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Expert Review of Neurotherapeutics 2016Adult Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent psychiatric condition associated with high disability and frequent comorbidity. Current standard... (Review)
Review
Adult Attention Deficit Hyperactivity Disorder (ADHD) is a prevalent psychiatric condition associated with high disability and frequent comorbidity. Current standard pharmacotherapy (methylphenidate and atomoxetine) improves ADHD symptoms in the short-term, but poor data were published about long-term treatment. In addition a number of patients present partial or no response to methylphenidate and atomoxetine. Research into the main database sources has been conducted to obtain an overview of alternative pharmacological approaches in adult ADHD patients. Among alternative compounds, amphetamines (mixed amphetamine salts and lisdexamfetamine) have the most robust evidence of efficacy, but they may be associated with serious side effects (e.g. psychotic symptoms or hypertension). Antidepressants, particularly those acting as noradrenaline or dopamine enhancers, have evidence of efficacy, but they should be avoided in patients with comorbid bipolar disorder. Finally metadoxine and lithium may be particularly suitable in case of comorbid alcohol misuse or bipolar disorder.
Topics: Adrenergic alpha-Agonists; Adult; Amphetamines; Antidepressive Agents; Attention Deficit Disorder with Hyperactivity; Benzhydryl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Bupropion; Central Nervous System Stimulants; Desipramine; Dopamine Agents; Droxidopa; Drug Combinations; Duloxetine Hydrochloride; Guanfacine; Histamine Agents; Humans; Lisdexamfetamine Dimesylate; Lithium Compounds; Lobeline; Mecamylamine; Memantine; Modafinil; Morpholines; Nicotinic Agonists; Nicotinic Antagonists; Nomifensine; Paroxetine; Pyridines; Pyridoxine; Pyrrolidonecarboxylic Acid; Quinazolinones; Reboxetine; Venlafaxine Hydrochloride; Wakefulness-Promoting Agents
PubMed: 26693882
DOI: 10.1586/14737175.2016.1135735 -
Brain Sciences Nov 2022cocaine craving is a core feature of cocaine use disorder and remains a critical challenge for abstinence and relapse prevention. This review summarizes the anti-craving... (Review)
Review
BACKGROUND
cocaine craving is a core feature of cocaine use disorder and remains a critical challenge for abstinence and relapse prevention. This review summarizes the anti-craving efficacy of pharmacotherapies tested for cocaine use disorder, in the context of randomized-controlled clinical trials.
OBJECTIVES
we assessed the databases of the U.S. National Library of Medicine, Google Scholar, and PsycINFO, without date restrictions up to August 2022, to identify relevant studies.
STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTIONS
we included double-blinded randomized-controlled trials investigating pharmacotherapies for cocaine craving and/or cocaine use disorder whose outcomes included cocaine craving.
STUDY APPRAISAL AND SYNTHESIS METHODS
Two authors screened studies' titles and abstracts for inclusion, and both read all the included studies. We systematically gathered information on the following aspects of each study: title; author(s); year of publication; sample size; mean age; sample characteristics; study set-ting; whether participants were treatment-seeking; study design; craving measures; study interventions; drop-out rates; and other relevant outcomes.
RESULTS
Overall, we appraised 130 clinical trials, including 8137 participants. We further considered the drugs from the studies that scored equal to or greater than six points in the quality assessment. There was a correlation between craving and cocaine use outcomes (self-reports, timeline follow-back or urinary benzoylecgonine) in the vast majority of studies. In the short-term treatment, acute phenylalanine-tyrosine depletion, clonidine, fenfluramine, meta-chlorophenylpiperazine (m-CPP) and mecamylamine presented promising effects. In the long term, amphetamine, biperiden, carbamazepine, lisdexamfetamine, lorcaserin, methamphetamine, mirtazapine, pioglitazone, progesterone, guanfacine, levodopa, nefazodone presented promising anti-craving effects. Unfortunately, the highly tested medications were not successful in most of the trials, as follows: propranolol in the short term; amantadine, aripiprazole, bromocriptine, citicoline, ketamine, modafinil, olanzapine, topiramate in the long term. The remaining 52 medications had no positive anti-craving outcomes.
LIMITATIONS
Our review was limited by high heterogeneity of craving assessments across the studies and by a great range of pharmacotherapies. Further, the majority of the studies considered abstinence and retention in treatment as the main outcomes, whereas craving was a secondary outcome and some of the studies evaluated patients with cocaine use disorder with comorbidities such as opioid or alcohol use disorder, schizophrenia, bipolar disorder or attention deficit hyperactivity. Lastly, most of the studies also included non-pharmacological treatments, such as counseling or psychotherapy.
CONCLUSIONS
There is a direct association between craving and cocaine use, underscoring craving as an important treatment target for promoting abstinence among persons with cocaine use disorder. Clonidine, fenfluramine and m-CPP showed to be promising medications for cocaine craving in the short-term treatment, and amphetamine, biperiden, carbamazepine, lisdexamfetamine, lorcaserin, methamphetamine, mirtazapine, pioglitazone, progesterone, guanfacine, levodopa, nefazodone in the long-term treatment.
PubMed: 36421870
DOI: 10.3390/brainsci12111546 -
Nicotine & Tobacco Research : Official... Feb 2022Ingestion of nicotine by smoking, vaping, or other means elicits various effects including reward, antinociception, and aversion due to irritation, bitter taste, and... (Review)
Review
INTRODUCTION
Ingestion of nicotine by smoking, vaping, or other means elicits various effects including reward, antinociception, and aversion due to irritation, bitter taste, and unpleasant side effects such as nausea and dizziness.
AIMS AND METHODS
Here we review the sensory effects of nicotine and the underlying neurobiological processes.
RESULTS AND CONCLUSIONS
Nicotine elicits oral irritation and pain via the activation of neuronal nicotinic acetylcholine receptors (nAChRs) expressed by trigeminal nociceptors. These nociceptors excite neurons in the trigeminal subnucleus caudalis (Vc) and other brainstem regions in a manner that is significantly reduced by the nAChR antagonist mecamylamine. Vc neurons are excited by lingual application of nicotine and exhibit a progressive decline in firing to subsequent applications, consistent with desensitization of peripheral sensory neurons and progressively declining ratings of oral irritation in human psychophysical experiments. Nicotine also elicits a nAChR-mediated bitter taste via excitation of gustatory afferents. Nicotine solutions are avoided even when sweeteners are added. Studies employing oral self-administration have yielded mixed results: Some studies show avoidance of nicotine while others report increased nicotine intake over time, particularly in adolescents and females. Nicotine is consistently reported to increase human pain threshold and tolerance levels. In animal studies, nicotine is antinociceptive when delivered by inhalation of tobacco smoke or systemic infusion, intrathecally, and by intracranial microinjection in the pedunculopontine tegmentum, ventrolateral periaqueductal gray, and rostral ventromedial medulla. The antinociception is thought to be mediated by descending inhibition of spinal nociceptive transmission. Menthol cross-desensitizes nicotine-evoked oral irritation, reducing harshness that may account for its popularity as a flavor additive to tobacco products.
IMPLICATIONS
Nicotine activates brain systems underlying reward and antinociception, but at the same time elicits aversive sensory effects including oral irritation and pain, bitter taste, and other unpleasant side effects mediated largely by nicotinic acetylcholine receptors (nAChRs). This review discusses the competing aversive and antinociceptive effects of nicotine and exposure to tobacco smoke, and the underlying neurobiology. An improved understanding of the interacting effects of nicotine will hopefully inform novel approaches to mitigate nicotine and tobacco use.
Topics: Adolescent; Animals; Female; Humans; Mecamylamine; Nicotine; Receptors, Nicotinic; Nicotiana; Tobacco Products; Tobacco Use
PubMed: 33955474
DOI: 10.1093/ntr/ntab086 -
Journal of Psychopharmacology (Oxford,... Oct 2021Animal models are critical to improve our understanding of the neuronal mechanisms underlying nicotine withdrawal. Nicotine dependence in rodents can be established by... (Review)
Review
BACKGROUND
Animal models are critical to improve our understanding of the neuronal mechanisms underlying nicotine withdrawal. Nicotine dependence in rodents can be established by repeated nicotine injections, chronic nicotine infusion via osmotic minipumps, oral nicotine intake, tobacco smoke exposure, nicotine vapor exposure, and e-cigarette aerosol exposure. The time course of nicotine withdrawal symptoms associated with these methods has not been reviewed in the literature.
AIM
The goal of this review is to discuss nicotine withdrawal symptoms associated with the cessation of nicotine, tobacco smoke, nicotine vapor, and e-cigarette aerosol exposure in rats and mice. Furthermore, age and sex differences in nicotine withdrawal symptoms are reviewed.
RESULTS
Cessation of nicotine, tobacco smoke, nicotine vapor, and e-cigarette aerosol exposure leads to nicotine withdrawal symptoms such as somatic withdrawal signs, changes in locomotor activity, anxiety- and depressive-like behavior, learning and memory deficits, attention deficits, hyperalgesia, and dysphoria. These withdrawal symptoms are most pronounced within the first week after cessation of nicotine exposure. Anxiety- and depressive-like behavior, and deficits in learning and memory may persist for several months. Adolescent (4-6 weeks old) rats and mice display fewer nicotine withdrawal symptoms than adults (>8 weeks old). In adult rats and mice, females show fewer nicotine withdrawal symptoms than males. The smoking cessation drugs bupropion and varenicline reduce nicotine withdrawal symptoms in rodents.
CONCLUSION
The nicotine withdrawal symptoms that are observed in rodents are similar to those observed in humans. Tobacco smoke and e-cigarette aerosol contain chemicals and added flavors that enhance the reinforcing properties of nicotine. Therefore, more valid animal models of tobacco and e-cigarette use need to be developed by using tobacco smoke and e-cigarette aerosol exposure methods to induce dependence.
Topics: Animals; Disease Models, Animal; Electronic Nicotine Delivery Systems; Humans; Mice; Nicotine; Rats; Sex Factors; Smoking Cessation; Smoking Cessation Agents; Substance Withdrawal Syndrome; Tobacco Use Disorder
PubMed: 33888006
DOI: 10.1177/02698811211005629 -
Cureus Feb 2023A chronic, recurring illness, known as nicotine addiction and dependence, is defined by a person's dependence on the substance up to the extent that their normal... (Review)
Review
A chronic, recurring illness, known as nicotine addiction and dependence, is defined by a person's dependence on the substance up to the extent that their normal day-to-day activities are compromised in the absence of the substance. This paper will highlight first-line smoking cessation treatments, such as nicotine replacement therapy (NRT), bupropion, and varenicline, and second-line medications, such as clonidine, nortriptyline, anxiolytics, mecamylamine, naltrexone, and NicVAX (Nabi Biopharmaceuticals, Rockville, MD, USA). NRT offers many options for nicotine delivery methods, comprising nicotine gum, rapid-release gum, lozenges, transdermal patches, high-dose nicotine patches, oral inhalers, nasal sprays, electronic nicotine delivery systems (ENDS), and sublingual tablets. Pharmacotherapies for quitting tobacco should lessen withdrawal symptoms and stop nicotine's reinforcing effects without having too many side effects.
PubMed: 36938244
DOI: 10.7759/cureus.35086 -
Pharmacological Research Mar 2023Despite recent advances in understanding the causes of epilepsy, especially the genetic, comprehending the biological mechanisms that lead to the epileptic phenotype...
Despite recent advances in understanding the causes of epilepsy, especially the genetic, comprehending the biological mechanisms that lead to the epileptic phenotype remains difficult. A paradigmatic case is constituted by the epilepsies caused by altered neuronal nicotinic acetylcholine receptors (nAChRs), which exert complex physiological functions in mature as well as developing brain. The ascending cholinergic projections exert potent control of forebrain excitability, and wide evidence implicates nAChR dysregulation as both cause and effect of epileptiform activity. First, tonic-clonic seizures are triggered by administration of high doses of nicotinic agonists, whereas non-convulsive doses have kindling effects. Second, sleep-related epilepsy can be caused by mutations on genes encoding nAChR subunits widely expressed in the forebrain (CHRNA4, CHRNB2, CHRNA2). Third, in animal models of acquired epilepsy, complex time-dependent alterations in cholinergic innervation are observed following repeated seizures. Heteromeric nAChRs are central players in epileptogenesis. Evidence is wide for autosomal dominant sleep-related hypermotor epilepsy (ADSHE). Studies of ADSHE-linked nAChR subunits in expression systems suggest that the epileptogenic process is promoted by overactive receptors. Investigation in animal models of ADSHE indicates that expression of mutant nAChRs can lead to lifelong hyperexcitability by altering i) the function of GABAergic populations in the mature neocortex and thalamus, ii) synaptic architecture during synaptogenesis. Understanding the balance of the epileptogenic effects in adult and developing networks is essential to plan rational therapy at different ages. Combining this knowledge with a deeper understanding of the functional and pharmacological properties of individual mutations will advance precision and personalized medicine in nAChR-dependent epilepsy.
Topics: Animals; Receptors, Nicotinic; Nicotinic Agonists; Seizures; Phenotype; Epilepsy
PubMed: 36796465
DOI: 10.1016/j.phrs.2023.106698 -
Molecular Medicine (Cambridge, Mass.) Oct 2023Acute pancreatitis is a common and serious inflammatory condition currently lacking disease modifying therapy. The cholinergic anti-inflammatory pathway (CAP) is a...
BACKGROUND
Acute pancreatitis is a common and serious inflammatory condition currently lacking disease modifying therapy. The cholinergic anti-inflammatory pathway (CAP) is a potent protective anti-inflammatory response activated by vagus nerve-dependent α7 nicotinic acetylcholine receptor (α7nAChR) signaling using splenic CD4 T cells as an intermediate. Activating the CAP ameliorates experimental acute pancreatitis. Galantamine is an acetylcholinesterase inhibitor (AChEI) which amplifies the CAP via modulation of central muscarinic ACh receptors (mAChRs). However, as mAChRs also activate pancreatitis, it is currently unknown whether galantamine would be beneficial in acute pancreatitis.
METHODS
The effect of galantamine (1-6 mg/kg-body weight) on caerulein-induced acute pancreatitis was evaluated in mice. Two hours following 6 hourly doses of caerulein (50 µg/kg-body weight), organ and serum analyses were performed with accompanying pancreatic histology. Experiments utilizing vagotomy, gene knock out (KO) technology and the use of nAChR antagonists were also performed.
RESULTS
Galantamine attenuated pancreatic histologic injury which was mirrored by a reduction in serum amylase and pancreatic inflammatory cytokines and an increase the anti-inflammatory cytokine IL-10 in the serum. These beneficial effects were not altered by bilateral subdiaphragmatic vagotomy, KO of either choline acetyltransferase T cells or α7nAChR, or administration of the nAChR ganglionic blocker mecamylamine or the more selective α7nAChR antagonist methyllycaconitine.
CONCLUSION
Galantamine improves acute pancreatitis via a mechanism which does not involve previously established physiological and molecular components of the CAP. As galantamine is an approved drug in widespread clinical use with an excellent safety record, our findings are of interest for further evaluating the potential benefits of this drug in patients with acute pancreatitis.
Topics: Humans; Mice; Animals; Galantamine; alpha7 Nicotinic Acetylcholine Receptor; Acetylcholinesterase; Ceruletide; Acute Disease; Pancreatitis; Cytokines; Anti-Inflammatory Agents; Body Weight
PubMed: 37907853
DOI: 10.1186/s10020-023-00746-y -
Expert Review of Clinical Pharmacology Mar 2019Green tobacco sickness occurs from transdermal absorption of chemicals from freshly harvested, green tobacco leaves. Signs and symptoms include nausea, vomiting,... (Review)
Review
Green tobacco sickness occurs from transdermal absorption of chemicals from freshly harvested, green tobacco leaves. Signs and symptoms include nausea, vomiting, headache, and abdominal cramps. Prevalence has shifted from the United States and Europe to China, India, and Brazil. Worldwide 8 million individuals are afflicted, including women and children. Areas covered: Mecamylamine (Inversine®, Vecamyl®), a nicotinic acetylcholine receptor (nAChR) antagonist, should be tested as a remedy for green tobacco sickness. Mecamylamine is approved as an oral tablet for the treatment of hypertension, is safe, and is off-patent. Mecamylamine attenuates many of the effects of nicotine and tobacco including seizures, thereby supporting its use as an effective pharmacotherapy for tobacco dependence. Varenicline (Chantix®) and cytisine (Tabex®) are low efficacy (i.e. intrinsic activity) nAChR agonists, are used as smoking cessation aids, and are viable options to test as remedies against green tobacco sickness. Nicotine immunization strategies may provide further options for future testing. Expert commentary: Efforts to demonstrate reversal and/or prevention of green tobacco sickness by mecamylamine will underscore the importance of nicotine in this illness and highlight a new medication for effective treatment of tobacco poisoning.
Topics: Agricultural Workers' Diseases; Humans; Mecamylamine; Nicotine; Nicotinic Agonists; Nicotinic Antagonists; Plant Leaves; Nicotiana; Vaccines; Varenicline
PubMed: 30650314
DOI: 10.1080/17512433.2019.1570844 -
The Journal of Pharmacology and... Mar 2021Nicotine is the major addictive component in tobacco. Cotinine is the major metabolite of nicotine and a weak agonist for nicotinic acetylcholine receptors (nAChRs).... (Comparative Study)
Comparative Study
Nicotine is the major addictive component in tobacco. Cotinine is the major metabolite of nicotine and a weak agonist for nicotinic acetylcholine receptors (nAChRs). Nicotine supports self-administration in rodents. However, it remains undetermined whether cotinine can be self-administered. This study aimed to characterize cotinine self-administration in rats, to compare effects of cotinine to those of nicotine, and to determine potential involvement of nAChRs in cotinine's effects. Adult Wistar rats were trained to self-administer cotinine or nicotine (0.0075, 0.015, 0.03, or 0.06 mg/kg per infusion) under fixed-ratio (FR) and progressive-ratio (PR) schedules. Blood nicotine and cotinine levels were determined after the last FR session. Effects of mecamylamine, a nonselective nAChR antagonist, and varenicline, a partial agonist for 42* nAChRs, on cotinine and nicotine self-administration were determined. Rats readily acquired cotinine self-administration, responded more on active lever, and increased motivation to self-administer cotinine when the reinforcement requirement increased. Blood cotinine levels ranged from 77 to 792 ng/ml. Nicotine induced more infusions at lower doses during FR schedules and greater breakpoints at higher doses during the PR schedule than cotinine. There was no difference in cotinine self-administration between male and female rats. Mecamylamine and varenicline attenuated nicotine but not cotinine self-administration. These results indicate that cotinine was self-administered by rats. These effects of cotinine were less robust than nicotine and exhibited no sex difference. nAChRs appeared to be differentially involved in self-administration of nicotine and cotinine. These results suggest cotinine may play a role in the development of nicotine use and misuse. SIGNIFICANCE STATEMENT: Nicotine addiction is a serious public health problem. Cotinine is the major metabolite of nicotine, but its involvement in nicotine reinforcement remains elusive. Our findings indicate that cotinine, at doses producing clinically relevant blood cotinine levels, supported intravenous self-administration in rats. Cotinine self-administration was less robust than nicotine. Mecamylamine and varenicline attenuated nicotine but not cotinine self-administration. These results suggest cotinine may play a role in the development of nicotine use and misuse.
Topics: Animals; Cotinine; Dose-Response Relationship, Drug; Drug Interactions; Female; Male; Mecamylamine; Nicotine; Rats; Rats, Wistar; Receptors, Nicotinic; Self Administration; Varenicline
PubMed: 33361363
DOI: 10.1124/jpet.120.000367