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Enquist J.,Ernest Gallo Clinic and Research Center | Ferwerda M.,Ernest Gallo Clinic and Research Center | Madhavan A.,Ernest Gallo Clinic and Research Center | Hok D.,Ernest Gallo Clinic and Research Center | And 2 more authors.
Neuropsychopharmacology | Year: 2012

Alleviating anxiety and depression is pivotal for reducing the risk of relapse in alcoholics. Currently available anxiolytic treatments are limited by side effects, including reduced efficacy in alcoholics, addiction, and sedation. We examined whether the neuropeptide S receptor (NPSR) was effective at controlling ethanol consumption and the anxiety and depression produced by forced abstinence from ethanol. We found that the anxiolytic and anti-depressant effects of NPS are enhanced in acute ethanol abstinent mice. In addition, we found that NPS reduced ethanol consumption and is not in and of itself rewarding. We also provide evidence that ethanol consumption increases the ability of NPS to modulate neuronal activity in the basolateral amygdala. Finally, we found that local injection of NPS in the basolateral amygdala promotes anxiolysis after chronic ethanol consumption, thereby providing insight into the molecular mechanism underlying the changes in behavioral response to NPS. In light of the improved anxiolytic efficacy and benign side effects of NPS in ethanol-withdrawn animals, the NPSR may prove a suitable target for reducing relapse in alcoholism. © 2012 American College of Neuropsychopharmacology. All rights reserved. Source

Joslyn G.,Ernest Gallo Clinic and Research Center | Ravindranathan A.,Ernest Gallo Clinic and Research Center | Brush G.,Ernest Gallo Clinic and Research Center | Schuckit M.,University of California at San Diego | White R.L.,University of California at San Francisco
Alcoholism: Clinical and Experimental Research | Year: 2010

Background: Alcohol use disorders (AUD) exhibit the properties shared by common conditions and diseases classified as genetically complex. The etiology of AUDs is heterogeneous involving mostly unknown interactions of environmental and heritable factors. A person's level of response (LR) to alcohol is inversely correlated with a family history and the development of AUDs. As an AUD endophenotype, alcohol LR is hypothesized to be less genetically complex and closer to the primary etiology of AUDs. Methods: A genome wide association study (GWAS) was performed on subjects characterized for alcohol LR phenotypes. Gene Set Enrichment Analysis (GSEA) of the GWAS data was performed to determine whether, as a group, genes that participate in a common biological function (a gene set) demonstrate greater genetic association than would be randomly expected. Results: The GSEA analysis implicated variation in neuronal signaling genes, especially glutamate signaling, as being involved in alcohol LR variability in the human population. Conclusions: These data, coupled with cell and animal model data implicating neuronal signaling in alcohol response, support the conclusion that neuronal signaling is mechanistically involved in alcohol's cellular and behavioral effects. Further, these data suggest that genetic variation in these signaling pathways contribute to human variation in alcohol response. Finally, this concordance of the cell, animal, and human findings supports neuronal signaling, particularly glutamate signaling, as a prime target for translational studies to understand and eventually modulate alcohol's effects. Copyright © 2010 by the Research Society on Alcoholism. Source

Enquist J.,Ernest Gallo Clinic and Research Center | Ferwerda M.,Ernest Gallo Clinic and Research Center | Milan-Lobo L.,Ernest Gallo Clinic and Research Center | Whistler J.L.,Ernest Gallo Clinic and Research Center | Whistler J.L.,University of California at San Francisco
Journal of Pharmacology and Experimental Therapeutics | Year: 2012

Chronic treatment of pain with opiate drugs can lead to analgesic tolerance and drug dependence. Although all opiate drugs can promote tolerance and dependence in practice, the severity of those unwanted side effects differs depending on the drug used. Although each opiate drug has its own unique set of pharmacological profiles, methadone is the only clinically used opioid drug that produces substantial receptor endocytosis at analgesic doses. Here, we examined whether moderate doses of methadone carry any benefits over chronic use of equianalgesic morphine, the prototypical opioid. Our data show that chronic administration of methadone produces significantly less analgesic tolerance than morphine. Furthermore, we found significantly reduced precipitated withdrawal symptoms after chronic methadone treatment than after chronic morphine treatment. Finally, using a novel animal model with a degrading μ-opioid receptor we showed that, although endocytosis seems to protect against tolerance development, endocytosis followed by receptor degradation produces a rapid onset of analgesic tolerance to methadone. Together, these data indicated that opioid drugs that promote receptor endocytosis and recycling, such as methadone, may be a better choice for chronic pain treatment than morphine and its derivatives that do not. Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics. Source

Milan-Lobo L.,Ernest Gallo Clinic and Research Center | Whistler J.L.,Ernest Gallo Clinic and Research Center | Whistler J.L.,University of California at San Francisco
Journal of Pharmacology and Experimental Therapeutics | Year: 2011

Heteromerization of opioid receptors has been shown to alter opioid receptor pharmacology. However, how receptor heteromerization affects the processes of endocytosis and postendocytic sorting has not been closely examined. This question is of particular relevance for heteromers of the μ-opioid receptor (MOR) and δ-opioid receptor (DOR), because the MOR is recycled primarily after endocytosis and the DOR is degraded in the lysosome. Here, we examined the endocytic and postendocytic fate of MORs, DORs, and DOR/MOR heteromers in human embryonic kidney 293 cells stably expressing each receptor alone or coexpressing both receptors. We found that the clinically relevant MOR agonist methadone promotes endocytosis of MOR but also the DOR/MOR heteromer. Furthermore, we show that DOR/MOR heteromers that are endocytosed in response to methadone are targeted for degradation, whereas MORs in the same cell are significantly more stable. It is noteworthy that we found that the DOR-selective antagonist naltriben mesylate could block both methadone- and [D-Ala2,NMe-Phe4,Gly-ol5]-enkephalin-induced endocytosis of the DOR/ MOR heteromers but did not block signaling from this heteromer. Together, our results suggest that the MOR adopts novel trafficking properties in the context of the DOR/MOR heteromer. In addition, they suggest that the heteromer shows "biased antagonism," whereby DOR antagonist can inhibit trafficking but not signaling of the DOR/MOR heteromer. Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics. Source

Feduccia A.A.,Ernest Gallo Clinic and Research Center | Chatterjee S.,Ernest Gallo Clinic and Research Center | Bartlett S.E.,Ernest Gallo Clinic and Research Center | Bartlett S.E.,Queensland University of Technology
Frontiers in Molecular Neuroscience | Year: 2012

Addictive drugs can activate systems involved in normal reward-related learning, creating long-lasting memories of the drug's reinforcing effects and the environmental cues surrounding the experience. These memories significantly contribute to the maintenance of compulsive drug use as well as cue-induced relapse which can occur even after long periods of abstinence. Synaptic plasticity is thought to be a prominent molecular mechanism underlying drug-induced learning and memories. Ethanol and nicotine are both widely abused drugs that share a common molecular target in the brain, the neuronal nicotinic acetylcholine receptors (nAChRs). The nAChRs are ligand-gated ion channels that are vastly distributed throughout the brain and play a key role in synaptic neurotransmission. In this review, we will delineate the role of nAChRs in the development of ethanol and nicotine addiction. We will characterize both ethanol and nicotine's effects on nAChR-mediated synaptic transmission and plasticity in several key brain areas that are important for addiction. Finally, we will discuss some of the behavioral outcomes of drug-induced synaptic plasticity in animal models. An understanding of the molecular and cellular changes that occur following administration of ethanol and nicotine will lead to better therapeutic strategies. © 2012 Feduccia, Chatterjee and Bartlett. Source

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