Research with rats germane to medication for alcoholism: consequences of noncompliance.

Results of prior work indicate that (a) rats take stable, toxic levels of ethanol when they receive a daily regimen of limited opportunities to take both water and sweetened ethanol solution and (b) the combination of isradipine plus naltrexone persistently reduces those intakes. What are the effects of periodically missing doses of isradipine, naltrexone, or both? That is, what are the effects of differing levels of compliance? To get relevant information, rats were placed on a daily regimen, leading them to take, by choice, large amounts of ethanol (>2.0 g of ethanol per kilogram of body weight during 2 h a day). After being on this regimen for more than 60 days and after 28 days of no opportunity to take ethanol, 55 rats were divided into five groups. The opportunity to drink was then reinstated. One group received placebos, and another group received the combination of isradipine plus naltrexone daily. The other three groups received doses periodically, thereby conforming to good, moderate, and poor compliance. After abstinence, the intakes for rats receiving placebos rapidly returned to high levels. Intakes for rats receiving daily isradipine plus naltrexone did not return to high levels. The intakes for the other three groups were intermediate to intakes of the reference groups, corresponding to frequency of medication. When medication was not given, intakes approached placebo control levels, but the combination of isradipine plus naltrexone was effective when given subsequently. Daily dosing clearly is effective in reducing intakes, and suspension of dosing leads to higher intakes. A missed day of dosing, however, has limited consequences, provided that administration of medication is resumed.

Amlodipine, a calcium channel inhibitor, and cocaine and ethanol's reinforcing effects.

The effects of amlodipine (from 0.1 to 3.0 mg/kg) on rats' pressing for rewarding brain stimulation, with and without cocaine administration, were assessed. None of the doses reliably modified the effects of cocaine. Also, amlodipine was given to two groups of rats taking alcohol: one group that was regularly taking a sweetened alcoholic beverage and the other taking an unsweetened alcoholic beverage. The only discernible effects of amlodipine on alcohol intake were associated with the highest dose and only with rats taking the sweetened beverage. The effects of this high dose could easily be attributable to behavioral toxicity elicited by the dose. In contrast, and confirming previous work, isradipine, another calcium channel inhibitor, produced reliable reductions on both cocaine's and alcohol's reinforcing effects. Despite the similarity of isradipine and amlodipine, isradipine apparently has some unique features with respect to cocaine and alcohol.

Responding for rewarding brain stimulation: cocaine and isradipine plus naltrexone.

Rats, fixed with chronically indwelling electrodes for electrical intracranial stimulation (ICS) of the lateral hypothalamus, were taught to press a bar for ICS. Once pressing rates became stable, during daily 20-min sessions, rats were given cocaine (5 or 20 mg/kg) before the sessions. When given daily, cocaine consistently enhanced rates of pressing. When a combination of small doses of isradipine (e.g., 1 mg/kg) and naltrexone (3 mg/kg) were given before cocaine administration. the combination blocked cocaine's enhancement of pressing for ICS. The combination, however, neither reduced rates of pressing below those observed under placebos (i.e., baseline conditions) nor reduced rates when no cocaine was given. Naltrexone and isradipine (in the dose used in the combination) by themselves did not block cocaine's effects. This profile of effects indicates that a combination of isradipine and naltrexone is apt to be useful in treating cocaine use disorders.

A combination of isradipine and naltrexone blocks cocaine's enhancement of a cocaine place preference.

Rats were conditioned by pairing cocaine with one side of an alley and placebo with the other. After conditioning, compared to Baseline and a placebo-control group, rats spent more time in the place of cocaine experience. Subsequently, there were further tests except now cocaine was given just before the test session in addition to one of two other kinds of injections. One of these additional injections was a placebo and the other was a combination of a small dose of isradipine (1 mg/kg) and a dose of naltrexone (3 mg/kg) (ISR + NTX). Measures of gross activity (movement from one side of the alley to the other) were taken during testing. ISR + NTX blocked cocaine's ability to sustain a place preference. ISR + NTX also blocked sensitization of cocaine's ability to enhance locomotor activity. This blockade of cocaine's usual effects indicates that ISR + NTX may have a role in treating cocaine use disorders.

Isradipine combined with naltrexone persistently reduces the reward-relevant effects of cocaine and alcohol.

Previous studies have revealed that the combination of small doses of isradipine and naltrexone (ISR&NTX) blocks the ability of cocaine to enhance pressing for rewarding, lateral hypothalamic brain stimulation. Further, such combinations also reduce rats' intakes of alcoholic beverages. Here, we asked whether ISR&NTX would lose its ability to reduce the reinforcing effects of cocaine and alcohol when given daily. Specifically, after almost 2 months of daily injections, ISR&NTX blocked the expression of a cocaine-induced conditioned place preference (CPP). By themselves, ISR and NTX were not effective at blocking cocaine's effects. Subsequent to the CPP procedures, the rats continued to receive daily injections for another 3 weeks. During this time, they were given access to water and an alcoholic beverage for 2 h a day. As expected, placebo controls gradually increased their daily intakes until they were taking about 2 g/kg of ethanol daily. ISR, NTX, and ISR&NTX blocked the typical pattern of intakes. At the end of the 3-week period, the rats had received 80 consecutive daily injections. The data suggest that the salient effects of ISR&NTX do not wane. The data support the idea that ISR&NTX would be a useful pharmacotherapy for poly drug abuse.

CGS 10746B, a novel dopamine release inhibitor, blocks the establishment of cocaine and MDMA conditioned place preferences.

Cocaine and methylenedioxymethamphetamine (MDMA), two drugs self-administered by humans and laboratory animals, have previously been shown to produce conditioned place preferences (CPPs) among rats, an index of drug-reward relevant events. Both of these agents increase functional levels of dopamine that may be critical to their rewarding properties. Here, the effects of doses of CGS 10746B, an agent reported to attenuate the release of dopamine without occupying dopamine receptors, are assessed on cocaine and MDMA's ability to produce a CPP. CGS 10746B dose dependently blocked the establishment of a MDMA CPP. A 30 mg/kg dose of CGS 10746B, which completely blocked the MDMA CPP, also blocked the establishment of a cocaine CPP. Release of dopamine appears critical to the ability of these agents to establish a CPP.

Valproate reduces intake of alcoholic beverage among rats.

A series of experiments was carried out to assess the effects of valproate (VAL) on the intake of ethanol by rats. In Experiment 1, the effects of VAL (150 and 200 mg/kg, i.p.) were assessed across 10 days. Compared with controls, the 200 mg/kg dose reliably reduced intake of ethanol while also reliably increasing intake of water. The 150 mg/kg dose did not reliably reduce the intake of ethanol across the initial days, but it did across later days. Neither dose affected the total intake of fluids. Similarly, 5 days of oral dosing with VAL (400 and 600 mg/kg) reliably reduced the intake of ethanol without affecting the intake of water. However, body weights were reduced by the oral doses across the procedure. In another procedure, VAL (200 mg/kg, i.p.) produced a mild conditioned taste aversion to a saccharin solution, suggesting that VAL may reduce intake of ethanol because it produces a general malaise. However, this dose of VAL enhanced the intoxicating effects of ethanol (2.0 g/kg). Overall, the results are equivocal with respect to VAL as a potential medicine for treating alcohol misuse and alcoholism.

Combination of naltrexone and fluoxetine on rats' propensity to take alcoholic beverage.

Naltrexone (NTX) and fluoxetine (FLU) are useful for treating alcoholism and depression, respectively. Furthermore, these afflictions covary. Given the possibility that people might be prescribed NTX and FLU concurrently, we assessed the effects of these two agents on rats' propensity to drink an alcoholic beverage. Rats were given 65 days of access to a sweetened alcoholic beverage and water for 2 hr daily. At first, they took little ethanol, but after 20 days, they took on average 2.0 to 2.5 g/kg of ethanol, daily during the 2-hr session. They also took sufficient water to maintain their health. After 30 days, they were divided into four groups to receive, 30 min before the drinking session, 1 of 4 different kinds of injections. For the next 20 days, one group received placebo daily. Another group received 5 mg/kg of NTX daily and another 5 mg/kg of FLU daily. The fourth group received both 5 mg/kg of NTX and 5 mg/kg of FLU daily. After 20 days, the doses of NTX and FLU were doubled across an additional 10 days. Both NTX and FLU reduced rats' intake of alcoholic beverage. The combinations of NTX and FLU, however, were no more effective in reducing rats' intake of alcoholic beverage than either alone. Also, the small dose of NTX seemed to lose its effectiveness with repeated administrations. A second experiment confirmed the conclusion that small doses of NTX lose their effectiveness in suppressing intake of alcoholic beverage across repeated administrations. In summary, data provide no support for the idea that FLU and NTX would act synergistically to reduce propensity to take alcoholic beverages.

Isradipine in combination with naltrexone as a medicine for treating cocaine abuse.

Rats were fixed with chronically indwelling electrodes for intracranial stimulation (ICS) of the medial forebrain bundle of the lateral hypothalamus. They were trained to press a bar in a Skinner box for the ICS. After stable rates of pressing for both a low and a high intensity of ICS were achieved during daily sessions, the rats were given doses of cocaine before the daily sessions. Cocaine produced its characteristic effect of enhancing rates of pressing. With continuance of daily sessions under the influence of cocaine, the rats received daily for 5 days a combination of isradipine and naltrexone. Doses of isradipine and naltrexone were smaller than a dose of either one that might modify pressing. The combination of isradipine and naltrexone blocked cocaine's enhancement of pressing for ICS. The same combination of isradipine and naltrexone did not reduce rates of pressing for ICS when cocaine was not given. These results indicate that a combination of isradipine and naltrexone is apt to be an effective pharmacological adjunct to other treatments for cocaine abuse.

Isradipine blocks cocaine's ability to facilitate pressing for intracranial stimulation.

Using rats pressing for rewarding electrical intracranial stimulation of the medial forebrain bundle, it was found that a single administration of isradipine blocked the rate-enhancing effects of cocaine (5.0 mg/kg) at doses of 3.0 and 10.0 mg/kg. Also, when isradipine (3.0 mg/kg) was administered alone (without cocaine) for 5 consecutive days, pressing for intracranial stimulation was not reduced relative to placebo levels. In another experiment, isradipine (3.0 mg/kg) persistently blocked the rate-enhancing effects of cocaine (5.0 mg/kg) across 5 consecutive days. These results support the continued investigation of isradipine as a useful adjunct to other treatments for cocaine addiction.

Isradipine and naltrexone in combination with isradipine interact with a period of abstinence to reduce rats' intakes of an alcoholic beverage.

Individually housed rats were placed on a daily regimen of only 2 hr a day to drink both water and a sweetened alcoholic beverage. Initially, rats took little ethanol, but after 3 weeks, they took, on average, >2.0 g/kg daily. With achievement of stable intakes, the rats were deprived of opportunity to drink ethanol for 24 days and then the daily regimen was reinstated. With the reinstatement, various injections were given daily for 25 days or more: placebos, doses of isradipine (1.0 or 3.0 mg/kg), naltrexone (3.0 mg/kg), and a combination of isradipine (1.0 mg/kg) and naltrexone (3.0 mg/kg). The combination produced favorable effects with the fewest limiting side-effects. The period of abstinence decreased daily intakes of ethanol and interacted with the drugs to produce large, sustained decreases in intakes of ethanol.

Periodic naltrexone and propensity to take alcoholic beverage.

For over 2 months, 45 rats were maintained on a daily regimen involving 2 hr a day of access to both water and palatable alcoholic beverage. At first, they took little ethanol. As days progressed, they eventually took over 2 g/kg of ethanol during the 2 hr. Previous research indicates that, without intervention, they would maintain this level of intake indefinitely. All rats were taken off the daily regimen for 30 days and then returned to it, i.e., rats received 30 days of "abstinence". For 35 days following abstinence, one-third of the subjects received placebos daily, one-third received naltrexone (NTX), 10 mg/kg, daily, and the one-third received NTX on days 1-5, 11-15, 21-25, and 31-35 and placebos on the other days. Abstinence reduced all rats' intakes of alcohol compared with pre-abstinence levels. Rats that received only placebos quickly returned to taking alcohol at pre-abstinence levels. Rats that received NTX daily increased their intakes up to the level normally expected for receiving NTX and no abstinence. Because rats receiving daily NTX always drank a fraction of the alcohol consumed by those receiving placebos, NTX's effects did not diminish. As rats sampled alcoholic beverage, however, the effects of abstinence did diminish. The rats of periodic NTX drank as rats getting NTX when they were given NTX and as rats getting placebos when they were given placebos. Furthermore, the rats of periodic NTX showed no carry-over effects from periods of NTX to no NTX. Abstinence and NTX together, apparently, reduce propensity to take alcoholic beverage more than either alone.

Naltrexone persistently reduces rats' intake of a palatable alcoholic beverage.

Rats were given 30 days of opportunity to take a sweetened alcoholic beverage and water for 2 hr/day. At first, they took little alcohol, but subsequently took, on average, 2.3 g/kg of alcohol/daily session. They also took sufficient water, during the 2-hr period, to maintain their health and to steadily gain weight. At the end of the 30 days, they were divided into four groups so that their intakes of alcohol were similar. All groups continued on the daily regimen, but each group received different injections. One group received placebos, whereas the other two groups received either 5.0 or 10.0 mg/kg, respectively, of naltrexone daily, 30 min before the drinking session. The fourth group received 5.0 mg/kg of naltrexone 12.5 hr before the session and another 5.0 mg/kg 30 min before the session. This regimen of dosing and daily opportunities to drink continued for 30 days. With the end of injections, subjects continued on the regimen for another 5 days. Naltrexone, dose-relatedly, reduced rats' intake of alcoholic beverage. Furthermore, with respect to reducing intake of alcohol, no tolerance or refractoriness were observed across the 30 days of dosing. Within a couple of days after dosing, levels of intake returned to predosing levels.

Naltrindole, a delta-opioid antagonist, blocks MDMA's ability to enhance pressing for rewarding brain stimulation.

Twelve rats were each fixed with a chronically indwelling bipolar electrode for stimulation of the medial forebrain bundle as it courses through the hypothalamus. These rats were trained to press a bar for intracranial stimulation of 0.3-s trains of 60 Hz sine waves for 10 min daily at three intensities. One intensity was just above threshold for maintaining pressing, one intensity was a high intensity that sustained considerable pressing, but not maximum pressing, and the other was intermediate to the others. After stable rates of pressing were obtained, rats received MDMA daily. MDMA significantly increased rates of pressing. Prior to a day when rats received MDMA, they also received an injection of naltrindole, a selective delta-opioid receptor antagonist. Naltrindole blocked MDMA's enhancement of pressing for reinforcing brain stimulation.

Endogenous opioids and alcohol dependence: opioid alkaloids and the propensity to drink alcoholic beverages.

Rats consume alcoholic beverages in a wide variety of circumstances. Opioid antagonists, naloxone and naltrexone, decrease intake of many ingesta, including alcoholic beverages. Small doses of morphine increase intake of alcoholic beverages. Further, the effects of small doses of morphine are persistent and there is no sign that tolerance to morphine's ability to increase alcohol intake develops as seen with morphine's ability to produce analgesia. Morphine's effects can combine with other variables that enhance intake of alcoholic beverages to produce very large daily intakes of ethanol. These generalizations, from a large number of separate experiments, support the conclusion that alcoholism is a special case of an ingestive disorder involving opioidergic systems.

Cocaine self-administration and naltrindole, a delta-selective opioid antagonist.

Recent reports from several laboratories have suggested a role for delta opioid receptors in expressing some of the biochemical and behavioral effects of cocaine. Here, this possibility has been further explored by evaluating the propensity of rats to self-administer i.v. cocaine in the absence or presence of naltrindole, a selective delta opioid antagonist. Following a number of days of stable cocaine intake, and before a day's session, naltrindole (3 or 10 mg kg-1) reduced pressing for cocaine, regardless of the schedule of reinforcement. These data further support the role of processes associated with delta opioid receptors in the ability of cocaine to reinforce its own use.

alpha(2)-Adrenoceptor antagonists and propensity to take alcoholic beverages.

Rats were maintained on a daily regimen involving a 2h opportunity to take both water and a sweetened alcoholic beverage (12% ethanol, 0.25% saccharin). After 3 weeks on this regimen, rats regularly take substantial amounts of alcohol. After stabilization, injections of alpha(2)-adrenergic antagonists were administered, 15min before the opportunity to drink. Yohimbine and methoxyidazoxan dose relatedly decreased intake of alcoholic beverage and increased intake of water. In Experiment 2, a number of rats were taken off the daily regimen for 9 days, then returned to it. Across the first 12 days of the reinstated daily regimen, half the rats received placebo and half methoxyidazoxan. The group receiving placebo rapidly returned to taking large amounts of alcoholic beverage while the group receiving methoxyidazoxan did not. In Experiment 3, it was shown that a dose of methoxyidazoxan that decreased intakes of alcoholic beverage did not decrease intakes of other palatable beverages. In Experiment 4, it was shown that yohimbine persistently reduced intakes of alcoholic beverage with daily administration. These results indicate that alpha(2)-antagonists might be effective pharmaceutical adjuncts to other treatments for alcohol abuse and alcoholism.

An assessment of the addiction potential of the opioid associated with milk.

Eighty-four male rats were tested to determine their preference for one of two distinctive places in an experimental space. After an initial determination of place preference, rats were assigned to six groups. They were then subjected to procedures to condition a place preference using doses of beta-casomorphin, a standard dose of morphine, or placebo. Subsequently, rats were tested for place preferences. No evidence emerged indicating that injections of beta-casomorphin conditioned a place preference, but evidence indicated that morphine conditioned a place preference. Consequently, systemically administered beta-casomorphin has very limited or no reinforcing properties similar to those of morphine. Ingestion of milk products containing beta-casomorphin is not likely to become the focus of an addiction.

A small dose of morphine leads rats to drink more alcohol and achieve higher blood alcohol concentrations.

Male Sprague-Dawley rats were maintained on a daily regimen of 22 hr of fluid deprivation followed by a 2-hr opportunity to take a sweetened alcoholic beverage and water for over 6 months. During the week before the formal procedures of the experiment described herein, access to the alcoholic beverage was limited to 1.5 hr, but access to water was still for 2 hr. Intakes of ethanol, in terms of g/kg, were tabulated at 30 min for half of the rats and at 90 min for the rest. On the day of formal procedures, half of the rats of the 30- and 90-min measures were given 1 mg/kg of morphine sulfate just before the drinking session, whereas the rest received physiological saline. Morphine increased mean g/kg intakes of ethanol, as compared with controls, at 30 and 90 min. Blood alcohol levels were also increased. These data suggest that the well-documented ability of small doses of morphine to increase rats' intake of ethanol is probably not related to its ability to produce gastrointestinal effects, but rather due to its ability to modulate central motivational mechanisms associated with ingestion.