Pharmacotherapies for alcoholism: the old and the new.
ABSTRACT Alcoholism and other alcohol use disorders are major public health problems, and the success rates of non-pharmacological treatment of these disorders such as psychotherapy, cognitive-behavioral therapy, group therapy, or residential treatment programs,remain only modest at best. High rates of recidivism (relapse) in alcoholics attempting to remain abstinent are prevalent worldwide. In recent years abundant evidence has accumulated demonstrating that alcoholism is a complex and multifaceted disease of the brain caused by numerous genetic, neurobiological, developmental, environmental, and socioeconomic factors that are still not yet fully understood.There is thus a great need to improve the success rates of all forms of treatment of alcoholism not only in preventing relapse, but curbing active alcohol consumption and craving. The development of improved pharmacotherapies that could be used as adjuncts to the aforementioned non-pharmacological treatment approaches is one avenue of great interest to the scientific community and the general public. Currently there are only three medications approved by the U.S. Food and Drug Administration (FDA) for use in the treatment of alcohol abuse and alcoholism--disulfiram, naltrexone, and acamprosate. Yet medication compliance issues and the modest efficacy of these compounds leave substantial room for improvement. This special issue is devoted to reviewing the current status of these FDA approved medications in the treatment of alcoholism. In addition, preclinical and clinical evidence suggesting that other classes of medications might also be of potential use are reviewed, including anticonvulsants, GABAB receptor agonists, cholinergic receptor partial agonists, corticotropin-releasing factor and cannabinoid CB1 receptor antagonists, nociceptin receptor ligands, and the novel antipsychotic aripiprazole.
- [Show abstract] [Hide abstract]
ABSTRACT: Ethanol abuse can lead to addiction, brain damage and premature death. The cycle of alcohol addiction has been described as a composite consisting of three stages: intoxication, withdrawal and craving/abstinence. There is evidence for contributions of both genotype and sex to alcoholism, but an understanding of the biological underpinnings is limited. Utilizing both sexes of genetic animal models with highly divergent alcohol withdrawal severity, Withdrawal Seizure-Resistant (WSR) and Withdrawal Seizure-Prone (WSP) mice, the distinct contributions of genotype/phenotype and of sex during addiction stages on neuroadaptation were characterized. Transcriptional profiling was performed to identify expression changes as a consequence of chronic intoxication in the medial prefrontal cortex. Significant expression differences were identified on a single platform and tracked over a behaviorally-relevant time course that covered each stage of alcohol addiction; i.e., after chronic intoxication, during peak withdrawal, and after a defined period of abstinence. Females were more sensitive to ethanol with higher fold expression differences. Bioinformatics showed a strong effect of sex on the data structure of expression profiles during chronic intoxication and at peak withdrawal irrespective of genetic background. However, during abstinence, differences were observed instead between the lines/phenotypes irrespective of sex. Confirmation of identified pathways showed distinct inflammatory signaling following intoxication at peak withdrawal, with a pro-inflammatory phenotype in females but overall suppression of immune signaling in males. Combined, these results suggest that each stage of the addiction cycle is influenced differentially by sex vs. genetic background and support the development of stage- and sex-specific therapies for alcohol withdrawal and the maintenance of sobriety.Neuroscience 09/2014; · 3.33 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Taurine is one of the most abundant amino acids in the retina, throughout the CNS, and in heart and muscle cells. In keeping with its broad tissue distribution, taurine serves as a modulator of numerous basic processes, such as enzyme activity, cell development, myocardial function, and cytoprotection. Despite this multitude of functional roles, the precise mechanism underlying taurine's actions has not yet been identified. In this study we report findings that indicate a novel role for taurine in the regulation of voltage-gated delayed rectifier potassium (KV) channels in retinal neurons by means of a metabotropic receptor pathway. The metabotropic taurine response was insensitive to the Cl- channel blockers, picrotoxin and strychnine, but it was inhibited by a specific serotonin 5-HT2A receptor antagonist, MDL11939. Moreover, we found that taurine enhanced KV channels via intracellular PKC-mediated pathways. When 5-HT2A receptors were expressed in HEK cells, taurine and AL34662, a non-specific 5-HT2 receptor activator, produced a similar regulation of KIR channels. In sum, this study provides new evidence that taurine activates a serotonin system, apparently via 5-HT2A receptors and related intracellular pathways.The Journal of Physiology 10/2012; · 4.38 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Aripiprazole is an antipsychotic that acts as a partial agonist at dopamine receptors. Since the effects of most drugs of abuse converge to enhance dopamine-mediated neurotransmission, the present study was designed to test the hypothesis that aripiprazole would inhibit the acute effects of ethanol, a widely abused substance. Male Swiss mice received acute injections and were evaluated for motor activity in three distinct tests. In the open field, ethanol (1.5, 2.5 and 3.5 g/kg) induced an increase in locomotion in a U-shaped dose-related fashion, whereas aripiprazole (0.1, 1 and 10 mg/kg) did not affect this parameter. All the doses of the antipsychotic were able to prevent the stimulant effects of 2.5 g/kg of ethanol. In the rotarod test, ethanol (2.5 and 3.5 g/kg) reduced the latency to fall from the apparatus, an effect also observed with the higher dose of aripiprazole. Contrary to what was observed in the open field, this antipsychotic did not interfere with the effects of ethanol in motor balance. Finally, we tested animals in the wire hang test, in which ethanol, but not aripiprazole, reduced latency to fall at all doses. In this test, aripiprazole did not change ethanol effects. The present data lead to the conclusion that aripiprazole prevents the stimulant effects of ethanol on locomotion, without interfering with the motor impairment induced by this drug.Basic & Clinical Pharmacology & Toxicology 11/2012; · 2.18 Impact Factor