Rationale: Nicotine (NIC) potently increases operant responding for non-NIC reinforcers, and this effect may depend on drug-mediated increases in incentive motivation. According to this hypothesis, NIC should also potently increase approach to Pavlovian-conditioned stimuli associated with rewards. Objective: The present studies explored the effects of NIC on Pavlovian-conditioned approach responses. Method: To do so, liquid dippers were used to deliver an unconditioned stimulus (US; 0.1 ml sucrose) after presentation of a conditioned stimulus (CS; 30 s illumination of a stimulus light) - both the CS and US were presented in receptacles equipped to monitor head entries. Results: In experiment 1, the CS and US were presented in the same receptacle, but NIC pretreatment (0.4 mg/kg base) did not increase conditioned approach responses. Delivery of the sucrose US was then shifted to receptacle in a different location. All rats learned to approach the new US location (goal-tracking) at similar rates. Approach to the CS receptacle (sign-tracking) declined for saline-pretreated rats, but NIC pretreatment increased sign-tracking. In experiment 2, NIC pretreatment increased sign-tracking when the CS and US were spatially separated during acquisition. In experiment 3, NIC pretreatments were replaced with saline, but the effect of NIC persisted for an additional 24 test sessions. Conclusion: The findings suggest that NIC increases incentive motivation and that this effect is long-lasting, persisting beyond the pharmacological effects of NIC.

Rationale: Nicotine (NIC) potently increases operant responding for non-NIC reinforcers, and this effect may depend on drug-mediated increases in incentive motivation. According to this hypothesis, NIC should also potently increase approach to Pavlovian-conditioned stimuli associated with rewards. Objective: The present studies explored the effects of NIC on Pavlovian-conditioned approach responses. Method: To do so, liquid dippers were used to deliver an unconditioned stimulus (US; 0.1 ml sucrose) after presentation of a conditioned stimulus (CS; 30 s illumination of a stimulus light) - both the CS and US were presented in receptacles equipped to monitor head entries. Results: In experiment 1, the CS and US were presented in the same receptacle, but NIC pretreatment (0.4 mg/kg base) did not increase conditioned approach responses. Delivery of the sucrose US was then shifted to receptacle in a different location. All rats learned to approach the new US location (goal-tracking) at similar rates. Approach to the CS receptacle (sign-tracking) declined for saline-pretreated rats, but NIC pretreatment increased sign-tracking. In experiment 2, NIC pretreatment increased sign-tracking when the CS and US were spatially separated during acquisition. In experiment 3, NIC pretreatments were replaced with saline, but the effect of NIC persisted for an additional 24 test sessions. Conclusion: The findings suggest that NIC increases incentive motivation and that this effect is long-lasting, persisting beyond the pharmacological effects of NIC.

Theories of the neurobiological basis of Attention-Deficit/Hyperactivity Disorder (ADHD) have largely focused on dysregulation of central dopaminergic function. However, other neurotransmitter systems may be implicated in specific cognitive deficits in ADHD. Interest in the potential involvement of nicotinic cholinergic systems in ADHD has arisen in part from the observation that adolescents and adults with ADHD smoke cigarettes at significantly higher rates than people without this disorder. In addition, several studies report that nicotine alleviates ADHD symptoms, and recent neuro-genetics studies indicate that cholinergic systems may be altered in persons with ADHD. In this review, we describe the evidence for a role of central nicotinic cholinergic systems in cognitive deficits in ADHD. We also propose mechanisms by which alterations in cholinergic function may contribute directly and/or indirectly to these deficits. Finally, we identify specific paradigms and models to guide future investigations into the specific involvement of nicotinic cholinergic systems in ADHD, possibly leading to the development of more effective pharmacotherapies for ADHD.

Anticholinergic therapy has long been a cornerstone of management of chronic obstructive pulmonary disease (COPD) but has not been included in treatment guidelines for asthma. In September 2015, tiotropium bromide was approved for use in adults with asthma; the indication has since been expanded to children ages 6 years and older. This article discusses appropriate patient selection and dosing, and the role of tiotropium bromide in asthma management.

At the neuromuscular junction, nicotinic acetylcholine receptors (AChRs) convert chemical stimuli into electrical signals. They are heteropentameric membrane protein complexes assembled from four evolutionary related subunits (two α subunits, and one each of the β-, δ-, and ε-subunits), arranged around a central ion-conducting pore, which is regulated by the neurotransmitter acetylcholine. Understanding how the binding of acetylcholine leads to channel opening is of fundamental importance. While it is known that channel opening results from a global conformational change involving the cooperative action of all five subunits, how the subunits achieve this cooperativity is unclear. Our hypothesis is that this subunit cooperation is maintained through coevolution of the subunits, and thus studies of subunit coevolution can provide insight into subunit cooperativity. Using an ancestral reconstruction approach, combined with single-molecule patch clamp electrophysiology, we have begun dissecting the mechanistic consequences of preventing coevolution of the acetylcholine receptor β-subunit. This approach has allowed us to identify new amino acid determinants of acetylcholine receptor function.

Organophosphates (OPs), including nerve agents, target the cholinergic system via inhibition of acetylcholinesterase (AChE), with subsequent overstimulation resulting in neural damage and potential detrimental long-term effects. The efficacy of novel pyridinium oxime reactivators, created with moieties to increase blood-brain barrier penetration, was tested using highly relevant sarin and VX surrogates. Glial fibrillary acidic protein (GFAP; an indicator of neural damage) and monoamines (dopamine, serotonin, and their metabolites) were measured in select brain regions via immunohistochemistry and HPLC, respectively. Adult male rats were treated ip with high, sub-lethal doses of surrogates for sarin or VX, nitrophenyl isopropyl methylphosphonate (NIMP) or nitrophenyl ethyl methylphosphonate (NEMP), respectively. Surrogate treatment was followed after 1 hr by im administration of novel oxime. Seizure activity was monitored, and kainic acid (KA) served as a positive control. Administration of KA or surrogate (NIMP or NEMP) significantly increased GFAP expression compared to control animals. Two different formulations of one particular oxime (bromide vs. mesylate salt) attenuated seizures and reduced GFAP levels over NIMP or NEMP treatments alone to levels near those of controls in both the piriform cortex and dentate gyrus region of the hippocampus, while 2-PAM did not provide protection. Serotonergic activity was increased in several brain regions, including the piriform cortex, one hr after NIMP treatment. Markers of oxidative stress (isoprostanes) were also tested. Overall, these results indicate the potential therapeutic efficacy of these oximes and suggest this innovative chemistry may protect against neural damage induced by OP.

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The temporal nature of ectopic activity is important to elucidating the mechanisms that can lead to arrhythmogenesis. However, challenges remain in distinguishing between ectopic and non-ectopic beats. A new methodology was developed and validated to distinguish between beat types. Rapid pacing was used to induce both ectopic and non-ectopic beats. Using an electrocardiogram, the post-pacing recovery beat cycle length (RCL) and QRS were normalized to pre-paced R-R and QRS intervals and analyzed using a K-means clustering algorithm. Control hearts only produced beats with RCL ratios that increased with rapid pacing, suggestive of non-ectopic activity. Hypercalcemia and digoxin both produced significantly earlier beats with wider QRS durations, suggestive of ectopic activity. Increasing pacing further shortened RCL during digoxin + hypothermia, a mechanistic identifier of ectopic activity. When tested against a previously validated analysis, our algorithm performed well. Therefore, this electrocardiogram based algorithm distinguishes between ectopic and non-ectopic beats. In a prospective study, tetrodotoxin increased RCL ratio without changing the QRS duration of excited beats, suggesting neuronal sodium channels play an important role in ectopic beat timing. The next goal was to create a consistent model of ectopic activity. Both sympathetic and parasympathetic stimulation independently potentiate arrhythmogenesis, and we investigated the effects of independent and simultaneous stimulation on the temporal nature of arrhythmogenesis. Isoproterenol (ISO), a sympathetic agonist, transiently produced ectopic activity and increased heart rate. Acetylcholine (ACh), a parasympathetic agonist, did not significantly produce ectopic activity but did slow heart rate. ACh added after ISO also transiently produced ectopic activity, while heart rate remained slowed. Importantly, ISO following ACh persistently increased ectopic activity and heart rate. Therefore, ISO following ACh is an ideal model for creating sustained ectopic activity. Mature animals exhibited sustained arrhythmogenesis while young animals did not. When ACh was removed and then followed by ISO, ectopic activity and heart rate transiently increased, similar to ISO alone. This suggests that maintained ACh perfusion can sustain ISO sensitivity, in contrast to ISO perfusion alone. The data in this dissertation provide an insight into the mechanisms that affect the ectopic beat timing and arrhythmia propensity. / Ph. D.