Publications by authors named "Christie D Fowler"

38 Publications

Huntington's disease mice and human brain tissue exhibit increased G3BP1 granules and TDP43 mislocalization.

J Clin Invest 2021 May 4. Epub 2021 May 4.

Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, United States of America.

Chronic cellular stress associated with neurodegenerative disease can result in the persistence of stress granule (SG) structures, membraneless organelles that form in response to cellular stress. In Huntington's disease (HD), chronic expression of mutant huntingtin generates various forms of cellular stress, including activation of the unfolded protein response and oxidative stress. However, it has yet to be determined whether SGs are a feature of HD neuropathology. We examined the miRNA composition of extracellular vesicles (EVs) present in the cerebrospinal fluid (CSF) of HD patients and show that a subset of their target mRNAs were differentially expressed in the prefrontal cortex of HD patients. Of these targets, SG components were enriched, including the SG nucleating Ras GTPase-activating protein-binding protein 1 (G3BP1). We investigated localization and levels of G3BP1 and found a significant increase in the density of G3BP1-positive granules in the cortex and hippocampus of R6/2 transgenic mice and in the superior frontal cortex of HD patient brains. Intriguingly, we also observed that the SG-associated TAR DNA-Binding Protein-43 (TDP43), a nuclear RNA/DNA binding protein, was mislocalized to the cytoplasm of G3BP1-granule positive HD cortical neurons. These findings suggest that G3BP1 SG dynamics may play a role in the pathophysiology of HD.
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http://dx.doi.org/10.1172/JCI140723DOI Listing
May 2021

Potentiation of (α4)2(β2)3, but not (α4)3(β2)2, nicotinic acetylcholine receptors reduces nicotine self-administration and withdrawal symptoms.

Neuropharmacology 2021 Apr 18;190:108568. Epub 2021 Apr 18.

Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA, USA. Electronic address:

The low sensitivity (α4)3(β2)2 (LS) and high sensitivity (α4)2(β2)3 (HS) nAChR isoforms may contribute to a variety of brain functions, pathophysiological processes, and pharmacological effects associated with nicotine use. In this study, we examined the contributions of the LS and HS α4β2 nAChR isoforms in nicotine self-administration, withdrawal symptoms, antinociceptive and hypothermic effects. We utilized two nAChR positive allosteric modulators (PAMs): desformylflustrabromine (dFBr), a PAM of both the LS and HS α4β2 nAChRs, and CMPI, a PAM selective for the LS nAChR. We found that dFBr, but not CMPI, decreased intravenous nicotine self-administration in male mice in a dose-dependent manner. Unlike dFBr, which fully reverses somatic and affective symptoms of nicotine withdrawal, CMPI at doses up to 15 mg/kg in male mice only partially reduced nicotine withdrawal-induced somatic signs, anxiety-like behavior and sucrose preference, but had no effects on nicotine withdrawal-induced hyperalgesia. These results indicate that potentiation of HS α4β2 nAChRs is necessary to modulate nicotine's reinforcing properties that underlie nicotine intake and to reverse nicotine withdrawal symptoms that influence nicotine abstinence. In contrast, both dFBr and CMPI enhanced nicotine's hypothermic effect and reduced nicotine's antinociceptive effects in male mice. Therefore, these results indicate a more prevalent role of HS α4β2 nAChR isoforms in mediating various behavioral effects associated with nicotine, whereas the LS α4β2 nAChR isoform has a limited role in mediating body temperature and nociceptive responses. These findings will facilitate the development of more selective, efficacious, and safe nAChR-based therapeutics for nicotine addiction treatment.
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http://dx.doi.org/10.1016/j.neuropharm.2021.108568DOI Listing
April 2021

E-cigarette vape and lung ACE2 expression: Implications for coronavirus vulnerability.

Environ Toxicol Pharmacol 2021 Apr 7;86:103656. Epub 2021 Apr 7.

Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, 92697, USA. Electronic address:

Evidence in humans suggests a correlation between nicotine smoking and severe respiratory symptoms with COVID-19 infection. In lung tissue, angiotensin-converting enzyme 2 (ACE2) appears to mechanistically underlie viral entry. Here, we investigated whether e-cigarette vapor inhalation alters ACE2 and nicotinic acetylcholine receptor (nAChR) expression in male and female mice. In male lung, nicotine vapor inhalation induced a significant increase in ACE2 mRNA and protein, but surprisingly, these differences were not found in females. Further, both vehicle and nicotine vapor inhalation downregulated α5 nAChR subunits in both sexes, while differences were not found in α7 nAChR subunit expression. Finally, blood ACE2 levels did not differ with exposure, indicating that blood sampling is not a sufficient indicator of lung ACE2 changes. Together, these data indicate a direct link between e-cigarette vaping and increased ACE2 expression in male lung tissue, which thereby reveals an underlying mechanism of increased vulnerability to coronavirus infection in individuals vaping nicotine.
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http://dx.doi.org/10.1016/j.etap.2021.103656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025581PMC
April 2021

Multidimensional Intersection of Nicotine, Gene Expression, and Behavior.

Front Behav Neurosci 2021 22;15:649129. Epub 2021 Mar 22.

Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, Unites States.

The cholinergic system plays a crucial role in nervous system function with important effects on developmental processes, cognition, attention, motivation, reward, learning, and memory. Nicotine, the reinforcing component of tobacco and e-cigarettes, directly acts on the cholinergic system by targeting nicotinic acetylcholine receptors (nAChRs) in the brain. Activation of nAChRs leads to a multitude of immediate and long-lasting effects in specific cellular populations, thereby affecting the addictive properties of the drug. In addition to the direct actions of nicotine in binding to and opening nAChRs, the subsequent activation of circuits and downstream signaling cascades leads to a wide range of changes in gene expression, which can subsequently alter further behavioral expression. In this review, we provide an overview of the actions of nicotine that lead to changes in gene expression and further highlight evidence supporting how these changes can often be bidirectional, thereby inducing subsequent changes in behaviors associated with further drug intake.
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http://dx.doi.org/10.3389/fnbeh.2021.649129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019722PMC
March 2021

Method for Primary Epithelial Cell Culture from the Rat Choroid Plexus.

Bio Protoc 2020 Feb 20;10(4):e3532. Epub 2020 Feb 20.

Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA.

The choroid plexus consists of a network of secretory epithelial cells localized throughout the lateral, third and fourth ventricles of the brain. Cerebrospinal fluid (CSF) is generated by the choroid plexus and released into the ventricular environment. This biofluid contains an enriched source of proteins, ions, and other signaling molecules for extracellular support of neurons and glial cells within the central nervous system. Given that other cells in the brain also release factors into the CSF, investigations of choroid plexus function are necessary to isolate processes selectively occurring within and released from this tissue. Here, we describe a protocol to isolate choroid plexus tissue from each of the ventricular locations, and the cell culture conditions required to support growth and maintenance of these epithelial cells. This technique allows for investigations of the functional significance of the choroid plexus, such as for the examination of stimuli promoting the release of growth factors and extracellular vesicles , exosomes and microvesicles) from ventricle-specific choroid plexus epithelial cells.
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http://dx.doi.org/10.21769/BioProtoc.3532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842687PMC
February 2020

Nicotine e-cigarette vapor inhalation and self-administration in a rodent model: Sex- and nicotine delivery-specific effects on metabolism and behavior.

Addict Biol 2021 Feb 23:e13024. Epub 2021 Feb 23.

Department of Neurobiology and Behavior, University of California Irvine, Irvine, California, USA.

E-cigarettes, which deliver vaporized nicotine, have dramatically risen in popularity in recent years, despite many unanswered questions about safety, efficacy in reducing dependence, and overall impact on public health. Other factors, such as sex, also play an important role in determining behavioral and neurochemical responses to drugs of abuse. In these studies, we sought to develop a protocol for vaporized e-cigarette nicotine self-administration in rats, as a foundation to better understand the differing effects of nicotine exposure routes on behavior and physiological function. We report a novel method that elicits robust nicotine vapor self-administration in male and female rats. Our findings indicate that 5-mg/ml nicotine vape solution provides a high level of consistency in lever-pressing behavior for both males and females. Moreover, in male rats, we find that such e-cigarette nicotine vapor induces similar blood levels of nicotine's main metabolite, cotinine, as that found with intravenous nicotine self-administration. Therefore, the breathing pattern during vapor exposure in males leads to similar levels of titrated nicotine intake as with intravenous nicotine self-administration. Interestingly, a differential effect was found in the females, in which the same conditions of vapor exposure led to decreased cotinine levels with vapor compared to intravenous self-administration. Finally, differences in nicotine-mediated locomotion provide further support of the physiological effects of e-cigarette vapor inhalation. Taken together, our findings reveal important sex differences in nicotine intake based on the route of exposure, and we further establish a protocol for nicotine vapor self-administration in rats.
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http://dx.doi.org/10.1111/adb.13024DOI Listing
February 2021

α3* Nicotinic Acetylcholine Receptors in the Habenula-Interpeduncular Nucleus Circuit Regulate Nicotine Intake.

J Neurosci 2021 Feb 30;41(8):1779-1787. Epub 2020 Dec 30.

Nash Family Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York 10029

Allelic variation in , the gene encoding the α3 nicotinic acetylcholine receptor (nAChR) subunit, increases vulnerability to tobacco dependence and smoking-related diseases, but little is known about the role for α3-containing (α3*) nAChRs in regulating the addiction-related behavioral or physiological actions of nicotine. α3* nAChRs are densely expressed by medial habenula (mHb) neurons, which project almost exclusively to the interpeduncular nucleus (IPn) and are known to regulate nicotine avoidance behaviors. We found that hypomorphic mice, which express constitutively low levels of α3* nAChRs, self-administer greater quantities of nicotine (0.4 mg kg per infusion) than their wild-type littermates. Microinfusion of a lentivirus vector to express a short-hairpin RNA into the mHb or IPn to knock-down transcripts markedly increased nicotine self-administration behavior in rats (0.01-0.18 mg kg per infusion). Using whole-cell recordings, we found that the α3β4* nAChR-selective antagonist α-conotoxin AuIB almost completely abolished nicotine-evoked currents in mHb neurons. By contrast, the α3β2* nAChR-selective antagonist α-conotoxin MII only partially attenuated these currents. Finally, micro-infusion of α-conotoxin AuIB (10 μm) but not α-conotoxin MII (10 μm) into the IPn in rats increased nicotine self-administration behavior. Together, these data suggest that α3β4* nAChRs regulate the stimulatory effects of nicotine on the mHb-IPn circuit and thereby regulate nicotine avoidance behaviors. These findings provide mechanistic insights into how risk alleles can increase the risk of tobacco dependence and smoking-related diseases in human smokers. Allelic variation in , which encodes the α3 nicotinic acetylcholine receptor (nAChR) subunit gene, increases risk of tobacco dependence but underlying mechanisms are unclear. We report that hypomorphic mice consume greater quantities of nicotine than wild-type mice and that knock-down of gene transcripts in the habenula or interpeduncular nucleus (IPn) increases nicotine intake in rats. α-Conotoxin AuIB, a potent antagonist of the α3β4 nAChR subtype, reduced the stimulatory effects of nicotine on habenular neurons, and its infusion into the IPn increased nicotine intake in rats. These data suggest that α3β4 nAChRs in the habenula-IPn circuit regulate the motivational properties of nicotine.
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http://dx.doi.org/10.1523/JNEUROSCI.0127-19.2020DOI Listing
February 2021

The Interpeduncular-Ventral Hippocampus Pathway Mediates Active Stress Coping and Natural Reward.

eNeuro 2020 Nov/Dec;7(6). Epub 2020 Nov 19.

Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA 92697

Maladaptive stress-related behaviors are integral to multiple complex psychiatric disorders, and it has been well established that serotonergic signaling mediates various aspects of these maladaptive states. In these studies, we sought to uncover the function of a previously undefined serotonergic pathway, which projects from the interpeduncular nucleus (IPN) to the ventral hippocampus (vHipp). Intersectional retrograde and chemogenetic viral manipulation strategies were employed to manipulate the function of the IPN-vHipp pathway during a variety of behavioral measures in male mice. We found a significant effect of circuit inhibition on behaviors associated with coping strategies and natural reward. Specifically, inhibition of the IPN-vHipp pathway dramatically increased active stress-induced escape behaviors, in addition to moderately affecting sucrose consumption and food self-administration. During inhibition of this pathway, agonist activation of serotonergic 5-HT receptors in the vHipp reversed the effects of IPN-vHipp circuit inhibition on active escape behaviors, thereby supporting the synaptic mechanism underlying the behavioral effects evidenced. IPN-vHipp inhibition did not induce differences in generalized locomotion, anxiety-associated behavior, and intravenous nicotine self-administration. Importantly, these findings are in opposition to the canonical understanding of serotonin in such escape behaviors, indicating that serotonin exerts opposing effects on behavior in a pathway-specific manner in the brain. Taken together, these findings thereby have important implications for our understanding of serotonergic signaling and associated therapeutic approaches for the treatment of disease symptomology.
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http://dx.doi.org/10.1523/ENEURO.0191-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7688303PMC
November 2020

Nicotinic Receptors Underlying Nicotine Dependence: Evidence from Transgenic Mouse Models.

Curr Top Behav Neurosci 2020 ;45:101-121

Department of Neurobiology and Behavior, University of California, Irvine, CA, USA.

Nicotine underlies the reinforcing properties of tobacco cigarettes and e-cigarettes. After inhalation and absorption, nicotine binds to various nicotinic acetylcholine receptor (nAChR) subtypes localized on the pre- and postsynaptic membranes of cells, which subsequently leads to the modulation of cellular function and neurotransmitter signaling. In this chapter, we begin by briefly reviewing the current understanding of nicotine's actions on nAChRs and highlight considerations regarding nAChR subtype localization and pharmacodynamics. Thereafter, we discuss the seminal discoveries derived from genetically modified mouse models, which have greatly contributed to our understanding of nicotine's effects on the reward-related mesolimbic pathway and the aversion-related habenulo-interpeduncular pathway. Thereafter, emerging areas of research focusing on modulation of nAChR expression and/or function are considered. Taken together, these discoveries have provided a foundational understanding of various genetic, neurobiological, and behavioral factors underlying the motivation to use nicotine and related dependence processes, which are thereby advancing drug discovery efforts to promote long-term abstinence.
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http://dx.doi.org/10.1007/7854_2020_134DOI Listing
November 2020

Adolescent Cannabinoid and Nicotine Exposure Differentially Alters Adult Nicotine Self-Administration in Males and Females.

Nicotine Tob Res 2020 07;22(8):1364-1373

Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA.

Introduction: During adolescence, exposure to nicotine or cannabis independently induces effects on neuromaturation and later cognitive function. However, the potential effect of both drugs under co-use conditions has become of increasing concern given the prevalence of e-cigarettes, legalization of cannabis, and availability of synthetic "spice" cannabinoid agonists.

Aims And Methods: The current studies investigated the effects of exposure to a cannabinoid receptor agonist (WIN55,212-2) and/or nicotine over a discrete time period in mid-adolescence on later intravenous nicotine self-administration in adult male and female mice. We further examined whether cannabinoid agonist administration in adulthood would alter nicotine reinforcement, with either acute or chronic pairing across 7 days.

Results: We found that adult males exhibited increased nicotine self-administration at a lower, rewarding nicotine dose following adolescent cannabinoid exposure, either alone or with nicotine coadministration. In contrast, adult females demonstrated an opposing effect in which adolescent cannabinoid and nicotine coexposure resulted in decreased nicotine intake compared with the nicotine only and control groups. Furthermore, after maintaining nicotine self-administration across sessions, pretreatment with a low dose of the cannabinoid agonist decreased nicotine intake in both male and female control mice, and this lowering effect was evidenced after both acute and chronic treatment. However, the cannabinoid agonist was ineffective in altering nicotine intake in mice previously exposed to nicotine, cannabinoid agonist, or both during adolescence.

Conclusions: These data provide evidence that adolescent drug exposure can alter later nicotine reinforcement in a sex-specific manner and can further modulate the effectiveness of interventions in reducing nicotine intake during adulthood.

Implications: These studies demonstrate a significant impact of nicotine, cannabinoids, or coexposure on developmental processes during adolescence. Differential effects were observed within each sex, with opposing results found for cannabinoid exposure on nicotine intake in males and females. Intriguingly, we also evidenced resistance to the lowering effects of a cannabinoid agonist on nicotine intake in adulthood based on adolescent drug exposure. Thus, these findings have important implications for our understanding of the impact of nicotine and cannabinoids (eg, Δ9-tetrahydrocannabinol (THC) and synthetic "spice" cannabinoids) during development, with further implications for the effectiveness of therapeutic interventions based on prior drug exposure in youth.
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http://dx.doi.org/10.1093/ntr/ntaa084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7364841PMC
July 2020

Paternal nicotine enhances fear memory, reduces nicotine administration, and alters hippocampal genetic and neural function in offspring.

Addict Biol 2021 01 28;26(1):e12859. Epub 2019 Nov 28.

Department of Biobehavioral Health, Penn State University, University Park, Pennsylvania.

Nicotine use remains highly prevalent with tobacco and e-cigarette products consumed worldwide. However, increasing evidence of transgenerational epigenetic inheritance suggests that nicotine use may alter behavior and neurobiology in subsequent generations. We tested the effects of chronic paternal nicotine exposure in C57BL6/J mice on fear conditioning in F1 and F2 offspring, as well as conditioned fear extinction and spontaneous recovery, nicotine self-administration, hippocampal cholinergic functioning, RNA expression, and DNA methylation in F1 offspring. Paternal nicotine exposure was associated with enhanced contextual and cued fear conditioning and spontaneous recovery of extinguished fear memories. Further, nicotine reinforcement was reduced in nicotine-sired mice, as assessed in a self-administration paradigm. These behavioral phenotypes were coupled with altered response to nicotine, upregulated hippocampal nicotinic acetylcholine receptor binding, reduced evoked hippocampal cholinergic currents, and altered methylation and expression of hippocampal genes related to neural development and plasticity. Gene expression analysis suggests multigenerational effects on broader gene networks potentially involved in neuroplasticity and mental disorders. The changes in fear conditioning similarly suggest phenotypes analogous to anxiety disorders similar to post-traumatic stress.
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http://dx.doi.org/10.1111/adb.12859DOI Listing
January 2021

NeuroEVs: Characterizing Extracellular Vesicles Generated in the Neural Domain.

J Neurosci 2019 11;39(47):9262-9268

Department of Neurobiology and Behavior, University of California Irvine, Irvine, California 92697

Intercellular communication has recently been shown to occur via transfer of cargo loaded within extracellular vesicles (EVs). Present within all biofluids of the body, EVs can contain various signaling factors, including coding and noncoding RNAs (e.g., mRNA, miRNA, lncRNA, snRNA, tRNA, yRNA), DNA, proteins, and enzymes. Multiple types of cells appear to be capable of releasing EVs, including cancer, stem, epithelial, immune, glial, and neuronal cells. However, the functional impact of these circulating signals among neural networks within the brain has been difficult to establish given the complexity of cellular populations involved in release and uptake, as well as inherent limitations of examining a biofluid. In this brief commentary, we provide an analysis of the conceptual and technical considerations that limit our current understanding of signaling mediated by circulating EVs relative to their impact on neural function.
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http://dx.doi.org/10.1523/JNEUROSCI.0146-18.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6867818PMC
November 2019

The Novel CYP2A6 Inhibitor, DLCI-1, Decreases Nicotine Self-Administration in Mice.

J Pharmacol Exp Ther 2020 01 18;372(1):21-29. Epub 2019 Oct 18.

Department of Neurobiology and Behavior, University of California Irvine, Irvine, California (Y.-C.C., J.P.F., Y.S., A.S., C.D.F.); and Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, Washington (J.W., C.J.W.W., P.L., T.T.D.)

During tobacco and e-cigarette use, nicotine is mainly metabolized in the human liver by cytochrome P450 2A6 (CYP2A6). Given that a slower CYP2A6 metabolism has been associated with less vulnerability to develop nicotine dependence, the current studies sought to validate a novel CYP2A6 inhibitor, (5-(4-ethylpyridin-3-yl)thiophen-2-yl)methanamine (DLCI-1), for its effects on intravenous nicotine self-administration. Male and female mice were trained to self-administer nicotine across daily sessions. Once stable responding was achieved, DLCI-1 or vehicle control was administered prior to nicotine sessions. We found that the lower 25 mg/kg and moderate 50 mg/kg doses of DLCI-1 induced a significant decrease in nicotine intake for both males and females. DLCI-1 was further shown to be more effective than a moderate 1 mg/kg dose of bupropion on reducing nicotine intake and did not exert the adverse behavioral effects found with a high 75 mg/kg dose of bupropion. Although mice treated with DLCI-1 self-administered significantly less nicotine, similar nicotine-mediated behavioral effects on locomotion were observed. Together, along with the analysis of nicotine metabolites during self-administration, these findings support the contention that blocking hepatic nicotine metabolism would allow for similar activation of nicotinic acetylcholine receptors at lower nicotine doses. Moreover, these effects of DLCI-1 were specific to nicotine self-administration, as DLCI-1 did not result in any behavioral changes during food self-administration. Taken together, these studies validate DLCI-1 as a novel compound to decrease nicotine consumption, which may thereby promote tobacco and nicotine product cessation. SIGNIFICANCE STATEMENT: Current pharmacological approaches for nicotine and tobacco cessation have only been able to achieve limited efficaciousness in promoting long-term abstinence. In this work, we characterize the effects of a novel compound, (5-(4-ethylpyridin-3-yl)thiophen-2-yl)methanamine (DLCI-1), which inhibits the main enzyme that metabolizes nicotine, and we report a significant decrease in intravenous nicotine self-administration in male and female mice, supporting the potential of DLCI-1 as a novel tobacco cessation pharmacotherapeutic.
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http://dx.doi.org/10.1124/jpet.119.260653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904882PMC
January 2020

Molecular Mechanisms Associated with Nicotine Pharmacology and Dependence.

Handb Exp Pharmacol 2020 ;258:373-393

Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, USA.

Tobacco dependence is a leading cause of preventable disease and death worldwide. Nicotine, the main psychoactive component in tobacco cigarettes, has also been garnering increased popularity in its vaporized form, as derived from e-cigarette devices. Thus, an understanding of the molecular mechanisms underlying nicotine pharmacology and dependence is required to ascertain novel approaches to treat drug dependence. In this chapter, we review the field's current understanding of nicotine's actions in the brain, the neurocircuitry underlying drug dependence, factors that modulate the function of nicotinic acetylcholine receptors, and the role of specific genes in mitigating the vulnerability to develop nicotine dependence. In addition to nicotine's direct actions in the brain, other constituents in nicotine and tobacco products have also been found to alter drug use, and thus, evidence is provided to highlight this issue. Finally, currently available pharmacotherapeutic strategies are discussed, along with an outlook for future therapeutic directions to achieve to the goal of long-term nicotine cessation.
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http://dx.doi.org/10.1007/164_2019_252DOI Listing
September 2020

Nicotine Acts on Cholinergic Signaling Mechanisms to Directly Modulate Choroid Plexus Function.

eNeuro 2019 Mar-Apr;6(2). Epub 2019 Apr 23.

Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, 92697.

Neuronal cholinergic circuits have been implicated in cognitive function and neurological disease, but the role of cholinergic signaling in other cellular populations within the brain has not been as fully defined. Here, we show that cholinergic signaling mechanisms are involved in mediating the function of the choroid plexus, the brain structure responsible for generating CSF and releasing various factors into the brain. The choroid plexus was found to express markers of endogenous cholinergic signaling, including multiple nicotinic acetylcholine receptor (nAChR) subtypes in a region-specific manner, and application of nicotine was found to induce cellular activation, as evidenced by calcium influx in primary tissue. During intravenous nicotine self-administration in male rats, nicotine increased expression of transthyretin, a protein selectively produced and released by the choroid plexus, and microRNA-204 (mir-204), a transcript found in high levels in the choroid plexus and CSF. Finally, human choroid plexus tissue from both sexes was found to exhibit similar nAChR, transthyretin and mir-204 expression profiles, supporting the translational relevance of the findings. Together, these studies demonstrate functionally active cholinergic signaling mechanisms in the choroid plexus, the resulting effects on transthyretin and mir-204 expression, and reveal the direct mechanism by which nicotine modulates function of this tissue.
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http://dx.doi.org/10.1523/ENEURO.0051-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529591PMC
February 2020

Cannabinoid and nicotine exposure during adolescence induces sex-specific effects on anxiety- and reward-related behaviors during adulthood.

PLoS One 2019 31;14(1):e0211346. Epub 2019 Jan 31.

Department of Neurobiology and Behavior, University of California, Irvine, Irvine, CA, United States of America.

Nicotine and cannabis use during adolescence has the potential to induce long lasting changes on affective and cognitive function. Here, we examined whether adolescent exposure to nicotine, the cannabinoid agonist WIN55-212,2 (WIN), or co-exposure to both would alter operant learning, locomotion, and anxiety- and reward-related behaviors in male and female mice during adulthood. Males exposed to a moderate dose of WIN (2 mg/kg) or co-exposed to nicotine and the moderate dose of WIN exhibited decreased anxiety-associated behaviors and increased cognitive flexibility, but did not differ in operant learning or generalized locomotion. In contrast, differences were not found among the females in these measures at the moderate WIN dose or in both sexes with exposure to a low WIN dose (0.2 mg/kg). Furthermore, a sex-dependent dissociative effect was found in natural reward consumption. Males exposed to the moderate dose of WIN or co-exposed to nicotine and the moderate dose of WIN demonstrated increased sucrose consumption. In contrast, females exposed to the moderate dose of WIN exhibited a decrease in sucrose consumption, which was ameliorated with co-administration of nicotine. Together, these novel findings demonstrate that adolescent exposure to cannabinoids in the presence or absence of nicotine results in altered affective and reward-related behaviors during adulthood.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211346PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354968PMC
October 2019

Altered Baseline and Nicotine-Mediated Behavioral and Cholinergic Profiles in ChAT-Cre Mouse Lines.

J Neurosci 2018 02 25;38(9):2177-2188. Epub 2018 Jan 25.

Department of Neurobiology and Behavior, University of California Irvine, Irvine, California 92697

The recent development of transgenic rodent lines expressing cre recombinase in a cell-specific manner, along with advances in engineered viral vectors, has permitted in-depth investigations into circuit function. However, emerging evidence has begun to suggest that genetic modifications may introduce unexpected caveats. In the current studies, we sought to extensively characterize male and female mice from both the ChAT-Cre mouse line, created with the bacterial artificial chromosome (BAC) method, and ChAT-Cre mouse line, generated with the internal ribosome entry site (IRES) method. ChAT-Cre transgenic and wild-type mice did not differ in general locomotor behavior, anxiety measures, drug-induced cataplexy, nicotine-mediated hypolocomotion, or operant food training. However, ChAT-Cre transgenic mice did exhibit significant deficits in intravenous nicotine self-administration, which paralleled an increase in vesicular acetylcholine transporter and choline acetyltransferase (ChAT) hippocampal expression. For the ChAT-Cre line, transgenic mice exhibited deficits in baseline locomotor, nicotine-mediated hypolocomotion, and operant food training compared with wild-type and hemizygous littermates. No differences among ChAT-Cre wild-type, hemizygous, and transgenic littermates were found in anxiety measures, drug-induced cataplexy, and nicotine self-administration. Given that increased cre expression was present in the ChAT-Cre transgenic mice, as well as a decrease in ChAT expression in the hippocampus, altered neuronal function may underlie behavioral phenotypes. In contrast, ChAT-Cre hemizygous mice were more similar to wild-type mice in both protein expression and the majority of behavioral assessments. As such, interpretation of data derived from ChAT-Cre rodents must consider potential limitations dependent on the line and/or genotype used in research investigations. Altered baseline and/or nicotine-mediated behavioral profiles were discovered in transgenic mice from the ChAT-Cre and ChAT-Cre lines. Given that these cre-expressing mice have become increasingly used by the scientific community, either independently with chemicogenetic and optogenetic viral vectors or crossed with other transgenic lines, the current studies highlight important considerations for the interpretation of data from previous and future experimental investigations. Moreover, the current findings detail the behavioral effects of either increased or decreased baseline cholinergic signaling mechanisms on locomotor, anxiety, learning/memory, and intravenous nicotine self-administration behaviors.
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http://dx.doi.org/10.1523/JNEUROSCI.1433-17.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830509PMC
February 2018

Basic Science and Public Policy: Informed Regulation for Nicotine and Tobacco Products.

Nicotine Tob Res 2018 06;20(7):789-799

Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA.

Introduction: Scientific discoveries over the past few decades have provided significant insight into the abuse liability and negative health consequences associated with tobacco and nicotine-containing products. While many of these advances have led to the development of policies and laws that regulate access to and formulations of these products, further research is critical to guide future regulatory efforts, especially as novel nicotine-containing products are introduced and selectively marketed to vulnerable populations.

Discussion: In this narrative review, we provide an overview of the scientific findings that have impacted regulatory policy and discuss considerations for further translation of science into policy decisions. We propose that open, bidirectional communication between scientists and policy makers is essential to develop transformative preventive- and intervention-focused policies and programs to reduce appeal, abuse liability, and toxicity of the products.

Conclusions: Through these types of interactions, collaborative efforts to inform and modify policy have the potential to significantly decrease the use of tobacco and alternative nicotine products and thus enhance health outcomes for individuals.

Implications: This work addresses current topics in the nicotine and tobacco research field to emphasize the importance of basic science research and provide examples of how it can be utilized to inform public policy. In addition to relaying current thoughts on the topic from experts in the field, the article encourages continued efforts and communication between basic scientists and policy officials.
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http://dx.doi.org/10.1093/ntr/ntx175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991436PMC
June 2018

Corticostriatal plasticity, neuronal ensembles, and regulation of drug-seeking behavior.

Prog Brain Res 2017 12;235:93-112. Epub 2017 Oct 12.

Medical University of South Carolina, Charleston, SC, United States. Electronic address:

The idea that interconnected neuronal ensembles code for specific behaviors has been around for decades; however, recent technical improvements allow studying these networks and their causal role in initiating and maintaining behavior. In particular, the role of ensembles in drug-seeking behaviors in the context of addiction is being actively investigated. Concurrent with breakthroughs in quantifying ensembles, research has identified a role for synaptic glutamate spillover during relapse. In particular, the transient relapse-associated changes in glutamatergic synapses on accumbens neurons, as well as in adjacent astroglia and extracellular matrix, are key elements of the synaptic plasticity encoded by drug use and the metaplasticity induced by drug-associated cues that precipitate drug-seeking behaviors. Here, we briefly review the recent discoveries related to ensembles in the addiction field and then endeavor to link these discoveries with drug-induced striatal plasticity and cue-induced metaplasticity toward deeper neurobiological understandings of drug seeking.
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http://dx.doi.org/10.1016/bs.pbr.2017.07.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5794216PMC
June 2018

More Than Just Chillin': Interactive Effects of Menthol and Nicotine in Drug Reward.

Neuropsychopharmacology 2017 11 5;42(12):2283-2284. Epub 2017 Jul 5.

Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA, USA.

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http://dx.doi.org/10.1038/npp.2017.107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5645734PMC
November 2017

GLP-1 acts on habenular avoidance circuits to control nicotine intake.

Nat Neurosci 2017 May 3;20(5):708-716. Epub 2017 Apr 3.

Department of Molecular Therapeutics, The Scripps Research Institute Jupiter, Florida, USA.

Tobacco smokers titrate their nicotine intake to avoid its noxious effects, sensitivity to which may influence vulnerability to tobacco dependence, yet mechanisms of nicotine avoidance are poorly understood. Here we show that nicotine activates glucagon-like peptide-1 (GLP-1) neurons in the nucleus tractus solitarius (NTS). The antidiabetic drugs sitagliptin and exenatide, which inhibit GLP-1 breakdown and stimulate GLP-1 receptors, respectively, decreased nicotine intake in mice. Chemogenetic activation of GLP-1 neurons in NTS similarly decreased nicotine intake. Conversely, Glp1r knockout mice consumed greater quantities of nicotine than wild-type mice. Using optogenetic stimulation, we show that GLP-1 excites medial habenular (MHb) projections to the interpeduncular nucleus (IPN). Activation of GLP-1 receptors in the MHb-IPN circuit abolished nicotine reward and decreased nicotine intake, whereas their knockdown or pharmacological blockade increased intake. GLP-1 neurons may therefore serve as 'satiety sensors' for nicotine that stimulate habenular systems to promote nicotine avoidance before its aversive effects are encountered.
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http://dx.doi.org/10.1038/nn.4540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5541856PMC
May 2017

Emerging Role of the Cerebrospinal Fluid - Neuronal Interface in Neuropathology.

Neuro 2015 Dec 13;2(3):92-98. Epub 2015 Oct 13.

Department of Neurobiology and Behavior, University of California, Irvine, CA 92697, USA.

The choroid plexus and cerebrospinal fluid have recently begun to emerge as essential regulators of neural function. Factors produced by the choroid plexus are released into the ventricular environment and thus provide a rich source of extracellular signaling molecules throughout the central nervous system. Identified factors in the cerebrospinal fluid include growth factors, hormones, proteins, peptides, lipids, glucose, microRNAs (miRNAs), messenger RNA (mRNA), and enzymes. In addition to mediating neural function, these factors have the potential to serve as biomarkers of disease states. In this review, we highlight recent advances demonstrating the importance of extracellular signaling mechanisms in mediating neural function and provide recent evidence for their role in neuropathology.
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http://dx.doi.org/10.17140/NOJ-2-118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502773PMC
December 2015

Nicotine aversion: Neurobiological mechanisms and relevance to tobacco dependence vulnerability.

Neuropharmacology 2014 Jan 18;76 Pt B:533-44. Epub 2013 Sep 18.

Laboratory of Behavioral and Molecular Neuroscience, Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL 33458, USA; Department of Neuroscience, The Scripps Research Institute, Jupiter, FL 33458, USA.

Nicotine stimulates brain reward circuitries, most prominently the mesocorticolimbic dopamine system, and this action plays a critical in establishing and maintaining the tobacco smoking habit. Compounds that attenuate nicotine reward are considered promising therapeutic candidates for tobacco dependence, but many of these agents have other actions that limit their potential utility. Nicotine is also highly noxious, particularly at higher doses, and aversive reactions to nicotine after initial exposure can decrease the likelihood of developing a tobacco habit in many first time smokers. Nevertheless, relatively little is known about the mechanisms of nicotine aversion. The purpose of this review is to present recent new insights into the neurobiological mechanisms that regulate avoidance of nicotine. First, the role of the mesocorticolimbic system, so often associated with nicotine reward, in regulating nicotine aversion is highlighted. Second, genetic variation that modifies noxious responses to nicotine and thereby influences vulnerability to tobacco dependence, in particular variation in the CHRNA5-CHRNA3-CHRNB4 nicotinic acetylcholine receptor (nAChR) subunit gene cluster, will be discussed. Third, the role of the habenular complex in nicotine aversion, primarily medial habenular projections to the interpeduncular nucleus (IPN) but also lateral habenular projections to rostromedial tegmental nucleus (RMTg) and ventral tegmental area (VTA) are reviewed. Forth, brain circuits that are enriched in nAChRs, but whose role in nicotine avoidance has not yet been assessed, will be identified. Finally, the feasibility of developing novel therapeutic agents for tobacco dependence that act not by blocking nicotine reward but by enhancing nicotine avoidance will be considered. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.
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http://dx.doi.org/10.1016/j.neuropharm.2013.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3858456PMC
January 2014

Role of α5* nicotinic acetylcholine receptors in the effects of acute and chronic nicotine treatment on brain reward function in mice.

Psychopharmacology (Berl) 2013 Aug 20. Epub 2013 Aug 20.

Laboratory of Behavioral and Molecular Neuroscience, Department of Molecular Therapeutics, The Scripps Research Institute-Florida, 130 Scripps Way, Jupiter, FL, 33458, USA.

Objective: Allelic variation in the α5 nicotinic acetylcholine receptor (nAChR) subunit gene, CHRNA5, increases vulnerability to tobacco addiction. Here, we investigated the role of α5* nAChRs in the effects of nicotine on brain reward systems.

Materials And Methods: Effects of acute (0.03125-0.5 mg/kg SC) or chronic (24 mg/kg per day; osmotic minipump) nicotine and mecamylamine-precipitated withdrawal on intracranial self-stimulation (ICSS) thresholds were assessed in wild-type and α5 nAChR subunit knockout mice. Noxious effects of nicotine were further investigated using a conditioned taste aversion procedure.

Results: Lower nicotine doses (0.03125-0.125 mg/kg) decreased ICSS thresholds in wild-type and α5 knockout mice. At higher doses (0.25-0.5 mg/kg), threshold-lowering effects of nicotine were diminished in wild-type mice, whereas nicotine lowered thresholds across all doses tested in α5 knockout mice. Nicotine (1.5 mg/kg) conditioned a taste aversion to saccharine equally in both genotypes. Mecamylamine (5 mg/kg) elevated ICSS thresholds by a similar magnitude in wild-type and α5 knockout mice prepared with minipumps delivering nicotine. Unexpectedly, mecamylamine also elevated thresholds in saline-treated α5 knockout mice.

Conclusion: α5* nAChRs are not involved in reward-enhancing effects of lower nicotine doses, the reward-inhibiting effects of nicotine withdrawal, or the general noxious effects of higher nicotine doses. Instead, α5* nAChRs regulate the reward-inhibiting effects nicotine doses that oppose the reward-facilitating effects of the drug. These data suggest that disruption of α5* nAChR signaling greatly expands the range of nicotine doses that facilitate brain reward activity, which may help explain the increased tobacco addiction vulnerability associated with CHRNA5 risk alleles.
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http://dx.doi.org/10.1007/s00213-013-3235-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3930613PMC
August 2013

Targeted deletion of the mouse α2 nicotinic acetylcholine receptor subunit gene (Chrna2) potentiates nicotine-modulated behaviors.

J Neurosci 2013 May;33(18):7728-41

Department of Psychiatry and Biobehavioral Sciences, Hatos Center for Neuropharmacology, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, California 90024, USA.

Baseline and nicotine-modulated behaviors were assessed in mice harboring a null mutant allele of the nicotinic acetylcholine receptor (nAChR) subunit gene α2 (Chrna2). Homozygous Chrna2(-/-) mice are viable, show expected sex and Mendelian genotype ratios, and exhibit no gross neuroanatomical abnormalities. A broad range of behavioral tests designed to assess genotype-dependent effects on anxiety (elevated plus maze and light/dark box), motor coordination (narrow bean traverse and gait), and locomotor activity revealed no significant differences between mutant mice and age-matched wild-type littermates. Furthermore, a panel of tests measuring traits, such as body position, spontaneous activity, respiration, tremors, body tone, and startle response, revealed normal responses for Chrna2-null mutant mice. However, Chrna2(-/-) mice do exhibit a mild motor or coordination phenotype (a decreased latency to fall during the accelerating rotarod test) and possess an increased sensitivity to nicotine-induced analgesia in the hotplate assay. Relative to wild-type, Chrna2(-/-) mice show potentiated nicotine self-administration and withdrawal behaviors and exhibit a sex-dependent enhancement of nicotine-facilitated cued, but not trace or contextual, fear conditioning. Overall, our results suggest that loss of the mouse nAChR α2 subunit has very limited effects on baseline behavior but does lead to the potentiation of several nicotine-modulated behaviors.
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http://dx.doi.org/10.1523/JNEUROSCI.4731-12.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831006PMC
May 2013

Hypocretin-1 receptors regulate the reinforcing and reward-enhancing effects of cocaine: pharmacological and behavioral genetics evidence.

Front Behav Neurosci 2012 24;6:47. Epub 2012 Jul 24.

Laboratory of Behavioral and Molecular Neuroscience, Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter FL, USA.

Considerable evidence suggests that transmission at hypocretin-1 (orexin-1) receptors (Hcrt-R1) plays an important role in the reinstatement of extinguished cocaine-seeking behaviors in rodents. However, far less is known about the role for hypocretin transmission in regulating ongoing cocaine-taking behavior. Here, we investigated the effects of the selective Hcrt-R1 antagonist SB-334867 on cocaine intake, as measured by intravenous (IV) cocaine self-administration in rats. The stimulatory effects of cocaine on brain reward systems contribute to the establishment and maintenance of cocaine-taking behaviors. Therefore, we also assessed the effects of SB-334867 on the reward-enhancing properties of cocaine, as measured by cocaine-induced lowering of intracranial self-stimulation (ICSS) thresholds. Finally, to definitively establish a role for Hcrt-R1 in regulating cocaine intake, we assessed IV cocaine self-administration in Hcrt-R1 knockout mice. We found that SB-334867 (1-4 mg/kg) dose-dependently decreased cocaine (0.5 mg/kg/infusion) self-administration in rats but did not alter responding for food rewards under the same schedule of reinforcement. This suggests that SB-334867 decreased cocaine reinforcement without negatively impacting operant performance. SB-334867 (1-4 mg/kg) also dose-dependently attenuated the stimulatory effects of cocaine (10 mg/kg) on brain reward systems, as measured by reversal of cocaine-induced lowering of ICSS thresholds in rats. Finally, we found that Hcrt-R1 knockout mice self-administered far less cocaine than wildtype mice across the entire dose-response function. These data demonstrate that Hcrt-R1 play an important role in regulating the reinforcing and reward-enhancing properties of cocaine and suggest that hypocretin transmission is likely essential for establishing and maintaining the cocaine habit in human addicts.
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http://dx.doi.org/10.3389/fnbeh.2012.00047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3402880PMC
October 2012

Utility of genetically modified mice for understanding the neurobiology of substance use disorders.

Hum Genet 2012 Jun 22;131(6):941-57. Epub 2011 Dec 22.

Laboratory of Behavioral and Molecular Neuroscience, Department of Molecular Therapeutics, The Scripps Research Institute, Scripps, Florida, Jupiter, FL 33458, USA.

Advances in our ability to modify the mouse genome have enhanced our understanding of the genetic and neurobiological mechanisms contributing to addiction-related behaviors underlying substance use and abuse. These experimentally induced manipulations permit greater spatial and temporal specificity for modification of gene expression within specific cellular populations and during select developmental time periods. In this review, we consider the current mouse genetic model systems that have been employed to understand aspects of addiction and highlight significant conceptual advances achieved related to substance use and abuse. The mouse models reviewed herein include conventional knock-out and knock-in, conditional knockout, transgenic, inducible transgenic, mice suitable for optogenetic control of discrete neuronal populations, and phenotype-selected mice. By establishing a reciprocal investigatory relationship between genetic findings in humans and genomic manipulations in mice, a far better understanding of the discrete neuromechanisms underlying addiction can be achieved, which is likely to provide a strong foundation for developing and validating novel therapeutics for the treatment of substance abuse disorders.
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http://dx.doi.org/10.1007/s00439-011-1129-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3977433PMC
June 2012

Habenular signaling in nicotine reinforcement.

Neuropsychopharmacology 2012 Jan;37(1):306-7

Laboratory of Behavioral and Molecular Neuroscience, Department of Molecular Therapeutics, Jupiter, FL, USA.

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http://dx.doi.org/10.1038/npp.2011.197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3238079PMC
January 2012

Recent advances in understanding nicotinic receptor signaling mechanisms that regulate drug self-administration behavior.

Biochem Pharmacol 2011 Oct 29;82(8):984-95. Epub 2011 Jun 29.

Laboratory of Behavioral and Molecular Neuroscience, Department of Molecular Therapeutics, The Scripps Research Institute - Scripps Florida, Jupiter, FL 33458, USA.

Tobacco smoking is one of the leading causes of disease and premature death in the United States. Nicotine is considered the major reinforcing component in tobacco smoke responsible for tobacco addiction. Nicotine acts in the brain through the neuronal nicotinic acetylcholine receptors (nAChRs). The predominant nAChR subtypes in mammalian brain are those containing α4 and β2 subunits. The α4β2 nAChRs, particularly those located in the mesoaccumbens dopamine pathway, play a key role in regulating the reinforcing properties of nicotine. Considering that twelve mammalian nAChR subunits have been cloned, it is likely that nAChRs containing subunits in addition to, or other than, α4 and β2 also play a role in the tobacco smoking habit. Consistent with this possibility, human genome-wide association studies have shown that genetic variation in the CHRNA5-CHRNA3-CHRNB4 gene cluster located in chromosome region 15q25, which encode the α5, α3 and β4 nAChR subunits, respectively, increases vulnerability to tobacco addiction and smoking-related diseases. Most recently, α5-containing nAChRs located in the habenulo-interpeduncular tract were shown to limit intravenous nicotine self-administration behavior in rats and mice, suggesting that deficits in α5-containing nAChR signaling in the habenulo-interpeduncular tract increases vulnerability to the motivational properties of nicotine. Finally, evidence suggests that nAChRs may also play a prominent role in controlling consumption of addictive drugs other than nicotine, including cocaine, alcohol, opiates and cannabinoids. The aim of the present review is to discuss recent preclinical findings concerning the identity of the nAChR subtypes that regulate self-administration of nicotine and other drugs of abuse.
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http://dx.doi.org/10.1016/j.bcp.2011.06.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3163076PMC
October 2011

Intravenous nicotine self-administration and cue-induced reinstatement in mice: effects of nicotine dose, rate of drug infusion and prior instrumental training.

Neuropharmacology 2011 Sep 25;61(4):687-98. Epub 2011 May 25.

Department of Molecular Therapeutics, The Scripps Research Institute-Scripps Florida, Jupiter, FL 33458, USA.

Intravenous nicotine self-administration is the most direct measure of nicotine reinforcement in laboratory animals, but this procedure has proven difficult to establish in mice. We found that stable responding for nicotine in C57BL6/J mice was facilitated by prior instrumental training for food reward, initial exposure of mice to a lower unit dose of nicotine (0.03 mg kg(-1) per infusion) before access to higher doses, a slower rate of drug delivery (3-s versus 1-s infusion), consistency in schedule of daily testing, and low extraneous noise during testing. Under these conditions, we found that mice lever-pressed for nicotine (0.03-0.4 mg kg(-1) per infusion; 60-min test sessions) under a fixed-ratio 5 time-out 20-s (FR5TO20) reinforcement schedule and consumed the drug according to an inverted 'U'-shaped dose-response curve. Mice switched their responding onto a previously non-reinforced lever to continue earning nicotine infusions when the active/inactive lever assignment was reversed. The nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine decreased responding for nicotine, but not food rewards, verifying that nAChRs regulate nicotine self-administration in mice. The cue-light paired with nicotine delivery did not support responding when delivered independently of nicotine infusions, further verifying that mice responded selectivity for the drug. Nicotine-seeking responses extinguished when nicotine infusions and the cue-light were withheld, and exposure to the cue-light reinstated responding. Finally, mice without prior instrumental food training acquired stable responding for nicotine under the FR5TO20 schedule, but required a greater number of sessions. These data demonstrate that nicotine is an effective reinforcer in mice and establish conditions under which the drug is reliably self-administered by mice.
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http://dx.doi.org/10.1016/j.neuropharm.2011.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3130070PMC
September 2011