (eg, female sex, low consumption of alcohol, history of motion or morning sickness, age under 50 years, previous CINV), the most contributory risk factor is the emetogenic potential of the chemotherapy regimen itself.8

KEY POINTS

• ▸ Poorly controlled CINV may lead to nutrient depletion, reduced functional ability, diminished quality of life, or the premature discontinuation of chemotherapy.
• ▸ Previous studies have examined the impact of CINV prophylaxis with palonosetron and other 5-HT₃RAs on cost and utilization, but this is the first systematic review of the published literature on this topic.
• ▸ A total of 32 studies were included in this systematic literature review, of which 14 studies report costs and 25 reported utilization.
• ▸ This review indicates that palonosetron is associated with higher treatment costs but also with lower rescue medication use and outpatient and inpatient services use compared with other 5-HT₃RAs.
• ▸ Based on this analysis, the use of palonosetron as a standard treatment may lead to reduced service utilization for CINV.

More than 90% of patients undergoing highly emetogenic chemotherapy (HEC) will experience emesis without antiemetic prophylaxis, and 30% to 90% of those undergoing moderately emetogenic chemotherapy (MEC) will vomit without the prophylactic administration of antiemetics.8 From 10% to 30% of the patients receiving low emetogenic risk chemotherapy (LEC), and <10% of patients receiving minimal emetogenic risk chemotherapy (MinEC), will experience emesis without the administration of antiemetics.3,6,7,9 The dose, frequency, and length of administration, as well as the combination of agents may impact the emetogenicity of the chemotherapy.7Poorly controlled CINV may lead to nutrient depletion, reduced functional ability, diminished quality of life, or the premature discontinuation of chemotherapy.1-4,6,7,9 The use of prophylactic antiemetic medications in patients undergoing HEC may reduce the incidence of CINV to as low as 30%.7 A multidrug regimen containing a 5-hydroxytryptamine receptor antagonist (5-HT₃RA) is the standard approach for CINV prophylaxis.7 Drugs in this category include dolasetron mesylate, granisetron, ondansetron, palonosetron, and tropisetron, with palonosetron recommended as the preferred 5-HT₃RA for CINV prophylaxis with MEC by the guidelines of the National Comprehensive Cancer Network (NCCN), the Multinational Association of Supportive Care in Cancer/Economic Society for Medical Oncology (MASCC/ESMO), and the American Society of Clinical Oncology (ASCO).5,7,10Secondary rescue medications are used to treat breakthrough CINV among patients who have received prophylaxis.7 These medications may include metoclopramide, lorazepam, diphenhydramine, olanzapine, prochlorperazine, or dexamethasone.CINV increases direct costs (eg, medication, office visits, or hospitalizations) and indirect costs (eg, missed work).3,4,9 The effective prevention of CINV may reduce these costs. The clinical and economic impact of CINV underscore the importance of achieving CINV prophylaxis.3,4,9 Palonosetron—which has greater binding affinity and a longer half-life than the other 5-HT₃RAs, binds allosterically, stimulates receptor internalization, demonstrates positive cooperativity, and cross talks with the neurokinin (NK)-1 signaling pathway—prevents both acute and delayed CINV more effectively than the other 5-HT₃RAs.7,11-14The extent to which the clinical benefit of 5-HT₃RAs translates into reduced costs or utilization of healthcare services among patients with CINV has been shown in individual studies for subsets of outcomes,3,15 but no summary of the literature exists. We conducted a systematic literature review of published research on the healthcare costs and utilization associated with the use of 5-HT₃RAs for the prevention of CINV in patients receiving chemotherapy, with the goal of comparing palonosetron with the other 5-HT₃RAs.     

Synthesis and pharmacological properties of novel benzamide derivatives acting as ligands to the 5-hydroxytryptamine 4 (5-HT4) receptor

Aseries of 4-amino-5-chloro-2-methoxy-N-(1-substituted piperidin-4-ylmethyl)benzamides was synthesized as novel gastroprokinetic agents. The affinity of these compounds for the 5-hydroxytryptamine 4 (5-HT₄) receptor was evaluated. Among these compounds, 4-amino-5-chloro-2-methoxy-N-[1-[5-(1-methylindol-3-ylcarbonylamino)pentyl]piperidin-4-ylmethyl]benzamide (3f, Y-34959) showed a higher affinity for the 5-HT₄ receptor (Ki = 0.30 nmol/L) than for other receptors, and was confirmed to be a potent 5-HT₄ receptor agonist having contractile effects in the isolated guinea-pig ascending colon (EC₅₀ = 1.2 nmol/L). In dogs, compound 3f increased gastroprokinetic motility of both the gastric antrum and the ascending colon. In addition, this effect on the colon was inhibited by azasetron, a selective 5-HT₃ receptor antagonist, demonstrating that the effect of gastroprokinetic agents having 5-HT₃ receptor antagonism on the colon were reduced compared with that of selective 5-HT₄ receptor agonists.