Effects of EMD 15,700 and disulfiram on ethanol intake in rats under schedule-induced polydipsia

Rats received 196 food pellets per day under a fixed-time 90-sec schedule with both 5% (w/v) ethanol and water freely available. More than 80% of the total daily fluid consumption was the 5% ethanol solution. Disulfiram, and a new aldehyde dehydrogenase inhibitor, EMD 15,700, both markedly decreased 5% ethanol intake and slightly increased water intake. These effects lasted for several days. The schedule-induced polydipsia model of ethanol consumption in rats appears to be sensitive to the effects of drugs that inhibit ethanol intake in man.     

Schedule-induced oral self administration of etonitazene.

Rats were induced to drink either a saline-etonitazene solution or a saline solution with a schedule-induced polydipsia paradigm. When water was freely available, the rats continued to drink the saline solution or the saline-etonitazene solution, rather than the water. When the locations of the solutions were switched, the rats that were drinking saline switched to water (drank at the usual location), but the rats that were drinking saline-etonitazene continued to drink the saline-etonitazene solution (drank from the bottle at the other location). Naloxone administration temporarily eliminated the drinking of saline-etonitazene solution, but not that of saline solution.     

Taste aversion learning and schedule-induced alcohol consumption in rats

Twelve hungry rats were exposed to the intermittent delivery of food with a 5% (v/v) ethanol solution freely available. All developed high levels of schedule-induced alcohol polydipsia within ten 1-hr sessions. Immediately following the eleventh session half of the animals received an intraperitoneal injection of lithium chloride (experimental group) and the other half received an injection of sodium chloride (control group). Their alcohol intakes did not differ during the twelfth session and so the treatments were repeated following the thirteenth session. During the fourteenth session, the experimental group drank very little alcohol compared to the control group, indicating that they had learned a taste-aversion to the alcohol in only two conditioning trials. These results extend previous work on the role of taste aversion in suppressing alcohol intake by demonstrating that the technique can be used to suppress schedule-induced alcohol polydipsia as well as thirst-motivated alcohol intake.     

Differential effects of pentylenetetrazol on REM sleep in naive and cobalt-epileptic rats

Spaced feeding of individual food pellets to food-deprived rats at 1-min intervals caused excessive drinking of 5 and 10% alcohol solutions, even though the solutions were available for only a 10-sec portion of each interval and even though the portion of availability occurred anywhere in the interval unpredictably from one interval to another. Thus schedule-induced ethanol polydipsia is not necessarily a post-reinforcement phenomenon.The diligent assistance of Marilyn Schwieder is gratefully acknowledged.     

Selective suppression of schedule-induced ethanol drinking by antialcoholic drugs in rats

Effects of disulfiram and calcium cyanamide, antialcoholic drugs, on schedule-induced ethanol drinking as well as on schedule-controlled response (lever-pressing) under a fixed interval 1 min schedule of food reinforcement were investigated in Wistar strain rats. When ethanol solution was available, the schedule-induced ethanol drinking decreased depending on the ethanol concentration (2-8%). However, the dose of ethanol intake during the 1 hr experimental session was at maximum (2.8 g/kg) when 4% ethanol solution was available. Thereafter, 4% ethanol solution was used in the experiment for studying the effects of disulfiram and calcium cyanamide on the schedule-induced ethanol drinking. Disulfiram (100-200 mg/kg, p.o.), pretreated at 1 hr before the start of the experiment, tended to suppress schedule-induced water drinking. However, the same treatment of calcium cyanamide (5-10 mg/kg, p.o.) did not produce a marked change in it. In contrast, disulfiram (100 and 200 mg/kg) and calcium cyanamide (5 and 10 mg/kg) markedly suppressed schedule-induced ethanol drinking without eliciting a marked change in schedule-controlled response. The present results suggest that both disulfiram and calcium cyanamide selectively suppress ethanol drinking in rats.     

Schedule-induced oral self-administration of cocaine and ethanol solutions: lack of effect of chronic desipramine

Groups of rats drinking either solutions of cocaine HCl (0.16 mg/ml), ethanol (2.5% v/v), or water, drank excessive, equivalent volumes in daily, 3-h sessions of food-pellet delivery under a fixed-time 1-min (FT 1-min) schedule. During single-session exposures to pellet-delivery schedules using longer inter-pellet values (FT 3- or 5-min probe sessions), the cocaine and ethanol groups, but not the water group, drank greater ml/pellet amounts, confirming previous research. Inasmuch as enhanced ml/pellet intake during the greater FT probes correlated with the abuse potential of the drinking solution in previous research, the effect of chronic desipramine HCl (2 mg/kg, i.p. daily) on this enhanced intake response was determined. For all groups, chronic desipramine treatment (2 mg/kg was judged to be the maximum dose free of non-specific, suppressive effects) affected neither FT 1-min schedule-induced polydipsia nor did it affect the enhanced ingestional response to the greater FT probes for the cocaine and ethanol groups. Chronic administration of desipramine may have therapeutic efficacy in treating cocaine abuse only in subjects attempting to refrain from cocaine who are aided in their passage through a withdrawal phase by desipramine.     

Ethanol dependence as a determinant of fluid preference

Rats made dependent on ethanol by a schedule-induced polydipsia procedure preferred 5% ethanol to an increasing concentration of dextrose solution to a greater extent than animals on a non-dependent, non-polydipsic procedure which allowed an equivalent opportunity to drink ethanol, confirming a previous study. Two corresponding groups of animals drinking isotonic (0.9%) NaCl rather than 5% ethanol behaved similarly to the latter group, changing to a dextrose preference at a lower dextrose concentration than the ethanol polydipsic group. Therefore, neither the intermittent food regimen (polydipsia-generating procedure) in itself, nor a history of isotonic saline polydipsia biased fluid preference against dextrose solution choices. The enhanced preference for ethanol over dextrose solutions shown by the ethanol polydipsic group can be attributed to physical dependence rather than regiment produced artifacts.     

Effects of acute and chronic administration of delta 9-tetrahy-drocannabinol or cocaine on ethanol intake in a rat model.

The acute and chronic administration of delta 9-tetrahydrocannabinol (delta 9-THC) or cocaine were studied in rats trained to obtain all of their daily food by lever pressing during four equally-spaced 30-min periods with water and 5% or 7.5% ethanol solutions freely available. With 5% ethanol available, rats consumed almost all of their daily fluid intake as ethanol, while with 7.5% ethanol available, rats consumed water and ethanol solution in approximately equal amounts. Rats consumed more food pellets with 7.5% ethanol available than with 5% ethanol available. Acute administration of delta 9-THC produced a dose-dependent decrease of 5% ethanol intake and food pellets consumed with a small increase in water intake, especially after the higher doses. Acute administration of delta 9-THC also depressed food intake when 7.5% ethanol was available, but decreases in ethanol solution intake were small. Chronic administration of delta 9-THC initially decreased ethanol intake, but tolerance occurred to this effect, so that during chronic delta 9-THC administration ethanol intake not only recovered, but increased above control levels. When the chronic administration of delta 9-THC was discontinued, ethanol intake was increased for 1 (5% ethanol) to 3 (7.5% ethanol) weeks. Animals with initially high, or initially low, but not with initially moderate ethanol intake, accounted for the increased ethanol intake during chronic delta 9-THC administration and withdrawal. Acute cocaine administration, at doses up to 30 mg/kg, had little effect on eating and drinking; however, during chronic cocaine administration, ethanol intake gradually increased, an increase which was sustained during cocaine withdrawal. The increased ethanol drinking was confined to the first 6-h period after cocaine administration. These data suggest that the chronic administration and withdrawal of other drugs can increase ethanol intake in this rat model.     

Effects of d-amphetamine, diazepam and buspirone on schedule-induced polydipsia suppressed by response-dependent and response-independent shock

Food deprived Wistar rats were exposed to a fixed time 60 s food schedule until they developed schedule-induced polydipsia. Rats were matched in pairs according to their licking rate, being designated experimental or yoked control at random. Every fifth lick by experimental rats was then followed by an electric shock (0.05, 0.1, or 0.2 mA) while the food schedule continued in operation. Yoked-control rats received the same shocks as experimental rats, but independently of their own licking. Drugs were then tested on the suppressed rates of licking. Diazepam (0.5-2.0 mg/kg) increased punished schedule-induced polydipsia, a result not observed in yoked controls. No increases in the licks per minute of experimental or control animals were found after d-amphetamine (0.25-4.0 mg/kg) or buspirone (0.5-8.0 mg/kg). In comparison with previous results it is concluded that the antipunishment effects of drugs on schedule-induced behaviour depend on the type of punishment contingency.     

Antipunishment effects of diazepam on two levels of suppression of schedule-induced drinking in rats

Food-deprived Wistar rats were exposed to a fixed-time (FT) 60-s food delivery schedule until they developed schedule-induced drinking. Rats were matched in pairs according to their licking rates and were designated master or yoked at random. Every fifth lick by master rats was followed by an electric shock during two signalled 5-min periods, which ran concurrently with the food delivery schedule. For the master rats, shock intensities were adjusted to reduce licking to 5-30% (low suppression) or 50-75% (high suppression) of the unpunished licking rates. Yoked rats received the same shocks as master rats, but independently of their own licking. The drinking by yoked animals was not decreased by the presentation of these lick-independent shocks. Diazepam (0.3-10.0 mg/kg) was studied for its effects on punished and nonpunished schedule-induced drinking. Intermediate doses of the drug increased the punished behavior of master rats, but only when schedule-induced drinking was highly suppressed. Diazepam dose dependently decreased licking rates in all other conditions. The antipunishment effects of benzodiazepines may depend on the level of suppression of schedule-induced drinking, and this is in keeping with the results of other experimental preparations where behavior was under aversive control.     

Ethanol withdrawal and discriminative motor control: effect of chronic intake level

Rats drinking a low concentration (2.5%) of ethanol in a chronic, schedule-induced polydipsia situation failed to show withdrawal signs as measured by a discriminative motor control task. When the concentration was raised to 5% ethanol, withdrawal signs were evident, confirming a previous study.     

The differential effects of naloxone hydrochloride on the acquisition and maintenance of schedule-induced polydipsia

Rats injected with the opiate antagonist, naloxone hydrochloride (10 mg/kg), 15 min prior to sessions in which they were given free food on a fixed time 75-sec schedule, displayed retarded acquisition of schedule-induced polydipsia relative to vehicle-injected subjects. Rats injected with naloxone after schedule-induced polydipsia had been acquired were unaffected, i.e., they continued to drink at control levels. Given that schedule-induced polydipsia has been considered non-opioid in nature, because of previous reports of its insensitivity to naloxone, the present report of differential effects of naloxone on the acquisition and maintenance of schedule-induced polydipsia suggests that some modification of this conclusion is necessary. Possible alternative mechanisms for these differential effects are discussed.     

Schedule-induced ethanol polydipsia: Function of ethanol concentration

Rats were maintained in cages with automatic food dispensers that provided a 24 hr feeding regimen known to produce schedule-induced ethanol polydipsia. For ten days water was the only available fluid; then for 17 days either 5% or 10% ethanol replaced water. The ethanol concentrations were then switched between groups for a final 13 days. Ethanol intake increased for both groups over the first seven days and then reached asymptote. The daily intake (ml) of 5% ethanol was two times that of 10%, resulting in no difference between groups in g/kg ethanol consumed. When the concentrations were switched, g/kg/day dropped, but returned to previous levels within seven days. Again intake (ml) of 5% was two times that of 10% but groups did not differ in g/kg/day. Mean blood ethanol concentration at 9:30 hr was 75.0 mg/100 ml with 5% ethanol and 127.8 mg/100 ml with 10% ethanol.     

Ethanol intakes and preferences in the desalivate rat

Desalivate and control rats were tested for ethanol versus water preference (5%, 10% and 20% (v/v) ethanol solutions). Each concentration of ethanol was presented for six days in an ascending, descending, or mixed presentation schedule. Following preference tests, intakes of first 10% (15 days), then 5% (15 days), and finally 10% (5 days) ethanol as the only available fluid were determined. Blood ethanol concentrations were measured (22:00 hr, 24:00 hr, 02:00 hr) during the final 10% ethanol intake test. Desalivate and control rats showed similar aversions to ethanol at all concentrations with relative ethanol intake being a negative function of concentration. During ethanol and water intake tests, desalivates drank significantly greater amounts (ml/100 g body weight) of all drinking fluids than controls. However, for both groups intake of 10% ethanol was reduced significantly from water baseline levels. Although desalivates consumed as much ethanol as controls, their blood ethanol concentrations at all times tested were slightly lower than controls. During the ethanol intake test desalivate rats lost body weight, while control rats gained body weight.     

Ethanol elimination rates in normal and ethanol dependent animals.

Ethanol elimination rates were determined in rats using an intravenous route of ethanol administration after several experimental manipulations. Twenty-four hr food deprivation resulted in a 30% reduction to 35 mg/100ml blood/hr in elimination rate from a non-deprived rate of 50 mg/100 ml blood/hr. After 2 months of ethanol drinking (5% v/v), 24 hr starvation resulted in only a 10% reduction in elimination rate (45 mg/100 ml blood/hr), and did not increase the non-food-deprived rate (49.2 mg/100 ml blood/hr) over that obtained in the above animals' drinking water rather than 5% ethanol. Animals which chronically overdrank ethanol or water for 3 months on a schedule-induced polydipsia procedure, known to result in ethanol physical dependence, showed a decreased rate of ethanol elimination (37.9 mg/100 ml blood/hr for water drinkers) in the non-food-deprived condition. By providing 750 mg of liver powder daily as a food supplement in the ethanol overdrinking regimen, the ethanol elimination rate remained at a rate comparable to the normal animal (48.4 mg/100 ml blood/hr).     

Midazolam oral self-administration

The technique of chronic schedule-induced drug solution intake was used to determine the possible addiction liability of the short-acting benzodiazepine midazolam. Schedule-induction produces polydipsia over a wide range of fluids as a function of the imposed schedule of food availability. The inducing schedule used presented food pellets automatically once per minute, fixed time (FT) 1-min, for 3 h daily. Two groups of rats, drinking either water or 0.05 mg/ml midazolam solution, were exposed to schedule-induction sessions for approx. 2 months. Then, other FT-values (0, 0.5, 3 and 5 min) were instituted on occasion for single sessions. Each of these 'probe' session determinations was done twice. Although midazolam concentration had been adjusted so that the mean group intakes were equal at FT 1-min, probe values greater than 1 min revealed a greater acceptance of midazolam compared to water. This technique produced session midazolam intakes as great as 25 mg/kg. In the next phase, the entire experiment was repeated except both groups were offered a choice between water and midazolam solution during sessions. Only at FT 0 and FT 5-min was there an indication that midazolam was preferred over water. Two additional groups of animals were exposed to the same schedule-induced polydipsia regimen, drinking water and midazolam solution, respectively. Pre-session administration of doses of Ro 15-1788, CGS 8216 (benzodiazepine antagonists) or midazolam had no effects on either water or midazolam intakes, although the higher dose of midazolam (2 mg/kg, s.c) had a moderately suppressive effect on the non-tolerant water-polydipsic group. All groups were tested on occasion for physical dependence on midazolam with an auditory stimulus as the precipitator and midazolam polydipsic groups were found to have a mild to moderate dependence (clonic seizures, running fits).     

Patterns of drinking in the rat following the administration of opiate antagonists

Durations of drinking were recorded for water-deprivated rats as they drank to satiety, following SC injections of naloxone (0.1–10.0 mg/kg), naltrexone (0.1–10.0 mg/kg) or saline vehicle. The results provided evidence for the effects of opiate antagonists on the temporal pattern of drinking exhibited by water-deprived animals. A separate, time-sampling procedure was used to supplement the drinking duration data, and showed that the opiate antagonists may suppress water consumption during a period 2.5–7.5 min after the start of the initial drinking bout. A second experiment confirmed that the pattern of drinking displayed during schedule-induced polydipsia in the rat is resistant to any suppressant effect of a moderate dose of an opiate antagonist. The similiarity between opiate receptor blockade and water preloading in their effect on drinking in response to water deprivation, and lack of effect on schedule-induced polydipsia is discussed. Opiate antagonists may affect drinking principally by imposing a thirst satiety signal.     

Control of polydipsic drinking by a taste aversion procedure

Rats were given daily sessions with free access to food and saccharin flavored water. After fluid consumption had stabilized food was delivered once every minute. Water was always available in the home cage. All rats showed the marked increase in fluid consumption known as schedule-induced polydipsia. The rats were then poisoned with lithium chloride after each of three sessions in an attempt to condition a taste aversion to the saccharin. On recovery from the toxicosis all rats showed first a reduction and then a recovery in saccharin intake. To establish the nature of this effect, the rats were poisoned after saccharin consumption in the home cage. Again there was a marked reduction in polydipsic drinking in the experimental chamber. These results indicate that common incentive mechanisms govern normal and polydipsic drinking and stand in contrast to published results pointing to different drive systems in the brain mediating normal and polydipsic drinking.     

Food,water and ethanol consumption by rats under a fixed-interval schedule of food presentation

Rats could lever press 24 hours a day for 97 mg food pellets under a fixed-interval (FI) 90 second schedule. During the first 4 days, an ethanol solution was the only available fluid, after which both water and ethanol solutions were available. At ethanol concentrations (w/v) of 5%, 7.5% and 10%, total caloric intake and total fluid intake remained constant, while ethanol consumption was inversely proportional to the concentration of the solution. When the FI 90 s schedule was changed to FI 45 s, or to FI 180 s, there were only small changes in total caloric intake, total fluid intake and in percentages of total fluid consumptipn and total caloric intake as ethanol. The data suggest that the intake of ethanol under this fixed-interval schedule depends more on the ethanol concentration than on the calories obtained from ethanol drinking.     

Behavioural and pharmacological specificity of the effects of drugs on punished schedule-induced polydipsia

Wistar rats were exposed to a multiple fixed-time 30-s food delivery schedule, with an on/off tone signalling the two components. Animals were matched in accordance with the levels of schedule-induced polydipsia. Drinking was then punished in one of the components: half of the rats received lick-dependent 10-s signalled delays and the other half lick-dependent electric shocks. The intensities of the shocks were adjusted to reduce behaviour by the same amount as the delays in food presentation. Unpunished components were used as yoked-control conditions, by presenting delays or shocks independently of the animals' behaviour. D-Amphetamine (0.3-2.0 mg/kg) and cocaine (1.0-10.0 mg/kg) dose-dependently increased (although only slightly) and then decreased schedule-induced polydipsia punished with lick-dependent delays in food presentation, a result not observed in control conditions or when the behaviour was suppressed by lick-dependent electric shocks. Diazepam (1.0-17.0 mg/kg) and pentobarbital (3.0-17.0 mg/kg) dose-dependently increased and then decreased only the schedule-induced drinking punished with lick-dependent shocks. Buspirone (0.1-1.0 mg/kg) and morphine (2.0-5.6 mg/kg) showed either no specific effects or further suppressed schedule-induced drinking. Results of these and previous experiments suggest that the antipunishment effects of drugs depend not only on the precise nature of the drug, but also on the manner in which the behaviour is maintained.