Journal of Pediatric Biochemistry - Volume 1, issue 2

Authors: Arias, Hugo R. | Bouzat, Cecilia

Article Type: Research Article

Abstract: Nicotinic acetylcholine receptors (AChRs) are the best characterized ion channels representing the Cys-loop receptor superfamily. AChRs have all the machinery to recognize the neurotransmitter ACh and other agonists such as nicotine, and to transduce the agonist-induced conformational changes into the opening of the intrinsic cation channel. The gating machinery couples ligand binding, located at the extracellular portion, to the opening of the ion channel, located at the transmembrane region. The interface between the …extracellular and the transmembrane domains is considered one of the most important structural and functional features for the process of gating. And finally, in the prolonged presence of agonists, the AChR becomes desensitized. Several drugs affect the functioning of these receptors. Among them, positive allosteric modulators (PAM) have acquired importance since are novel drugs for several neurological diseases. PAMs do not bind to the orthostetic binding sites but allosterically enhance the activity elicited by agonists by increasing the gating process and/or by decreasing desensitization. Instead, negative allosteric modulators (NAMs) produce the opposite effects. Interestingly, this negative effect is similar to that found for another class of allosteric drugs, i.e. non competitive antagonists (NCAs). However, the main difference between both categories of drugs is based on their distinct binding site locations. Although both NAMs and NCAs do not bind to the agonist sites, NACs bind to sites located in the ion channel, whereas NAMs bind to nonluminal sites. Interestingly, PAMs and NAMs might be developed as potential medications for the treatment of several diseases involving AChRs including, dementia-, skin-, and immunological-related diseases, drug addiction, and cancer. More exciting is the potential combination of specific agonists with PAMs. However, we are still in the beginning of understanding how these compounds act and how these drugs can be used therapeutically. Show more

Keywords: Nicotinic receptors, pharmacological properties, gating, allosteric modulators

DOI: 10.3233/JPB-2010-0017

Citation: Journal of Pediatric Biochemistry, vol. 1, no. 2, pp. 53-73, 2010

Authors: Ortells, Marcelo O. | Arias, Hugo R.

Article Type: Research Article

Abstract: Nicotine is the main psychoactive substance present in tobacco, targeting neuronal nicotinic acetylcholine receptors (AChRs). The main effects of nicotine associated with smoking are AChR activation, desensitization, and upregulation, with the subsequent modulation of the mesocorticolimbic dopaminergic system. However, there is a lack of a comprehensive explanation of their roles that effectively makes clear how nicotine dependence might be established on those grounds. Receptor upregulation is an unusual effect for a drug …of abuse, because theoretically this implies less need for drug consumption. Receptor upregulation and receptor desensitization are commonly viewed as opposite, homeostatic mechanisms. We here review the available information on smoking addiction, and drugs employed as aids in smoking cessation, especially under a recently presented model of nicotine dependence. In this model both receptor upregulation and receptor desensitization are responsible for establishing a biochemical mechanism of nicotine dependence, which have an important role in starting and maintaining tobacco addiction. Basically, a conclusion of this model is that those drugs used for smoking cessation should inhibit preferentially α4β2-containing AChRs and to have a low or null ability to upregulate AChRs, as this characteristic allows the smoker to achieve downregulation without abstinence symptoms. Show more

Keywords: Nicotinic receptors, nicotine addiction, neurotransmitter release, AChR upregulation, AChR desensitization

DOI: 10.3233/JPB-2010-0015

Citation: Journal of Pediatric Biochemistry, vol. 1, no. 2, pp. 75-89, 2010

Authors: Mousa, Shaker A. | Arias, Hugo R.

Article Type: Research Article

Abstract: Nicotine, one of the thousands of chemicals in cigarette smoke has a highly debated effect on cell proliferation and tissue healing. Recent studies documented its pro-angiogenesis effects by stimulating endothelial cell α7 non-neronal nicotinic acetylcholine receptors (α7 AChR). Angiogenesis is a critical physiological process for cell survival and development. Endothelial cells, necessary for the course of angiogenesis, express several non-neuronal AChRs. The most important functional non-neuronal AChRs are homomeric α7 AChRs and …several heteromeric AChRs formed by a combination of α3, α5, β2, and β4 subunits, including α3β4-containing AChRs. In endothelial cells, α7 AChR stimulation indirectly triggers the activation of the integrin α_{ν} β _{3} receptor and an intracellular MAP kinase (ERK) pathway that mediates angiogenesis. Non-selective cholinergic agonists such as nicotine have been shown to induce angiogenesis, enhancing tumor progression. Moreover, α7 AChR selective antagonists such as α-bungarotoxin and methyllycaconitine as well as the nonspecific antagonist mecamylamine have been shown to inhibit endothelial cell proliferation and ultimately blood vessel formation. Exploitation of such pharmacologic properties can lead to the discovery of new specific cholinergic antagonists as anti-cancer therapies. Conversely, the pro-angiogenic effect elicited by specific agonists can be used to treat diseases that respond to re-vascularization such as diabetic ischemia and atherosclerosis, as well as to accelerate wound healing. In this review we discuss the pharmacological evidence supporting the importance of non-neuronal AChRs in angiogenesis and potential intracellular mechanisms by which α7 AChR activation mediates these cellular processes. Show more

Keywords: Angiogenesis, non-neuronal nicotinic receptors, nicotinic agonists, nicotinic antagonists, wound healing, growth factors, intracellular pathways

DOI: 10.3233/JPB-2010-0013

Citation: Journal of Pediatric Biochemistry, vol. 1, no. 2, pp. 91-104, 2010

Authors: Koudsi, Nael Al | O'Loughlin, Jennifer | Rodriguez, Daniel | Audrain-McGovern, Janet | Tyndale, Rachel F.

Article Type: Research Article

Abstract: In humans, nicotine is extensively metabolized via multiple pathways that are catalyzed by genetically variable enzymes. As a result, there is large interindividual and interethnic variability observed in nicotine pharmacokinetics. Twin studies suggest an important role for genetic factors, although environmental and physiological factors also contribute to this variability. The present chapter focuses on the genetics of nicotine metabolism and its impact on smoking behaviors with specific emphasis on the adolescent period. …Enzymes involved in nicotine metabolism include cytochromes P450 (CYPs), aldehyde oxidase (AOX1), UDP-Glucuronosyltransferases (UGTs), and flavin-containing monooxygenase 3 (FMO3). CYP2A6 is the main enzyme involved in nicotine's metabolic inactivation; CYP2A6 genetic variants contribute substantially to the observed variability in nicotine metabolism. In addition, genetic variation in CYP2A6 has been associated with multiple smoking behaviors in adults (e.g. risk of smoking, level of cigarette consumption, depth of inhalation, and ability to stop smoking). Among adolescents, two longitudinal cohort studies showed a consistent effect of CYP2A6 genetic variation on level of smoking among dependent adolescents but found different effects with respect to the association of CYP2A6 with onset versus progression of nicotine dependence. We re-examined these two studies in detail in order to more fully understand these findings. Understanding variability in nicotine metabolism assists in understanding variability in response to nicotine and liability to smoking, providing the potential of identifying individuals at greater risk for smoking, sustained smoking and smoking related disorders and also may assist in personalizing treatment to improve efficacy of nicotine replacement therapies. Show more

Keywords: CYP2A6, nicotine, pharmacogenetics, adolescent, smoking

DOI: 10.3233/JPB-2010-0014

Citation: Journal of Pediatric Biochemistry, vol. 1, no. 2, pp. 105-123, 2010

Authors: Smith, Andrew M. | Dwoskin, Linda P. | Pauly, James R.

Article Type: Research Article

Abstract: Tobacco use during pregnancy continues to be a major problem with more than 16% of women in the United States continuing to smoke while pregnant. Tobacco smoke is known to contain more than 4,000 different chemicals, and while many of these compounds have the potential to interfere with proper neurodevelopment, there is direct evidence that nicotine, the major psychoactive substance present in tobacco, acts as a neuroteratogen. Nicotine activates, and subsequently desensitizes, neuronal nicotinic acetylcholine …receptor subtypes (AChRs), which are expressed in the developing central nervous system (CNS) prior to the in-growth of cholinergic neurons. Nicotinic AChRs are present by the first trimester of development in both humans and rodents, and activation of these receptors by acetylcholine is thought to play a critical role in CNS development. The purpose of the current review is to provide an overview of the role that nicotinic AChRs play in the developing CNS and to describe the effects of nicotine exposure during early development on neuronal cell biology, nicotinic AChR expression and neurotransmitter system (e.g., dopamine, norepinephrine, serotonin) function. In particular, differences that occur as a result of the timing and duration of nicotine exposure will be discussed. Emphasis will be placed on preclinical studies examining particular periods of time which correspond to periods of prenatal development in humans (i.e., first, second and third trimesters). Finally, the effects of early nicotine exposure on neurobehavioral development as it pertains to specific disorders, i.e., attention deficit hyperactivity disorder (ADHD), depression and addiction, will be discussed. Show more

Keywords: Nicotine, nicotinic acetylcholine receptors, neuroanatomy, dopamine, norepinephrine, serotonin, Attention Deficit Hyperactivity Disorder, depression, addiction

DOI: 10.3233/JPB-2010-0012

Citation: Journal of Pediatric Biochemistry, vol. 1, no. 2, pp. 125-141, 2010

Authors: Contreras, Gisèle A. | O'Loughlin, Jennifer | Rodriguez, Daniel | Wellman, Robert J. | DiFranza, Joseph R.

Article Type: Research Article

Abstract: Nicotine withdrawal and the compulsion to use tobacco resulting from withdrawal form the core clinical features of nicotine dependence (ND). However, some ND measures show little or no content overlap with these clinical features. Our objective was to review the content and psychometric properties of available measures of ND for youth. A literature search identified 27 English language articles published in 2000–2010 that evaluated ND measures in adolescents or young adults. A consensus process among the …authors was used to establish if each item in each measure assessed withdrawal or compulsion, or if the item tapped other aspects of cigarette smoking including tolerance, harm, triggers for smoking, cigarette use patterns, prioritizing smoking, perceived utility, or attitudes about smoking. Out of 14 measures identified, three (Hooked on Nicotine Checklist, Latency to Withdrawal, Withdrawal Symptom Cluster) measured the core clinical features of ND; six (Autonomy Over Smoking Scale, DSM IV, Dimensions of Tobacco Dependence Scale, ICD-10 Tobacco Dependence, ND/Cravings Symptom Cluster, Nicotine Dependence Syndrome Scale) measured withdrawal/compulsion and other aspects of smoking; and five (Fagerström Test for Nicotine Dependence, Modified Fagerström Tolerance Questionnaire, Nicotine Dependence Scale for Adolescents, Self-Medication Symptom Cluster, Stanford Dependence Index) had few or no withdrawal/compulsion indicators. Existing measures vary widely in the degree to which they assess the known clinical features of ND. Attempts to assess ND indirectly in youth by measuring other aspects of smoking may result in inaccuracy if items are endorsed for reasons other than ND. No existing measure assesses the full spectrum of clinically recognized features of ND. Show more

Keywords: Nicotine, dependence, adolescents, measurement

DOI: 10.3233/JPB-2010-0011

Citation: Journal of Pediatric Biochemistry, vol. 1, no. 2, pp. 143-164, 2010

Authors: Wu, Becky S. | George, Tony P.

Article Type: Research Article

Abstract: The prevalence of tobacco use has declined substantially in the past few decades, yet it remains the leading cause of preventable death globally. Smoking frequency in adolescents is also alarming and is often associated with greater susceptibility to health problems in their adult lives. Unlike the extensive body of literature that exists for adults, research on smoking cessation approaches for adolescents is scarce. This review discusses current pharmacological and psychosocial interventions available for both adults and …adolescents. Anti-smoking medications approved for adult smokers are either nicotine based (i.e., nicotine patch, gum, inhaler, nasal spray and lozenges) or non-nicotine based (i.e., sustained-release bupropion and varenicline), all of which improve abstinence by acting on nicotinic acetylcholine receptors (nAChRs) in the brain. Non-pharmacological interventions targeting the psychosocial aspects of smoking addiction include brief counselling, cognitive-behavioural therapy, motivational interviewing, contingency management, relapse-prevention strategies, social influence and mobile phone-based programs. Show more

Keywords: Addiction, dependence, adolescent, nicotine, smoking cessation

DOI: 10.3233/JPB-2010-0016

Citation: Journal of Pediatric Biochemistry, vol. 1, no. 2, pp. 165-174, 2010

Authors: Rollema, Hans | Faessel, Hélène M.

Article Type: Research Article

Abstract: This review describes the role of α4β2 containing nicotinic acetylcholine receptors in the mesolimbic reward pathway in the neurobiology of nicotine addiction and discusses the rationale for targeting this receptor with partial agonists as novel smoking cessation agents. Varenicline is a α4β2 nicotinic acetylcholine receptor partial agonist that is a smoking cessation aid with a dual mechanism of action: relief of craving and withdrawal symptoms, as well as attenuation of nicotine reinforcement. The pharmacological profile of …varenicline is consistent with that of a potent and selective partial agonist at the target receptor, both in in vitro and in vivo neurochemical and behavioral models. Varenicline was nominated for full clinical development in 1997, and later approved in the US and Europe as a smoking cessation aid in 2006. The recommended dose of varenicline is 1 mg BID for 12 weeks after an initial titration week in adult smokers motivated to stop smoking. The pharmacokinetics of varenicline is linear and consistent regardless of smoking status, age, gender or ethnic background. Varenicline is largely eliminated unchanged in the urine, and consequently a dose adjustment is warranted for patients with severe renal insufficiency. Although varenicline is currently not approved for use in smokers under age 18, its pharmacokinetic and tolerability profile in adolescents appeared generally similar to adults. Several large clinical trials have consistently shown the efficacy, tolerability and safety of varenicline in various ethnic smoking populations and in adult smokers with co-morbid chronic pulmonary or cardiovascular disease. Additional clinical studies in special patient populations are currently ongoing. Show more

Keywords: Varenicline, nicotine, smoking cessation, adolescent, safety, α4β2 AChR partial agonist

DOI: 10.3233/JPB-2010-0018

Citation: Journal of Pediatric Biochemistry, vol. 1, no. 2, pp. 175-184, 2010

Authors: Arias, Hugo R.

Article Type: Research Article

Abstract: This minireview focuses on the anti-nicotinic properties of bupropion (BP) at the molecular and cellular levels. The main pharmacological mechanism is based on the fact that BP induces the release as well as inhibits the reuptake of neurotransmitters such as a dopamine (DA) and norepinephrine (NE). Additional mechanisms of action have been also determined. For example, BP is a noncompetitive antagonist (NCA) of several nicotinic acetylcholine receptors (AChRs). Based on this evidence, the clinical activity of …BP is currently considered to be mediated by its stimulatory action on the DA and NE systems as well as its inhibitory action on AChRs. More specifically, BP inhibits presynaptic α4β2-containing AChRs in GABAergic neurons of the ventral tegmental area and α3β4-containing AChRs in the habenulo-intrerpeduncular pathway. This inhibition finally decreases the addictive effects mediated by nicotine. Based on studies on muscle AChRs at the molecular level, a sequential mechanism is hypothesized to explain the inhibitory action of BP on neuronal AChRs: (1) BP first binds to AChRs in the resting state, decreasing the probability of ion channel opening, (2) the remnant fraction of open ion channels is subsequently decreased by accelerating the desensitization process, and (3), BP interacts with a binding domain located between the serine (position 6') and valine (position 13') rings that is shared with other NCAs including, phencyclidine, tricyclic antidepressants, and serotonin selective reuptake inhibitors. This new evidence paves the way for further investigations using AChRs as targets for the action of safer antidepressants and novel anti-addictive compounds. Show more

Keywords: Nicotine addiction, bupropion, nicotinic acetylcholine receptors

DOI: 10.3233/JPB-2010-0010

Citation: Journal of Pediatric Biochemistry, vol. 1, no. 2, pp. 185-197, 2010