Smoking, nicotine and human performance

Nicotine addiction is a chronic brain disorder that is characterized by a negative mood state upon smoking cessation and relapse after periods of abstinence. Accumulating evidence indicates that this negative mood state deters people from trying to quit smoking, leads to craving, and contributes to relapse after a period of abstinence. The animal studies that are presented here provide evidence for a role of brain stress systems in the negative mood associated with nicotine withdrawal. These studies demonstrate that nicotine dysregulates corticotropin-releasing factor (CRF) and norepinephrine systems in rodents. Drugs that block CRF type 1 receptors or α1-adrenoceptors diminish the negative mood states associated with nicotine withdrawal. Similar effects have been observed in animal models with the widely used smoking cessation drugs bupropion (Zyban) and varenicline (Chantix). Therefore, drugs that blunt brain stress responses in smokers trying to quit may provide a novel and viable treatment option for nicotine addiction.

Tobacco smoking is the leading cause of preventable disease and health in the world, but quitting remains exceedingly difficult for many. A major contribution to this ubiquitous failure is nicotine withdrawal–related cognitive symptoms, which include attentional deficits. Tobacco smoking is disproportionately prevalent among psychiatric populations, which simultaneously and frequently suffer from attentional deficiencies. In this chapter, we therefore review the related literature and outline theories on nicotine withdrawal–related attentional deficits and their relationship with psychiatric disorders. We describe that smoking abstinence consistently results in impaired performance on behavioral measures of sustained attention in rodents and humans. There is also evidence that the particularly high rates of smoking among the mentally ill is in part due to nicotine enhancing attention. Mechanisms behind withdrawal-induced attentional deficits and those underpinning attention deficits in psychiatric patients may overlap, but they have yet to be thoroughly investigated. Acetylcholine and nicotinic acetylcholine receptors play a predominant role in attention and likely interact with other neural circuitry such as dopamine systems or glutamatergic receptors. Pharmacological and genetic studies in animals provide opportunities for greater detailed research on neuromechanisms underlying these mechanisms. Behavioral tasks analogous to tests used in humans are successfully being utilized in combination with animal models to decipher the roles of different neural systems and subunits of nicotine receptors in mediating attentional processes. Future studies should continue to combine these approaches and hopefully identify viable targets that can be used to improve quit rates by reducing withdrawal-related deficits, and improve attention in psychiatric populations.

Tobacco is a highly addictive drug and is one of the most widely abused drugs in the world. The first part of this review explores the role of stressors and stress-associated psychiatric disorders in the initiation of smoking, the maintenance of smoking, and relapse after a period of abstinence. The reviewed studies indicate that stressors facilitate the initiation of smoking, decrease the motivation to quit, and increase the risk for relapse. Furthermore, people with depression or an anxiety disorder are more likely to smoke than people without these disorders. The second part of this review describes animal studies that investigated the role of brain stress systems in nicotine addiction. These studies indicate that corticotropin-releasing factor, Neuropeptide Y, the hypocretins, and norepinephrine play a pivotal role in nicotine addiction. In conclusion, the reviewed studies indicate that smoking briefly decreases subjective stress levels but also leads to a further dysregulation of brain stress systems. Drugs that decrease the activity of brain stress systems may diminish nicotine withdrawal and improve smoking cessation rates.

The majority of smokers relapse during the acute withdrawal phase when withdrawal symptoms are most severe. The goal of the present studies was to investigate the role of corticotropin-releasing factor (CRF) and noradrenergic transmission in the central nucleus of the amygdala (CeA) in the dysphoria associated with smoking cessation. It was investigated if blockade of CRF1 receptors, blockade of α1-adrenergic receptors, or stimulation of α2-adrenergic receptors in the CeA diminishes the deficit in brain reward function associated with nicotine withdrawal in rats. Nicotine dependence was induced by implanting minipumps that delivered a nicotine solution. Withdrawal was precipitated with the nicotinic acetylcholine receptor antagonist mecamylamine. A discrete-trial intracranial self-stimulation procedure was used to assess the negative affective aspects of nicotine withdrawal. Elevations in brain reward thresholds are indicative of a deficit in brain reward function. In all the experiments, mecamylamine elevated the brain reward thresholds of the rats chronically treated with nicotine and did not affect the brain reward thresholds of the saline-treated control rats. Intra-CeA administration of the CRF1 receptor antagonist R278995/CRA0450 completely prevented the mecamylamine-induced elevations in brain reward thresholds in the nicotine-treated rats and did not affect the brain reward thresholds of the saline-treated control rats. R278995/CRA0450 has also been shown to block sigma-1 receptors but there is no evidence that this could affect negative mood states. Intra-CeA administration of the α1-adrenergic receptor antagonist prazosin or the α2-adrenergic receptor agonist clonidine did not affect the brain reward thresholds of the nicotine or saline-treated rats. These studies suggest that CRF1 receptor antagonists may diminish the dysphoria associated with smoking cessation by blocking CRF1 receptors in the CeA.

Epidemiological studies indicate that parental smoking increases the risk for smoking in children. However, the underlying mechanisms by which parental smoking increases the risk for smoking are not known. The aim of these studies was to investigate if preadolescent tobacco smoke exposure, postnatal days 21–35, affects the rewarding effects of nicotine and nicotine withdrawal in adult rats. The rewarding effects of nicotine were investigated with the conditioned place preference procedure. Nicotine withdrawal was investigated with the conditioned place aversion procedure and intracranial self-stimulation (ICSS). Elevations in brain reward thresholds in the ICSS paradigm reflect a dysphoric state. Plasma nicotine and cotinine levels in the preadolescent rats immediately after smoke exposure were 188 ng/ml and 716 ng/ml, respectively. Preadolescent tobacco smoke exposure led to the development of nicotine dependence as indicated by an increased number of mecamylamine-precipitated somatic withdrawal signs in the preadolescent tobacco smoke exposed rats compared to the control rats. Nicotine induced a similar place preference in adult rats that had been exposed to tobacco smoke or air during preadolescence. Furthermore, mecamylamine induced place aversion in nicotine dependent rats but there was no effect of preadolescent tobacco smoke exposure. Finally, preadolescent tobacco smoke exposure did not affect the elevations in brain reward thresholds associated with precipitated or spontaneous nicotine withdrawal. These studies indicate that passive exposure to tobacco smoke during preadolescence leads to the development of nicotine dependence but preadolescent tobacco smoke exposure does not seem to affect the rewarding effects of nicotine or nicotine withdrawal in adulthood.

Attention deficit/hyperactivity disorder (ADHD) is the most commonly diagnosed neurobehavioral disorder in children and adolescents, and in about half of these patients, significant symptomology continues into adulthood. Although impulsivity and hyperactivity are the most salient features of ADHD, cognitive deficits, particularly impairments in attention and executive function, are an important component, particularly in adolescents and adults, with over 90% of adults seeking treatment for ADHD manifesting cognitive dysfunction. Currently available medications treat the core ADHD symptoms but typically do not adequately address cognitive aspects of ADHD, underscoring the need for new therapeutics. Dopamine and norepinephrine are hypothesized to be particularly important in ADHD, but there is emerging evidence that cholinergic neurotransmission, particularly involving neuronal nicotinic acetylcholine receptors (nAChRs), may play a role in the pathophysiology of ADHD. Nicotine has demonstrated procognitive effects in both humans and experimental animals and has produced signals of efficacy in small proof-of-concept adult ADHD trials. Although adverse effects associated with nicotine preclude its development as a therapeutic, a number of novel nAChR agonists with improved safety/tolerability profiles have been discovered. Of these, ABT-418 and ABT-089 have both demonstrated signals of efficacy in adults with ADHD. Notably, tolerability issues that might be expected of a nAChR agonist, such as nausea and emesis, were not observed at efficacious doses of ABT-089. Further understanding of the effects of novel neuronal nAChR agonists on specific aspects of cognitive functioning in ADHD is required to assess the full potential of this approach.