Michael F. Stromberg

A Comparison of the Effects of the Opioid Antagonists Naltrexone, Naltrindole, and β-Funaltrexamine on Ethanol Consumption in the Rat

The effects of the universal opioid antagonist naltrexone were compared to the delta-selective opioid antagonist naltrindole and the mu-selective opioid antagonist beta-funaltrexamine on ethanol consumption in the absence of food or fluid deprivation using a limited access procedure in Wistar rats. Both naltrexone, at doses of 0.1, 0.25, 0.5, 1.0, 3.0, and 10 mg/kg, and beta-funaltrexamine, at doses of 5.0 and 20.0 mg/kg, significantly decreased consumption of a 6% ethanol solution compared to saline control groups. Naltrindole, at doses of 5.0 and 15.0 mg/kg, failed to significantly reduce ethanol consumption. In addition, the highest doses of naltrexone, which antagonize delta as well as mu-opioid receptors, did not differ significantly from the lowest doses in their ability to reduce ethanol consumption. These data suggest that ethanol consumption using the limited access paradigm in the outbred rat is modulated by mu rather than delta-opioid receptors. Although this is not consistent with other data showing that delta antagonists decrease ethanol consumption, it is suggested that these difference may be related to the alcohol-preferring rats used in those experiments.

Effect of acamprosate and naltrexone, alone or in combination, on ethanol consumption

Both acamprosate and naltrexone have demonstrated clinical utility in reducing relapse to alcohol use in recovering alcoholics. The present experiments examined the effects of acamprosate and naltrexone, either alone or in combination, on basal ethanol consumption in a limited-access model with the use of outbred Wistar rats. Naltrexone, 0.1 mg/kg, significantly reduced ethanol consumption as previously reported. Acamprosate, 50 mg/kg, did not significantly reduce ethanol consumption when administered alone and provided no evidence of additive or synergistic effects when combined with naltrexone. Acamprosate, 200 mg/kg, produced a modest reduction in ethanol consumption when administered alone but no evidence of additive or synergistic effects when combined with naltrexone. From these findings, it is suggested that a combination approach of these drugs may not be any more effective than monotherapy.

The effect of gamma-vinyl-GABA on the consumption of concurrently available oral cocaine and ethanol in the rat.

It has frequently been reported that a high percentage of individuals, identified as either alcohol- or cocaine-dependent, concurrently abuse both drugs. The experiments reported here represent a continuing effort to develop an animal model to predict the effects of a potential pharmacotherapeutic agent on concurrently available oral ethanol and cocaine. These experiments utilized drinkometer circuitry to assess the effects of gamma-vinyl-GABA (GVG), a gamma-aminobutyric acid (GABA) transaminase inhibitor, on the consumption and temporal pattern of responses for orally self-administered ethanol and cocaine. The results of these experiments showed that GVG, at doses of 100, 200 and 300 mg/kg, reduced both ethanol and cocaine consumption in a dose-related manner. When compared to vehicle, GVG at all doses significantly reduced ethanol consumption while consumption of cocaine was significantly reduced only at 300 mg/kg. This is consistent with data showing that GVG reduces consumption of these drugs when administered alone and data showing that GVG is more potent in reducing ethanol-induced compared to cocaine-induced extracellular dopamine in the nucleus accumbens. Analysis of the temporal pattern of drinking across the session suggests that GVGs effects are due to a disruption of the reinforcing properties of ethanol and cocaine rather than a more general reduction in motor behavior. These data suggest that GVG has potential for clinical use in populations that abuse either alcohol or cocaine alone or in combination.

The effect of baclofen alone and in combination with naltrexone on ethanol consumption in the rat

Naltrexone has been evaluated in preclinical animal models of ethanol consumption and found to be effective in most reports. In clinical use, naltrexone has not proved to be as efficacious in preventing relapse. While naltrexone targets opioid receptors, many other neurotransmitter systems are targeted by ethanol and, to a greater or lesser extent, contribute to modulating ethanols reinforcing effects. There has been indication that drugs active at the gamma amino butyric acid B (GABAB) receptors can affect the self-administration of many drugs with abuse potential. The experiments reported here evaluated the effect of three doses of baclofen (2.5, 5.0, or 7.5 mg/kg), a GABAB agonist, administered alone or in combination with a single dose of naltrexone (1.0 mg/kg). In Experiment 1, both naltrexone and baclofen, at the two higher doses tested, significantly reduced ethanol consumption in Wistar rats using a limited access procedure on Drug Days 1 and 2. When combined on Drug Days 3 and 4, baclofen/naltrexone was significantly more effective in reducing ethanol consumption than did either drug alone. Neither drug, alone or in combination, had an effect on water consumption. In Experiment 2, both baclofen and naltrexone again significantly reduced ethanol consumption, with no evidence that chronic administration across Drug Days 3 and 4 further reduced consumption compared with Drug Days 1 and 2. The clinical use of multiple pharmacotherapeutic agents in combination may allow for the use of lower doses of individual components, thereby reducing the negative side effects that contribute to lower compliance and higher relapse.

A comparison of the effects of 6-β naltrexol and naltrexone on the consumption of ethanol or sucrose using a limited-access procedure in rats

We recently reported that 6-beta naltrexol, the major metabolite of naltrexone in humans, reduced ethanol consumption in rats. Two new experiments were designed to compare 6-beta naltrexol and naltrexone across three dose levels on an ethanol or sucrose baseline using a limited-access procedure in Wistar rats. The results of Experiment 1 showed that both 6-beta naltrexol and naltrexone reduced ethanol consumption across a range of doses. An in vivo assay showed that naltrexone was approximately 25 times more potent than 6-beta naltrexol at comparable ED50 doses. In addition, there was no indication of systematic development of tolerance to the effect of either drug across the 4 days of drug administration. In Experiment 2, both 6-beta naltrexol and naltrexone reduced the consumption of a sucrose solution using a limited-access procedure. The implications of these data for the development of pharmacotherapeutic agents capable of reducing drinking in recovering alcoholics are discussed.

Effect of naltrexone on oral consumption of concurrently available ethanol and cocaine in the rat

Comorbid abuse of and dependency on multiple drugs is a common occurrence clinically. We have developed an animal model that provides rats with the opportunity to choose, through oral consumption, between concurrently available ethanol and cocaine with water also available. This provides the ability to screen for the effectiveness of potential pharmacotherapeutic agents on the baseline consumption of both drugs. We used this animal model to evaluate the effects of naltrexone, at doses of 0, 1.0, 3.0, and 10.0 mg/kg, on concurrent oral consumption of ethanol and cocaine solutions. Naltrexone at all doses significantly reduced both consumption of and preference for ethanol. Consumption of both cocaine and water was unaffected by naltrexone, supporting the suggestion that the effects of naltrexone were selective for ethanol. These findings support the suggestion that ethanol and cocaine act on different central reward pathways. The implications of these findings for the clinical use of naltrexone in populations with comorbid ethanol and cocaine abuse are discussed.

The effect of antagonists selective for μ- and δ-opioid receptor subtypes on alcohol consumption in C57BL/6 mice

Abstract Several studies have demonstrated that non-selective opioid receptor antagonists effectively reduce alcohol consumption in both animal models and at the clinical level. However, research examining the contribution of specific opioid receptor subtypes to this effect has yielded conflicting results. Some of these studies have shown that the effect is contingent upon the action of μ receptors while others have suggested that δ receptors are primarily responsible. The data reported here re-examine this question using the alcohol-preferring C57BL/6 mice. The results of this experiment demonstrate that d-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH 2 (CTOP), a μ-selective antagonist, and naltrindole, a δ-selective antagonist, are equally effective at reducing alcohol consumption in a limited access model compared to a saline control group. While there was no specific comparison of the effects of these drugs on alternative appetitive behavior, neither of these drugs had effects on measured off-session food or water consumption. The results of this experiment suggest that alcohol consumption is mediated by both μ- and δ-opioid receptor subtypes.

Effect of the combination of naltrexone and acamprosate on alcohol intake in mice.

Abstract  Both naltrexone and acamprosate have been utilized clinically in recovering alcoholics with varying success. In the experiment reported here the combination of naltrexone and acamprosate was examined in a limited access alcohol model using C57BL/6 mice to determine if there was evidence of additive or synergistic effects. The results of this experiment demonstrate that naltrexone, at the higher dose but not the lower dose, significantly reduced alcohol consumption. When combined with naltrexone, acamprosate reduced alcohol consumption across both doses of naltrexone. This effect was sensitive to both dose and number of days of exposure to the naltrexone/acamprosate combination.

Morphine Enhances Selection of Both Sucrose and Ethanol in a Two-Bottle Test

The influence of a low dose of morphine on the self-selection of alcohol and sucrose solutions is investigated. When given a choice between sucrose sweetened ethanol and plain water, rats show a significant preference for the sweetened ethanol. However, when given a choice between sweetened ethanol and sweetened water, rats increase consumption of sweetened water. These results suggest that the low-dose morphine enhancement of sweetened alcohol solutions is mediated by the reinforcing properties of sucrose not ethanol. However, when rats receive small doses of morphine and a choice between unsweetened ethanol and water, the rats increase consumption of ethanol. Therefore, a low dose of morphine enhances the self-selection of both sucrose and ethanol solutions. This provides additional confirmation that opioids may enhance the rewarding properties of a variety of appetite reinforcers.

Low dose of morphine and the consumption of a sweetened ethanol solution: Differential effects on acquisition and maintenance

The influence of a low dose of morphine was investigated on the acquisition and maintenance of consumption of a sweetened ethanol solution with water as the alternative in a two-bottle choice procedure. During acquisition in Experiment 1, morphine failed to significantly increase the consumption of a sweetened ethanol solution compared to either a postinjection period in the same animals or a no-treatment control group. Although morphine significantly increased sweetened ethanol consumption when compared to a saline control group, this appears to be due to a stress response to the injections, which suppressed ethanol consumption in the saline animals. During maintenance in Experiment 2, morphine significantly increased consumption of sweetened ethanol in all groups compared to consumption following saline control injections. There was no difference in this effect among the three groups, suggesting that prior history with morphine was not a factor. In addition, rats that were exposed to morphine during both experiments drank significantly more sweetened ethanol following injections in Experiment 2 than in Experiment 1. This suggests that morphines potentiation of ethanol consumption is due to its interaction with endogenous opioid receptors that modulate the reward value of ethanol rather than more general mechanisms affecting satiety or taste. The results of these experiments provide support for both the Deficit and Surfeit Hypotheses of ethanol consumption, both of which suggest that endogenous opioid receptors are responsible, in part, for ethanols reinforcing properties.