Publications by authors named "Shahrdad Lotfipour"

24 Publications

  • Page 1 of 1

Early adolescent subchronic low-dose nicotine exposure increases subsequent cocaine and fentanyl self-administration in Sprague-Dawley rats.

Behav Pharmacol 2021 Feb;32(1):86-91

Department of Pharmaceutical Sciences.

An exponential rise in nicotine-containing electronic-cigarette use has been observed during the period of adolescence. Preclinical studies have shown that nicotine exposure during early adolescence, but not adulthood, increases subsequent drug intake and reward. Although growing clinical trends highlight that stimulant use disorders are associated with the opioid epidemic, very few studies have assessed the effects of adolescent nicotine exposure on opioid intake. The objective of our current study is to develop a new animal model to assess the causal relationship of adolescent nicotine exposure on subsequent opioid intake. In this effort, we first replicate previous studies using a well-established 4-day nicotine paradigm. Rats are pretreated with a low dose of nicotine (2 × , 30 μg/kg/0.1 mL, intravenous) or saline during early adolescence (postnatal days 28-31) or adulthood (postnatal days 86-89). Following nicotine pretreatment on postnatal day 32 or postnatal day 90, animals underwent operant intravenous self-administration for the psychostimulant, cocaine [500 μg/kg/infusion (inf)] or the opioid, fentanyl (2.5 μg/kg/inf). We successfully show that adolescent but not adult, nicotine exposure enhances cocaine self-administration in male rats. Furthermore, we illustrate early adolescent but not adult nicotine exposure enhances fentanyl self-administration, independent of sex. Overall, our findings highlight that adolescence is a unique period of development that is vulnerable to nicotine-induced enhancement for cocaine and fentanyl self-administration in rats.
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http://dx.doi.org/10.1097/FBP.0000000000000593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790845PMC
February 2021

The role of the gut microbiome in opioid use.

Behav Pharmacol 2020 04;31(2&3):113-121

Department of Pharmaceutical Sciences, University of California.

Although the gut and brain are separate organs, they communicate with each other via trillions of intestinal bacteria that collectively make up one's gut microbiome. Findings from both humans and animals support a critical role of gut microbes in regulating brain function, mood, and behavior. Gut bacteria influence neural circuits that are notably affected in addiction-related behaviors. These include circuits involved in stress, reward, and motivation, with substance use influencing gut microbial abnormalities, suggesting significant gut-brain interactions in drug addiction. Given the overwhelming rates of opioid overdose deaths driven by abuse and addiction, it is essential to characterize mechanisms mediating the abuse potential of opioids. We discuss in this review the role of gut microbiota in factors that influence opioid addiction, including incentive salience, reward, tolerance, withdrawal, stress, and compromised executive function. We present clinical and preclinical evidence supporting a bidirectional relationship between gut microbiota and opioid-related behaviors by highlighting the effects of opioid use on gut bacteria, and the effects of gut bacteria on behavioral responses to opioids. Further, we discuss possible mechanisms of this gut-brain communication influencing opioid use. By clarifying the relationship between the gut microbiome and opioid-related behaviors, we improve understanding on mechanisms mediating reward-, motivation-, and stress-related behaviors and disorders, which may contribute to the development of effective, targeted therapeutic interventions in opioid dependence and addiction.
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http://dx.doi.org/10.1097/FBP.0000000000000538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7908675PMC
April 2020

Specificity of a rodent alpha(α)6 nicotinic acetylcholine receptor subunit antibody.

Psychopharmacology (Berl) 2020 01 30;237(1):283-285. Epub 2019 Nov 30.

Department of Pharmacuetical Sciences, College of Health Sciences, University of California Irvine, Irvine, CA, USA.

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http://dx.doi.org/10.1007/s00213-019-05413-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954311PMC
January 2020

Prenatal nicotine sex-dependently alters adolescent dopamine system development.

Transl Psychiatry 2019 11 18;9(1):304. Epub 2019 Nov 18.

Department of Pharmacology, University of California, 360 Med Surge II, Irvine, CA, 92697, USA.

Despite persistent public health initiatives, many women continue to smoke during pregnancy. Since maternal smoking has been linked to persisting sex-dependent neurobehavioral deficits in offspring, some consider nicotine to be a safer alternative to tobacco during pregnancy, and the use of electronic nicotine delivery systems is on the rise. We presently show, however, that sustained exposure to low doses of nicotine during fetal development, approximating plasma levels seen clinically with the nicotine patch, produces substantial changes in developing corticostriatal dopamine systems in adolescence. Briefly, pregnant dams were implanted on gestational day 4 with an osmotic minipump that delivered either saline (GS) or nicotine (3 mg/kg/day) (GN) for two weeks. At birth, pups were cross-fostered with treatment naïve dams and were handled daily. Biochemical analyses, signaling assays, and behavioral responses to cocaine were assessed on postnatal day 32, representative of adolescence in the rodent. GN treatment had both sex-dependent and sex-independent effects on prefrontal dopamine systems, altering Catechol-O-methyl transferase (COMT)-dependent dopamine turnover in males and norepinephrine transporter (NET) binding expression in both sexes. GN enhanced cocaine-induced locomotor activity in females, concomitant with GN-induced reductions in striatal dopamine transporter (DAT) binding. GN enhanced ventral striatal D2-like receptor expression and G-protein coupling, while altering the roles of D2 and D3 receptors in cocaine-induced behaviors. These data show that low-dose prenatal nicotine treatment sex-dependently alters corticostriatal dopamine system development, which may underlie clinical deficits seen in adolescents exposed to tobacco or nicotine in utero.
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http://dx.doi.org/10.1038/s41398-019-0640-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6861272PMC
November 2019

Nicotine Gateway Effects on Adolescent Substance Use.

West J Emerg Med 2019 Aug 20;20(5):696-709. Epub 2019 Aug 20.

University of California, Irvine, Department of Emergency Medicine and Pharmaceutical Sciences, Irvine, California.

Given the rise in teenage use of electronic nicotine delivery systems ("vaping") in congruence with the increasing numbers of drug-related emergencies, it is critical to expand the knowledge of the physical and behavioral risks associated with developmental nicotine exposure. A further understanding of the molecular and neurochemical underpinnings of nicotine's gateway effects allows emergency clinicians to advise patients and families and adjust treatment accordingly, which may minimize the use of tobacco, nicotine, and future substances. Currently, the growing use of tobacco products and electronic cigarettes among teenagers represents a major public health concern. Adolescent exposure to tobacco or nicotine can lead to subsequent abuse of nicotine and other substances, which is known as the gateway hypothesis. Adolescence is a developmentally sensitive time period when risk-taking behaviors, such as sensation seeking and drug experimentation, often begin. These hallmark behaviors of adolescence are largely due to maturational changes in the brain. The developing brain is particularly vulnerable to the harmful effects of drugs of abuse, including tobacco and nicotine products, which activate nicotinic acetylcholine receptors (nAChRs). Disruption of nAChR development with early nicotine use may influence the function and pharmacology of the receptor subunits and alter the release of reward-related neurotransmitters, including acetylcholine, dopamine, GABA, serotonin, and glutamate. In this review, we emphasize that the effects of nicotine are highly dependent on timing of exposure, with a dynamic interaction of nAChRs with dopaminergic, endocannabinoid, and opioidergic systems to enhance general drug reward and reinforcement. We analyzed available literature regarding adolescent substance use and nicotine's impact on the developing brain and behavior using the electronic databases of PubMed and Google Scholar for articles published in English between January 1968 and November 2018. We present a large collection of clinical and preclinical evidence that adolescent nicotine exposure influences long-term molecular, biochemical, and functional changes in the brain that encourage subsequent drug abuse.
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http://dx.doi.org/10.5811/westjem.2019.7.41661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6754186PMC
August 2019

Maternal nicotine exposure effects on adolescent learning and memory are abolished in alpha(α)2* nicotinic acetylcholine receptor-null mutant mice.

Neuropharmacology 2018 06 9;135:529-535. Epub 2018 Apr 9.

University of California, Los Angeles, Department of Psychiatry, United States; University of California, Irvine, Department of Emergency Medicine and Pharmacology, United States. Electronic address:

The objective of the current study is to test the hypothesis that the deletion of alpha(α)2* nicotinic acetylcholine receptors (nAChRs) (encoded by the Chrna2 gene) ablate maternal nicotine-induced learning and memory deficits in adolescent mice. We use a pre-exposure-dependent contextual fear conditioning behavioral paradigm that is highly hippocampus-dependent. Adolescent wild type and α2-null mutant offspring are exposed to vehicle or maternal nicotine exposure (200 μg/ml, expressed as base) in the drinking water throughout pregnancy until weaning. Adolescent male offspring mice are tested for alterations in growth and development characteristics as well as modifications in locomotion, anxiety, shock-reactivity and learning and memory. As expected, maternal nicotine exposure has no effects on pup number, weight gain and only modestly reduces fluid intake by 19%. Behaviorally, maternal nicotine exposure impedes extinction learning in adolescent wild type mice, a consequence that is abolished in α2-null mutant mice. The effects on learning and memory are not confounded by alternations in stereotypy, locomotion, anxiety or sensory shock reactivity. Overall, the findings highlight that the deletion of α2* nAChRs eliminate the effects of maternal nicotine exposure on learning and memory in adolescent mice.
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http://dx.doi.org/10.1016/j.neuropharm.2018.04.010DOI Listing
June 2018

Morphine hyposensitivity in streptozotocin-diabetic rats: Reversal by dietary l-arginine treatment.

Clin Exp Pharmacol Physiol 2018 Jan 26;45(1):42-49. Epub 2017 Oct 26.

School of Pharmacy, Faculty of Health and Behavioural Sciences, The University of Queensland, Brisbane, Qld, Australia.

Painful diabetic neuropathy (PDN) is a long-term complication of diabetes. Defining symptoms include mechanical allodynia (pain due to light pressure or touch) and morphine hyposensitivity. In our previous work using the streptozotocin (STZ)-diabetic rat model of PDN, morphine hyposensitivity developed in a temporal manner with efficacy abolished at 3 months post-STZ and maintained for 6 months post-STZ. As this time course mimicked that for the temporal development of hyposensitivity to the pain-relieving effects of the furoxan nitric oxide (NO) donor, PRG150 (3-methylfuroxan-4-carbaldehyde) in STZ-diabetic rats, we hypothesized that progressive depletion of endogenous NO bioactivity may underpin the temporal loss of morphine sensitivity in STZ-diabetic rats. Furthermore, we hypothesized that replenishment of NO bioactivity may restore morphine sensitivity in these animals. Diabetes was induced in male Dark Agouti rats by intravenous injection of STZ (85 mg/kg). Diabetes was confirmed on day 7 if blood glucose concentrations were ≥15 mmol/L. Mechanical allodynia was fully developed in the bilateral hindpaws by 3 weeks of STZ-diabetes in rats and this was maintained for the study duration. Morphine hyposensitivity developed in a temporal manner with efficacy abolished by 3 months post-STZ. Administration of dietary l-arginine (NO precursor) at 1 g/d to STZ-diabetic rats according to a 15-week prevention protocol initiated at 9 weeks post-STZ prevented abolition of morphine efficacy. When given as an 8-week intervention protocol in rats where morphine efficacy was abolished, dietary l-arginine at 1 g/d progressively rescued morphine efficacy and potency. Our findings implicate NO depletion in the development of morphine hyposensitivity in STZ-diabetic rats.
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http://dx.doi.org/10.1111/1440-1681.12855DOI Listing
January 2018

Optogenetic excitation of cholinergic inputs to hippocampus primes future contextual fear associations.

Sci Rep 2017 05 24;7(1):2333. Epub 2017 May 24.

Department of Psychology and Psychiatry, University of California, Los Angeles, California, 90095, USA.

Learning about context is essential for appropriate behavioral strategies, but important contingencies may not arise during initial learning. A variant of contextual fear conditioning, context pre-exposure facilitation, allows us to directly test the relationship between novelty-induced acetylcholine release and later contextual associability. We demonstrate that optogenetically-enhanced acetylcholine during initial contextual exploration leads to stronger fear after subsequent pairing with shock, suggesting that novelty-induced acetylcholine release primes future contextual associations.
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http://dx.doi.org/10.1038/s41598-017-02542-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5443779PMC
May 2017

α2* Nicotinic acetylcholine receptors influence hippocampus-dependent learning and memory in adolescent mice.

Learn Mem 2017 06 15;24(6):231-244. Epub 2017 May 15.

Department of Psychiatry, University of California, Los Angeles, Los Angeles, California 90095, USA.

The absence of α2* nicotinic acetylcholine receptors (nAChRs) in oriens lacunosum moleculare (OLM) GABAergic interneurons ablate the facilitation of nicotine-induced hippocampal CA1 long-term potentiation and impair memory. The current study delineated whether genetic mutations of α2* nAChRs ( and ) influence hippocampus-dependent learning and memory and CA1 synaptic plasticity. We substituted a serine for a leucine (L9'S) in the α2 subunit (encoded by the gene) to make a hypersensitive nAChR. Using a dorsal hippocampus-dependent task of preexposure-dependent contextual fear conditioning, adolescent hypersensitive male mice exhibited impaired learning and memory. The deficit was rescued by low-dose nicotine exposure. Electrophysiological studies demonstrated that hypersensitive α2 nAChRs potentiate acetylcholine-induced ion channel flux in oocytes and acute nicotine-induced facilitation of dorsal/intermediate CA1 hippocampal long-term potentiation in mice. Adolescent male mice null for the α2 nAChR subunit exhibited a baseline deficit in learning that was not reversed by an acute dose of nicotine. These effects were not influenced by locomotor, sensory or anxiety-related measures. Our results demonstrated that α2* nAChRs influenced hippocampus-dependent learning and memory, as well as nicotine-facilitated CA1 hippocampal synaptic plasticity.
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http://dx.doi.org/10.1101/lm.045369.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5435881PMC
June 2017

Reduced-Nicotine Cigarettes in Young Smokers: Impact of Nicotine Metabolism on Nicotine Dose Effects.

Neuropsychopharmacology 2017 Jul 24;42(8):1610-1618. Epub 2017 Jan 24.

Department of Psychiatry and Biobehavioral Sciences, Semel Institute, University of California, Los Angeles, CA, USA.

The use of cigarettes delivering different nicotine doses allows evaluation of the contribution of nicotine to the smoking experience. We compared responses of 46 young adult smokers to research cigarettes, delivering 0.027, 0.110, 0.231, or 0.763 mg nicotine, and conventional cigarettes. On five separate days, craving, withdrawal, affect, and sustained attention were measured after overnight abstinence and again after smoking. Participants also rated each cigarette, and the nicotine metabolite ratio (NMR) was used to identify participants as normal or slow metabolizers. All cigarettes equally alleviated craving, withdrawal, and negative affect in the whole sample, but normal metabolizers reported greater reductions of craving and withdrawal than slow metabolizers, with dose-dependent effects. Only conventional cigarettes and, to a lesser degree, 0.763-mg nicotine research cigarettes increased sustained attention. Finally, there were no differences between ratings of lower-dose cigarettes, but the 0.763-mg cigarettes and (even more so) conventional cigarettes were rated more favorably than lower-dose cigarettes. The findings indicate that smoking-induced relief of craving and withdrawal reflects primarily non-nicotine effects in slow metabolizers, but depends on nicotine dose in normal metabolizers. By contrast, relief of withdrawal-related attentional deficits and cigarette ratings depend on nicotine dose regardless of metabolizer status. These findings have bearing on the use of reduced-nicotine cigarettes to facilitate smoking cessation and on policy regarding regulation of nicotine content in cigarettes. They suggest that normal and slow nicotine metabolizers would respond differently to nicotine reduction in cigarettes, but that irrespective of metabolizer status, reductions to <0.763 mg/cigarette may contribute to temporary attentional deficits.
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http://dx.doi.org/10.1038/npp.2017.18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518898PMC
July 2017

Mechanisms and genetic factors underlying co-use of nicotine and alcohol or other drugs of abuse.

Am J Drug Alcohol Abuse 2017 03 17;43(2):171-185. Epub 2016 Aug 17.

a Department of Anatomy & Neurobiology , School of Medicine, University of California , Irvine , CA , USA.

Concurrent use of tobacco and alcohol or psychostimulants represents a major public health concern, with use of one substance influencing consumption of the other. Co-abuse of these drugs leads to substantial negative health outcomes, reduced cessation, and high economic costs, but the underlying mechanisms are poorly understood. Epidemiological data suggest that tobacco use during adolescence plays a particularly significant role. Adolescence is a sensitive period of development marked by major neurobiological maturation of brain regions critical for reward processing, learning and memory, and executive function. Nicotine exposure during this time produces a unique and long-lasting vulnerability to subsequent substance use, likely via actions at cholinergic, dopaminergic, and serotonergic systems. In this review, we discuss recent clinical and preclinical data examining the genetic factors and mechanisms underlying co-use of nicotine and alcohol or cocaine and amphetamines. We evaluate the critical role of nicotinic acetylcholine receptors throughout, and emphasize the dearth of preclinical studies assessing concurrent drug exposure. We stress important age and sex differences in drug responses, and highlight a brief, low-dose nicotine exposure paradigm that may better model early use of tobacco products. The escalating use of e-cigarettes among youth necessitates a closer look at the consequences of early adolescent nicotine exposure on subsequent alcohol and drug abuse.
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http://dx.doi.org/10.1080/00952990.2016.1209512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493323PMC
March 2017

α2-Null mutant mice have altered levels of neuronal activity in restricted midbrain and limbic brain regions during nicotine withdrawal as demonstrated by cfos expression.

Biochem Pharmacol 2015 Oct 22;97(4):558-565. Epub 2015 Jun 22.

Department of Psychiatry, University of California, Los Angeles, MRL Building, Room 2557, 675 Charles E. Young Drive South, Los Angeles, CA 90095, United States. Electronic address:

Neuronal nicotinic acetylcholine receptors (nAChRs) are the primary binding sites for nicotine within the brain. Using alpha(α)2 nAChR subunit-null mutant mice, the current study evaluates whether the absence of this gene product during mecamylamine-precipitated nicotine withdrawal eliminates neuronal activity within selective midbrain and limbic brain regions, as determined by the expression of the immediate early gene, cfos. Our results demonstrate that nicotine withdrawal enhances neuronal activity within the interpeduncular nucleus and dorsal hippocampus, which is absent in mice null for α2-containing nAChRs. In contrast, we observe that α2-null mutant mice exhibit a suppression of neuronal activity in the dentate gyrus in mice undergoing nicotine withdrawal. Interestingly, α2-null mutant mice display potentiated neuronal activity specifically within the stratum lacunosum moleculare layer of the hippocampus, independent of nicotine withdrawal. Overall, our findings demonstrate that α2-null mutant mice have altered cfos expression in distinct populations of neurons within selective midbrain and limbic brain structures that mediate baseline and nicotine withdrawal-induced neuronal activity.
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http://dx.doi.org/10.1016/j.bcp.2015.06.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4607355PMC
October 2015

Maternal cigarette smoking during pregnancy predicts drug use via externalizing behavior in two community-based samples of adolescents.

Addiction 2014 Oct 21;109(10):1718-29. Epub 2014 Jul 21.

Hatos Center for Neuropharmacology and Semel Institute for Neuroscience & Human Behavior, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.

Background And Aims: Prenatal exposure to maternal cigarette smoking (PEMCS) is associated with a higher probability of substance use in adolescence. We explore if externalizing behavior mediates this relationship, while controlling for a number of potential covariates of this mediation process.

Methods: We used data obtained in two geographically distinct community samples of adolescents. The first (cross-sectional) sample consisted of 996 adolescents (12-18 years of age) recruited from the Saguenay Youth Study (SYS) in Canada (47% with PEMCS). The second (longitudinal) sample consisted of 1141 adolescents (49% with PEMCS) from the Northern Finland Birth Cohort (NFBC1986). In both samples, externalizing behavior and substance use were assessed during adolescence. In the NFBC1986 cohort, externalizing behavior was also assessed in childhood.

Results: In both populations, PEMCS is associated with a higher likelihood of adolescent drug experimentation. In the NFBC1986 cohort, exposed (versus non-exposed) adolescents experiment with an extra 1.27 [B = 0.24, 95% confidence intervals (CI) = 0.15, 0.33 P < 0.001] drugs. In the SYS cohort, a clear protective effect of not being exposed is shown: non-exposed (versus exposed) adolescents are 1.5 times [B = -0.42, 95% CI = -0.75, -0.09, P = 0.013] less likely to take drugs. These associations between PEMCS and drug experimentation remain in the multivariate and mediational analyses.

Conclusions: Prenatal exposure to maternal cigarette smoking appears to be associated with a higher probability of experimenting with drugs during adolescence, both directly and indirectly via externalizing behavior and the number of peers reported as using drugs.
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http://dx.doi.org/10.1111/add.12665DOI Listing
October 2014

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

A single administration of low-dose varenicline saturates α4β2* nicotinic acetylcholine receptors in the human brain.

Neuropsychopharmacology 2012 Jun 7;37(7):1738-48. Epub 2012 Mar 7.

Hatos Center for Neuropharmacology, Semel Institute, University of California, Los Angeles, CA, USA.

The primary objective of this project was to determine the α4β2(*) nicotinic acetylcholine receptor (nAChR) occupancy in human brain of a single low dose of varenicline (0.5 mg), and to explore the relationship between receptor occupancy by varenicline and tobacco withdrawal symptoms ((*)denoting other putative nAChR subunits). Otherwise healthy smokers (n=9) underwent two positron emission tomography (PET) sessions with the selective α4β2(*) radioligand 2-FA. For the PET sessions, participants received either a low dose of varenicline (0.5 mg) or matching placebo pill (double-blind, random order) before imaging. For both sessions, participants received bolus plus continuous infusions of 2-FA, were scanned for 1 h after allowing the radiotracer to reach a steady state, smoked to satiety, and were scanned for 2 more hours. We estimated the fractional receptor occupancy by a single dose of varenicline (0.5 mg) and the corresponding varenicline dissociation constant (K(V)), along with the effect of low-dose varenicline, pill placebo, and smoking-to-satiety on withdrawal rating scales. The data are compatible with 100% occupancy of α4β2(*) nAChRs by a single dose of varenicline, with a 90% lower confidence limit of 89% occupancy for the thalamus and brainstem. The corresponding 90% upper limit on effective K(V) with respect to plasma varenicline was 0.49 nM. Smoking to satiety, but not low-dose varenicline, significantly reduced withdrawal symptoms. Our findings demonstrate that low-dose varenicline results in saturation of α4β2(*) nAChRs in the thalamus and brainstem without reducing withdrawal symptoms.
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http://dx.doi.org/10.1038/npp.2012.20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3358744PMC
June 2012

Quantitative Molecular Imaging of Neuronal Nicotinic Acetylcholine Receptors in the Human Brain with A-85380 Radiotracers.

Curr Med Imaging Rev 2011 May;7(2):107-112

Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, California, USA.

Neuronal nicotinic acetylcholine receptors (nAChRs) have been implicated in a spectrum of cognitive functions as well as psychiatric and neurodegenerative disorders, including tobacco addiction and Alzheimer's Disease. The examination of neuronal nAChRs in living humans is a relatively new field. Researchers have developed brain-imaging radiotracers for nAChRs, with radiolabeled A-85380 compounds having the most widespread use. We provide a brief background on nAChRs, followed by a discussion of the development and application of A-85380 radiotracers in human imaging studies. We describe potential future studies using nicotinic receptor radioligands for the study of tobacco addiction, including the mechanism of action of the smoking-cessation therapy varenicline. Throughout this review, we focus on the significant potential that resides in the identification and quantification of nAChRs in the living human brain.
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http://dx.doi.org/10.2174/157340511795445676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3389797PMC
May 2011

The monoamine oxidase (MAO) inhibitor tranylcypromine enhances nicotine self-administration in rats through a mechanism independent of MAO inhibition.

Neuropharmacology 2011 Jul-Aug;61(1-2):95-104. Epub 2011 Mar 23.

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

Our current study aims to evaluate the mechanisms of tranylcypromine (TCP)-mediated enhancement of nicotine self-administration. We replicated our previous findings which demonstrate that 1 h pretreatment with TCP (3 mg/kg, i.p.) enhances nicotine self-administration (7.5 μg/kg/inj, i.v.) when compared with vehicle-treated rodents. We tested whether TCP-mediated enhancement of nicotine self-administration was due to MAO inhibition or off-target effects by (i) extending the TCP pretreatment time from 1 to 20 h, and (ii) evaluating the role of the individual TCP stereoisomers in nicotine self-administration studies. While 20 h and (-)TCP pretreatment induced significant inhibition of MAO (60-90%), animals found nicotine only weakly reinforcing. Furthermore, while both (+) and (±)TCP treatment induced nearly 100% MAO inhibition, (+)TCP pretreated animals took longer to acquire nicotine self-administration compared to (±)TCP pretreated animals. Stable nicotine self-administration in (+)TCP pretreated animals was influenced by nicotinic receptor activation but not nicotine-paired cues. The opposite was found in (±)TCP pretreated animals. Treatment with (-) or (±)TCP increased dopamine and serotonin overflow, while the (+) and (±)TCP treatment enhanced monoamine overflow subsequent to nicotine. Together, our data suggests TCP enhancement of nicotine self-administration are mediated through mechanisms independent of MAO inhibition, including nicotine-paired cues and monoamine uptake inhibition.
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http://dx.doi.org/10.1016/j.neuropharm.2011.03.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3105177PMC
April 2012

Maternal smoking during pregnancy is associated with epigenetic modifications of the brain-derived neurotrophic factor-6 exon in adolescent offspring.

Am J Med Genet B Neuropsychiatr Genet 2010 Oct;153B(7):1350-4

Brain and Body Centre, University of Nottingham, Nottingham, UK.

Prenatal exposure to maternal cigarette smoking (PEMCS) is associated with variations in brain and behavior in adolescence. Epigenetic mechanisms may mediate some of the consequences of PEMCS through methylation of deoxyribonucleic acid (DNA) in genes important for brain development, such as the brain-derived neurotrophic factor (BDNF). In the current study, we used bisulfite sequencing to assess DNA methylation of the BDNF promoter in the blood of adolescents whose mothers smoked during pregnancy. We demonstrate that PEMCS is associated with higher rates of DNA methylation in the BDNF-6 exon. These results suggest that PEMCS may lead to long-term down-regulation of BDNF expression via the increase of DNA methylation in its promoter region. Such mechanisms could, in turn, lead to modifications in both development and plasticity of the brain exposed in utero to maternal cigarette smoking.
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http://dx.doi.org/10.1002/ajmg.b.31109DOI Listing
October 2010

Orbitofrontal cortex and drug use during adolescence: role of prenatal exposure to maternal smoking and BDNF genotype.

Arch Gen Psychiatry 2009 Nov;66(11):1244-52

Brain and Body Centre, University of Nottingham, University Park, Nottingham NG7 2RD, United Kingdom.

Context: Prenatal exposure to maternal cigarette smoking (PEMCS) may affect brain development and behavior in adolescent offspring.

Objective: To evaluate the involvement of the orbitofrontal cortex (OFC) in mediating the relationship between PEMCS and substance use.

Design: Cross-sectional analyses from the Saguenay Youth Study aimed at evaluating the effects of PEMCS on brain development and behavior among adolescents. Nonexposed adolescents were matched with adolescents exposed prenatally to cigarette smoking by maternal educational level.

Participants And Setting: A French Canadian founder population of the Saguenay-Lac-Saint-Jean region of Quebec, Canada. The behavioral data set included 597 adolescents (275 sibships; 12-18 years of age), half of whom were exposed in utero to maternal cigarette smoking. Analysis of cortical thickness and genotyping were performed using available data from 314 adolescents.

Main Outcome Measures: The likelihood of substance use was assessed with the Diagnostic Interview Schedule for Children Predictive Scales. The number of different drugs tried by each adolescent was assessed using another questionnaire. Thickness of the OFC was estimated from T1-weighted magnetic resonance images using FreeSurfer software.

Results: Prenatal exposure to maternal cigarette smoking is associated with an increased likelihood of substance use. Among exposed adolescents, the likelihood of drug experimentation correlates with the degree of OFC thinning. In nonexposed adolescents, the thickness of the OFC increases as a function of the number of drugs tried. The latter effect is moderated by a brain-derived neurotrophic factor (BDNF) genotype (Val66Met).

Conclusions: We speculate that PEMCS interferes with the development of the OFC and, in turn, increases the likelihood of drug use among adolescents. In contrast, we suggest that, among nonexposed adolescents, drug experimentation influences the OFC thickness via processes akin to experience-induced plasticity.
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http://dx.doi.org/10.1001/archgenpsychiatry.2009.124DOI Listing
November 2009

Involvement of alpha1-adrenergic receptors in tranylcypromine enhancement of nicotine self-administration in rat.

Psychopharmacology (Berl) 2007 Sep 8;193(4):457-65. Epub 2007 May 8.

Department of Pharmacology, School of Medicine, University of California, Room 360, MS2, Irvine, CA 92697, USA.

Rationale: The mechanisms mediating tobacco addiction remain elusive. Nicotine, the psychoactive component in tobacco, is generally believed to be the main cause of reward and addiction. However, tobacco smoke contains thousands of constituents, some of which may interact with nicotine to enhance reward. It has previously been shown that monoamine oxidase (MAO) inhibition, known to result from smoking, can enhance nicotine self-administration. The aim of the present study was to evaluate the role of noradrenergic systems in mediating this enhancement of nicotine reward.

Objective: The objective of this study was to test the hypothesis that MAO inhibitor pretreatment enhances nicotine self-administration by activation of noradrenergic pathways that regulate dopamine release in the nucleus accumbens (NAc).

Methods: The effect of prazosin (0.0625-0.5 mg/kg, i.p.), a specific alpha1-adrenergic receptor antagonist, was examined on male rats pretreated with tranylcypromine (3 mg/kg), an irreversible inhibitor of MAO A and B. Acquisition of nicotine (10 mug kg(-1) inj(-1), i.v.) self-administration behavior was examined over a 5-day period. Nicotine (60 mug kg(-1) inj(-1), i.v.)-induced increase in NAc extracellular dopamine levels was examined by in vivo microdialysis in non-self-administering animals.

Results: We have shown that (1) tranylcypromine enhances nicotine self-administration, (2) prazosin pretreatment blocks both the acquisition and the expression of nicotine self-administration, and (3) prazosin pretreatment diminishes nicotine-induced dopamine release in the NAc.

Conclusion: These data indicate that the stimulation of alpha1-adrenergic receptors is critical for tranylcypromine enhancement of nicotine reward and suggest a critical interplay between the noradrenergic and dopaminergic systems in tobacco addiction.
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http://dx.doi.org/10.1007/s00213-007-0799-7DOI Listing
September 2007

Oxycodone and morphine have distinctly different pharmacological profiles: radioligand binding and behavioural studies in two rat models of neuropathic pain.

Pain 2007 Dec 30;132(3):289-300. Epub 2007 Apr 30.

School of Pharmacy, The University of Queensland, St. Lucia Campus, St. Lucia, Brisbane, Qld 4072, Australia.

Previously, we reported that oxycodone is a putative kappa-opioid agonist based on studies where intracerebroventricular (i.c.v.) pre-treatment of rats with the kappa-selective opioid antagonist, nor-binaltorphimine (nor-BNI), abolished i.c.v. oxycodone but not morphine antinociception, whereas pretreatment with i.c.v. naloxonazine (mu-selective antagonist) produced the opposite effects. In the present study, we used behavioural experiments in rat models of mechanical and biochemical nerve injury together with radioligand binding to further examine the pharmacology of oxycodone. Following chronic constriction injury (CCI) of the sciatic nerve in rats, the antinociceptive effects of intrathecal (i.t.) oxycodone, but not i.t. morphine, were abolished by nor-BNI. Marked differences were found in the antinociceptive properties of oxycodone and morphine in streptozotocin (STZ)-diabetic rats. While the antinociceptive efficacy of morphine was abolished at 12 and 24 weeks post-STZ administration, the antinociceptive efficacy of s.c. oxycodone was maintained over 24 weeks, albeit with an approximately 3- to 4-fold decrease in potency. In rat brain membranes irreversibly depleted of mu- and delta-opioid binding sites, oxycodone displaced [(3)H]bremazocine (kappa(2)-selective in depleted membranes) binding with relatively high affinity whereas the selective mu- and delta-opioid ligands, CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2)) and DPDPE ([D-Pen(2,5)]-enkephalin), respectively, did not. In depleted brain membranes, the kappa(2b)-ligand, leu-enkephalin, prevented oxycodone's displacement of high-affinity [(3)H]bremazocine binding, suggesting the notion that oxycodone is a kappa(2b)-opioid ligand. Collectively, the present findings provide further support for the notion that oxycodone and morphine produce antinociception through distinctly different opioid receptor populations. Oxycodone appears to act as a kappa(2b)-opioid agonist with a relatively low affinity for mu-opioid receptors.
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http://dx.doi.org/10.1016/j.pain.2007.03.022DOI Listing
December 2007

Tranylcypromine enhancement of nicotine self-administration.

Neuropharmacology 2007 May 20;52(6):1415-25. Epub 2007 Feb 20.

Department of Pharmacology, School of Medicine, University of California, Irvine, CA 92697, USA.

Tobacco use has one of the highest rates of addiction of any abused drug. Paradoxically, in animal models, nicotine appears to be a weak reinforcer. We report here that the inhibition of monoamine oxidase (MAO), a major effect of tobacco smoke, increases the reinforcing effect of nicotine. Rats (aged postnatal day 27 and 90) were tested for self-administration, without prior response training, in five daily 3-h sessions. Whereas control rats did not self-administer nicotine, low doses of nicotine (2.5 to 21 microg/kg/injection) were avidly self-administered following a pretreatment with tranylcypromine (3 mg/kg), an irreversible and non-selective MAO inhibitor. Tranylcypromine-enhanced nicotine (10 microg/kg/injection, i.v.) self-administration was reduced by systemic injection of a D1-dopaminergic receptor antagonist, SCH23390 (0.02 mg/kg). Moreover, an increase in extracellular dopamine in the nucleus accumbens was detected, using microdialysis, following nicotine (60 microg/kg) injection in tranylcypromine pre-treated rats. Depending on the time of tranylcypromine pretreatment (20 or 1 h), MAO activity was decreased by 72% and 99% and nicotine intake at day 5 was increased by 619 and 997%, respectively. Taken together, these results indicate that in a stringent self-administration acquisition test, MAO inhibition increases the rewarding effect of low doses of nicotine, possibly via a dopamine-dependent mechanism.
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http://dx.doi.org/10.1016/j.neuropharm.2007.02.001DOI Listing
May 2007

Adolescent maturation of cocaine-sensitive neural mechanisms.

Neuropsychopharmacology 2007 Nov 14;32(11):2279-89. Epub 2007 Feb 14.

Department of Anatomy and Neurobiology, School of Medicine, University of California, Irvine, CA, USA.

Both clinical and animal studies have shown that adolescents undergo a late maturation of the central nervous system, which may underlie adolescent typical behaviors. In particular, decreased behavioral response to cocaine has been found in adolescents as compared to adults. In the present study, cocaine was used as a tool to explore adolescent brain maturation. Juvenile (postnatal day (P) 27), adolescent (P37), and adult (P90) male Sprague-Dawley rats were treated acutely with cocaine (750 microg/kg/injection x 2, i.v.), and c-fos mRNA expression, a marker of neuronal activation, was evaluated by in situ hybridization. Cocaine-induced c-fos mRNA was similar across ages in the dorsal caudate putamen (CPu), nucleus accumbens, and lateral bed nucleus of the stria terminalis. In contrast, there was a diminished response in juvenile/adolescent ventral CPu and in juvenile central nucleus of the amygdala, and an increased response in juvenile/adolescent cortex. Further studies evaluated the mechanism of the late maturation of cocaine response in ventral CPu. No significant age differences were observed in regional dopamine (DA) transporter binding. Although striatal DA content was significantly reduced at P27 as compared to adult, there was no difference between dorsal and ventral subregions. In contrast, basal- and cocaine-induced extracellular DA overflow, as measured by in vivo microdialysis, was lower in juvenile ventral CPu than in the adults. This age difference was not observed in dorsal CPu. These findings suggest that impulse activity in DA afferents to ventral CPu is immature in adolescents. In conclusion, the present study showed that cocaine-sensitive neuronal circuits continue to mature during adolescence.
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http://dx.doi.org/10.1038/sj.npp.1301349DOI Listing
November 2007

Adolescent development of forebrain stimulant responsiveness: insights from animal studies.

Ann N Y Acad Sci 2004 Jun;1021:148-59

Department of Pharmacology, College of Medicine, University of California, Irvine, CA 92697-4625, USA.

Although initiation of drug abuse occurs primarily during adolescence, little is known about the central effects of nicotine and other abused drugs during this developmental period. Here evidence, derived from studies in rodents, is presented that suggests that tobacco use initiation during early adolescence results from a higher reward value of nicotine. The developmental profiles of the rewarding effects of other abused drugs, such as cocaine, differ from that of nicotine. Using in situ hybridization to quantify mRNA levels of the immediate early gene, cfos, the neuronal activating effects of nicotine in limbic and sensory cortices at different developmental stages are evaluated. Significant age changes in basal levels of cfos mRNA expression in cortical regions are observed, with a peak of responding of limbic cortices during early adolescence. A changing pattern of nicotine-induced neuronal activation is seen across the developmental spectrum, with unique differences in both limbic and sensory cortex responding during adolescence. An attentional set-shifting task was also used to evaluate whether the observed differences during adolescence reflect early functional immaturity of prefrontal cortices that regulate motivated behavior and psychostimulant responding. The finding of significantly better responding during adolescence suggests apparent functional maturity of prefrontal circuits and greater cognitive flexibility at younger ages. These findings in rodent models suggest that adolescence is a period of altered sensitivity to environmental stimuli, including abused drugs. Further efforts are required to overcome technical challenges in order to evaluate drug effects systematically in this age group.
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http://dx.doi.org/10.1196/annals.1308.018DOI Listing
June 2004