Combination Pharmacotherapy: A Mixture of Small Doses of Naltrexone, Fluoxetine, and a Thyrotropin-Releasing Hormone Analogue Reduces Alcohol Intake in Three Strains of Alcohol-Preferring Rats

Abstract

It is common to treat some diseases with more than one medication simultaneously. Since more than one neurotransmitter system is involved in alcohol-seeking behaviour, then a therapeutic approach that targets more than one system should be more effective in reducing alcohol intake than one addressing a single system. To test this hypothesis, we compared the efficacy of low doses of individual drugs reported to reduce voluntary alcohol drinking to the efficacy of a mixture of these agents at the same low doses in reducing alcohol intake in three strains of alcohol-preferring rats (P, HAD, and Fawn-Hooded). After establishment of a stable baseline for alcohol intake in a continuous access paradigm, each rat received separate single i.p. injections of relatively low doses of either naltrexone (2.0 mg/kg), fluoxetine (1.0 mg/kg), the thyrotropin-releasing hormone analogue TA-0910 (0.2 mg/kg), a mixture of all three drugs, or the vehicle at 09:30. Each rat received all treatments, with an inter-injection washout period of at least 3 days. Alcohol and water intakes were measured at 6 and 24 h, and food intake was measured at 24 h, after the injection. Our results show that individual drugs did not significantly affect food, water, or alcohol intake. However, the mixture significantly reduced alcohol intake in all three strains, but had no effect on food intake. Similar results were obtained when the HAD rats received an oral dose of the individual drugs or the mixture. When P rats were given an i.p. injection of the mixture for 10 consecutive days, there was a continued suppressing effect. These findings show that a combination treatment designed to target simultaneously serotonergic, dopaminergic, and opioidergic systems can reduce alcohol intake, even though the doses of the individual drugs in the mixture are relatively low and ineffective when given singly.

Neonatal 6-hydroxydopamine lesions of the frontal cortex in rats: Persisting effects on locomotor activity, learning and nicotine self-administration

“…Evidence from both laboratory animals and human studies implicates dopamine as one of the major neurotransmitter being involved in drug self-administration and addiction (Piazza et al, 1991, Rezvani et al, 1992, Mason et al, 1997, Di Chiara, 1999, Volkow et al, 1999, Rezvani et al, 2000, Goldstein and Volkow, 2002, Volkow et al, 2002b, Kalivas and Volkow, 2005, Nader and Czoty, 2005. In addition to the mesolimbic dopaminergic system, several other neurotransmitter systems including the serotonergic system have been suggested to be involved in drug self-administration (Rezvani et al, 1990, Rezvani and Grady, 1994, Volkow and Li, 2004, Koob, 2000.…”

JNJ-39220675, a novel selective histamine H3 receptor antagonist, reduces the abuse-related effects of alcohol in rats

“…This particular strain of alcohol-drinking rat has been characterized and widely used to study the effects of different compounds on voluntary alcohol consumption (Overstreet et al 1999). Alcohol intake was determined using the standard two-bottle choice method as previously described (Rezvani et al 2007(Rezvani et al , 2000(Rezvani et al , 2009(Rezvani et al , 2010. Briefly, after establishment of a reliable baseline for alcohol and water intake, rats were administered systemically (subcutaneously) in the morning (10:00 am) either with the vehicle (20% (w/v) cyclodextrin), or one of the three doses of JNJ-39220675 (0.3, 3, and 10 mg/kg) or naltrexone (as a positive control, 5 mg/kg, s.c.).…”

Advances in the Use of Naltrexone an Integration of Preclinical and Clinical Findings

“…Hence, it is not surprising that preclinical studies are investigating whether combining opioid receptor antagonists with agents that alter activity within the 5-HT and glutamate systems enhances suppression of alcohol intake. It has been found that fluoxetine, a selective serotonin reuptake inhibitor (SSRI) widely prescribed for depression, decreases alcohol drinking in rodents (for a review, see Le et al, 1999) and, when combined with naloxone or naltrexone, is reportedly more effective than either agent alone in reducing alcohol intake (Rezvani et al, 2000;Zink, Rohrbach, & Froehlich, 1999), although increased efficacy is not always seen (Gardell et al, 1997). Preliminary clinical studies combining naltrexone and sertraline (Farren, Catapano, & O'Malley, 1997) and the 5-HT3 antagonist, ondansetron (Johnson, Ait-Daoud, & Prihoda, 2000), have shown promising results for drinkingrelated outcomes and are being followed up with larger randomized clinical trials.…”