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1.
Angew Chem Int Ed Engl ; : e202405706, 2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38687567

ABSTRACT

The utility of unconventional noncovalent interactions (NCIs) such as chalcogen bonding has lately emerged as a robust platform to access synthetically difficult glycosides stereoselectively. Herein, we disclose the versatility of a phosphonochalcogenide (PCH) catalyst to facilitate access into the challenging, but biologically interesting 7-membered ring α,α'-C-disubstituted oxepane core through an α-selective strain-release C-glycosylation. Methodically, this strategy represents a switch from more common but entropically less desired macrocyclizations to a thermodynamically favored ring-expansion approach. In light of the general lack of stereoselective methods to access C-septanosides, a remarkable palette of silyl-based nucleophiles can be reliably employed in our method. This include a broad variety of useful synthons, such as easily available silyl-allyl, silyl-enol ether, silyl-ketene acetal, vinylogous silyl-ketene acetal, silyl-alkyne and silylazide reagents. Mechanistic investigations suggest that a mechanistic shift towards an intramolecular aglycone transposition involving a pentacoordinate silicon intermediate is likely responsible in steering the stereoselectivity.

2.
J Am Chem Soc ; 146(15): 10608-10620, 2024 Apr 17.
Article in English | MEDLINE | ID: mdl-38564319

ABSTRACT

The use of noncovalent interactions (NCIs) has received significant attention as a pivotal synthetic handle. Recently, the exploitation of unconventional NCIs has gained considerable traction in challenging reaction manifolds such as glycosylation due to their capacity to facilitate entry into difficult-to-access sugars and glycomimetics. While investigations involving oxacyclic pyrano- or furanoside scaffolds are relatively common, methods that allow the selective synthesis of biologically important iminosugars are comparatively rare. Here, we report the capacity of a phosphonochalcogenide (PCH) to catalyze the stereoselective α-iminoglycosylation of iminoglycals with a wide array of glycosyl acceptors with remarkable protecting group tolerance. Mechanistic studies have illuminated the counterintuitive role of the catalyst in serially activating both the glycosyl donor and acceptor in the up/downstream stages of the reaction through chalcogen bonding (ChB). The dynamic interaction of chalcogens with substrates opens up new mechanistic opportunities based on iterative ChB catalyst engagement and disengagement in multiple elementary steps.

3.
Angew Chem Int Ed Engl ; 63(21): e202400912, 2024 May 21.
Article in English | MEDLINE | ID: mdl-38530140

ABSTRACT

Herein, we demonstrate the robustness of a synergistic chiral Pd/organoboron system in tackling a challenging suite of site-, regio-, enantio- and diastereoselectivity issues across a considerable palette of biologically relevant carbohydrate polyols, when prochiral alkoxyallenes were employed as electrophiles. In view of the burgeoning role of noncovalent interactions (NCIs) in stereoselective carbohydrate synthesis, our mechanistic experiments and DFT modeling of the reaction path unexpectedly revealed that NCIs such as hydrogen bonding and CH-π interactions between the resting states of the Pd-π-allyl complex and the borinate saccharide are critically involved in the stereoselectivity control. Our strategy thus illuminates the untapped potential of harnessing NCIs in the context of transition metal catalysis to tackle stereoselectivity challenges in carbohydrate functionalization.

4.
Angew Chem Int Ed Engl ; 63(7): e202316667, 2024 Feb 12.
Article in English | MEDLINE | ID: mdl-38116860

ABSTRACT

Harnessing unconventional noncovalent interactions (NCIs) is emerging as a formidable synthetic approach in difficult-to-access glycosidic chemical space. C-Glycosylation, in particular, has gained a flurry of recent attention. However, most reported methods are restricted to the relatively facile access to α-C-glycosides. Herein, we disclose a ß-stereoselective glycosylation of indoles by employing a phosphonoselenide catalyst. The robustness of this protocol is exemplified by its amenability for reaction at both the indolyl C- and N- reactivity sites. In contrast to previous reports, in which the chalcogens were solely involved in Lewis acidic activation, our mechanistic investigation unraveled that the often neglected flanking aromatic substituents of phosphonoselenides can substantially contribute to catalysis by engaging in π-interactions. Computations and NMR spectroscopy indicated that the chalcogenic and aromatic components of the catalyst can be collectively exploited to foster conformational distortion of the glycal away from the usual half-chair to the boat conformation, which liberates the convex ß-face for nucleophilic attack.

5.
J Am Chem Soc ; 145(49): 26611-26622, 2023 Dec 13.
Article in English | MEDLINE | ID: mdl-38032866

ABSTRACT

The exploitation of noncovalent interactions (NCIs) is emerging as a vital handle in tackling broad stereoselectivity challenges in synthesis. In particular, there has been significant recent interest in the harnessing of unconventional NCIs to surmount difficult selectivity challenges in glycosylations. Herein, we disclose the exploitation of an unconventional bifurcated chalcogen bonding and hydrogen bonding (HB) network, which paves the way for a robust catalytic strategy into biologically useful seven-membered ring sugars. Through 13C nuclear magnetic resonance (NMR) in situ monitoring, NMR titration experiments, and density functional theory (DFT) modeling, we propose a remarkable contemporaneous activation of multiple functional groups consisting of a bifurcated chalcogen bonding mechanism working hand-in-hand with HB activation. Significantly, the ester moiety installed on the glycosyl donor is critical in the establishment of the postulated ternary complex for stereocontrol. Through the 13C kinetic isotopic effect and kinetic studies, our data corroborated that a dissociative SNi-type mechanism forms the stereocontrolling basis for the excellent α-selectivity.

6.
Stereotact Funct Neurosurg ; 101(1): 68-71, 2023.
Article in English | MEDLINE | ID: mdl-36580909

ABSTRACT

The vagus nerve has motor, sensory, and parasympathetic components. Understanding the nerve's internal anatomy, its variations, and relationship to the glossopharyngeal nerve are crucial for neurosurgeons decompressing the lower cranial nerves. We present a case report demonstrating the location of the parasympathetic fibres within the vagus nerve rootlets. A 47-year-old woman presented with a 1-year history of medically refractory left-sided glossopharyngeal neuralgia and a more recent history of left-sided hemi-laryngopharyngeal spasm. magnetic resonance imaging showed her left posterior inferior cerebellar artery distorting the lower cranial nerves on the affected left side. The patient consented to microvascular decompression of the lower cranial nerves with possible sectioning of the glossopharyngeal and upper sensory rootlets of the vagus nerve. During surgery, electrical stimulation of the most caudal rootlet of the vagus nerve triggered profound bradycardia. None of the more rostral rootlets had a similar parasympathetic response. This case is the first demonstration, to our knowledge, of the location of the cardiac parasympathetic fibres within the human vagus nerve rootlets. This new understanding of the vagus nerve rootlets' distribution of pure sensory (most rostral), motor/sensory (more caudal), and parasympathetic (most caudal) fibres may lead to a better understanding and diagnosis of the vagal rhizopathies. Approximately 20% of patients with glossopharyngeal neuralgia also have paroxysmal cough. This could be due to the anatomical juxtaposition of the IXth cranial nerve with the rostral vagal rootlets with pure sensory fibres (which mediate a tickling sensation in the lungs). A subgroup of patients with glossopharyngeal neuralgia have neuralgia-induced syncope. The cause of this rare condition, "vago-glossopharyngeal neuralgia," has been debated since it was first described by Riley in 1942. Our case supports the theory that this neuralgia-induced bradycardia is reflexively mediated through the brainstem with afferent impulses in the IXth and efferent impulses in the Xth cranial nerve. The rarer co-occurrence of glossopharyngeal neuralgia with hemi-laryngopharyngeal spasm (as seen in this case) may be explained by the proximity of the IXth nerve with the more caudal vagus rootlets which have motor (and probably sensory) supply to the throat. Finally, if there is a vagal rhizopathy related to compression of its parasympathetic fibres, one would expect it to be at the most caudal rootlet of the vagus nerve.


Subject(s)
Glossopharyngeal Nerve Diseases , Neuralgia , Humans , Female , Middle Aged , Bradycardia , Vagus Nerve/physiology , Glossopharyngeal Nerve/surgery , Glossopharyngeal Nerve Diseases/surgery , Spasm
7.
Nat Chem ; 15(3): 424-435, 2023 Mar.
Article in English | MEDLINE | ID: mdl-36585443

ABSTRACT

Site-selective functionalization is a core synthetic strategy that has broad implications in organic synthesis. Particularly, exploiting chiral catalysis to control site selectivity in complex carbohydrate functionalizations has emerged as a leading method to unravel unprecedented routes into biologically relevant glycosides. However, robust catalytic systems available to overcome multiple facets of stereoselectivity challenges to this end still remain scarce. Here we report a synergistic chiral Rh(I)- and organoboron-catalysed protocol, which enables access into synthetically challenging but biologically relevant arylnaphthalene glycosides. Our method depicts the employment of chiral Rh(I) catalysis in site-selective carbohydrate functionalization and showcases the utility of boronic acid as a compatible co-catalyst. Crucial to the success of our method is the judicious choice of a suitable organoboron catalyst. We also determine that exquisite multiple aspects of stereocontrol, including enantio-, diastereo-, regio- and anomeric control and dynamic kinetic resolution, are concomitantly operative.

8.
J Exp Anal Behav ; 115(2): 495-509, 2021 03.
Article in English | MEDLINE | ID: mdl-33556201

ABSTRACT

Delay discounting is the loss in value of an outcome as a function of its delay. The present study focused on examining a trait-like characteristic of delay discounting in a preclinical animal model. Specifically, we were interested in whether there was a positive relation between discounting of 2 different outcomes in rats. That is, would rats that discount delayed food steeply also discount delayed water steeply? In addition, we examined how session-to-session variability in discounting could be attributed to differences between subjects (trait variability) and to differences within subjects (state variability). Finally, we measured discounting from early- to mid-adulthood, allowing us to examine changes in discounting as a function of age. Overall, we found a moderate, positive correlation between discounting of food and discounting of water in rats, providing further evidence that the relative consistency with which individuals discount different outcomes is a trait-like characteristic. In addition, we found a high degree of within-subject variability in discounting, indicating strong state-like differences from session to session. Finally, overall, discounting decreased as a function of age; however, individual-subject data showed variability in how discounting changed across time. Overall, our results show that differences in delay discounting between individuals reflect variability in both trait- and state-like characteristics.


Subject(s)
Delay Discounting , Animals , Rats , Reward , Water
9.
Nat Rev Chem ; 5(11): 792-815, 2021 Nov.
Article in English | MEDLINE | ID: mdl-37117666

ABSTRACT

Non-covalent interactions (NCIs) are a vital component of biological bond-forming events, and have found important applications in multiple branches of chemistry. In recent years, the biomimetic exploitation of NCIs in challenging glycosidic bond formation and glycofunctionalizations has attracted significant interest across diverse communities of organic and carbohydrate chemists. This emerging theme is a major new direction in contemporary carbohydrate chemistry, and is rapidly gaining traction as a robust strategy to tackle long-standing issues such as anomeric and site selectivity. This Review thus seeks to provide a bird's-eye view of wide-ranging advances in harnessing NCIs within the broad field of synthetic carbohydrate chemistry. These include the exploitation of NCIs in non-covalent catalysed glycosylations, in non-covalent catalysed glycofunctionalizations, in aglycone delivery, in stabilization of intermediates and transition states, in the existence of intramolecular hydrogen bonding networks and in aggregation by hydrogen bonds. In addition, recent emerging opportunities in exploiting halogen bonding and other unconventional NCIs, such as CH-π, cation-π and cation-n interactions, in various aspects of carbohydrate chemistry are also examined.

10.
Nat Commun ; 11(1): 4911, 2020 09 30.
Article in English | MEDLINE | ID: mdl-32999276

ABSTRACT

The development of noncovalent halogen bonding (XB) catalysis is rapidly gaining traction, as isolated reports documented better performance than the well-established hydrogen bonding thiourea catalysis. However, convincing cases allowing XB activation to be competitive in challenging bond formations are lacking. Herein, we report a robust XB catalyzed 2-deoxyglycosylation, featuring a biomimetic reaction network indicative of dynamic XB activation. Benchmarking studies uncovered an improved substrate tolerance compared to thiourea-catalyzed protocols. Kinetic investigations reveal an autoinductive sigmoidal kinetic profile, supporting an in situ amplification of a XB dependent active catalytic species. Kinetic isotopic effect measurements further support quantum tunneling in the rate determining step. Furthermore, we demonstrate XB catalysis tunability via a halogen swapping strategy, facilitating 2-deoxyribosylations of D-ribals. This protocol showcases the clear emergence of XB catalysis as a versatile activation mode in noncovalent organocatalysis, and as an important addition to the catalytic toolbox of chemical glycosylations.

11.
J Exp Anal Behav ; 114(2): 203-215, 2020 09.
Article in English | MEDLINE | ID: mdl-32852106

ABSTRACT

Delay discounting is the process by which a commodity loses value as the delay to its receipt increases. Rapid discounting predicts various maladaptive behaviors including tobacco use. Typically, delay discounting of different outcomes has been compared between cigarette smokers and nonsmokers. To better understand the relationship of delay discounting to different modes of tobacco use, we examined the differences in delay discounting of different outcomes between cigarette smokers, smokeless tobacco users, e-cigarette users, and non-tobacco users. In the present study, all participants completed 8 titrating delay-discounting tasks: $100 gain, $500 gain, $500 loss, alcohol, entertainment, food, a temporary health gain, and a temporary cure from a disease. Non-tobacco users discounted most outcomes less than tobacco users overall; however, there were no differences in discounting among the different types of tobacco users. These results suggest that nicotine consumption of any kind is associated with a higher degree of impulsivity compared to non-tobacco users. Adoption of tobacco products that have been perceived as less harmful (e.g., e-cigarettes) is not associated with a baseline difference or decrease in delay discounting if adopted after a history of cigarette use.


Subject(s)
Delay Discounting , Electronic Nicotine Delivery Systems , Tobacco Products , Tobacco, Smokeless , Humans , Smokers , Tobacco Use , Tobacco, Smokeless/adverse effects
12.
J Exp Anal Behav ; 113(3): 657-679, 2020 05.
Article in English | MEDLINE | ID: mdl-32147840

ABSTRACT

Steep delay discounting is characterized by a preference for small immediate outcomes relative to larger delayed outcomes and is predictive of drug abuse, risky sexual behaviors, and other maladaptive behaviors. Nancy M. Petry was a pioneer in delay discounting research who demonstrated that people discount delayed monetary gains less steeply than they discount substances with abuse liability. Subsequent research found steep discounting for not only drugs, but other nonmonetary outcomes such as food, sex, and health. In this systematic review, we evaluate the hypotheses proposed to explain differences in discounting as a function of the type of outcome and explore the trait- and state-like nature of delay discounting. We found overwhelming evidence for the state-like quality of delay discounting: Consistent with Petry and others' work, nonmonetary outcomes are discounted more steeply than monetary outcomes. We propose two hypotheses that together may account for this effect: Decreasing Future Preference and Decreasing Future Worth. We also found clear evidence that delay discounting has trait-like qualities: People who steeply discount monetary outcomes steeply discount nonmonetary outcomes as well. The implication is that changing delay discounting for one outcome could change discounting for other outcomes.


Subject(s)
Delay Discounting , Animals , Choice Behavior , Humans , Reward , Substance-Related Disorders/psychology
13.
Stereotact Funct Neurosurg ; 97(4): 244-248, 2019.
Article in English | MEDLINE | ID: mdl-31734659

ABSTRACT

The neurosurgical treatment of glossopharyngeal neuralgia includes microvascular decompression or rhizotomy of the nerve. When considering open section of the glossopharyngeal nerve, numerous authors have recommended additional sectioning of the 'upper rootlets' of the vagus nerve because these fibers can occasionally carry the pain fibers causing the patient's symptoms. Sacrifice of vagus nerve rootlets, however, carries the potential risk of dysphagia and dysphonia. In this study, the anatomy and physiology of the vagus nerve rootlets are characterized to provide guidance for surgical decision-making. Twelve patients who underwent posterior fossa craniotomy with intraoperative electrophysiological monitoring of the vagus nerve rootlets were included in this study. In the 7 patients with glossopharyngeal neuralgia, the clinical outcomes and complications were further analyzed. In half of the patients, electrophysiological data demonstrated pure sensory function in the rostral rootlet(s) of the vagus nerve and motor responses in its caudal rootlets. This orientation of the vagus nerve, with some pure sensory function in its most rostral rootlet(s), was defined as Type A. In the other half of patients, all vagus nerve rootlets (including the most rostral) had motor responses. This was defined as Type B. The surgical strategy was guided by whether the patient had a Type A or Type B vagus nerve. For those with Type B, no vagus nerve rootlets were sacrificed. None of the patients with glossopharyngeal neuralgia developed any permanent neurological deficits. We recommend intraoperative electrophysiological testing of the vagus nerve rootlets. If the testing reveals motor innervation in the rostral vagal rootlet (Type B), that rootlet may be decompressed but should not be sectioned to avoid a motor complication. Patients with pure sensory innervation of the rostral rootlet(s) (Type A) can have decompression or section of those rootlets without complication.


Subject(s)
Glossopharyngeal Nerve Diseases/surgery , Glossopharyngeal Nerve/anatomy & histology , Glossopharyngeal Nerve/surgery , Neurosurgical Procedures/methods , Vagus Nerve/anatomy & histology , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Glossopharyngeal Nerve/physiology , Glossopharyngeal Nerve Diseases/diagnosis , Humans , Male , Microvascular Decompression Surgery/methods , Middle Aged , Monitoring, Intraoperative/methods , Pain Measurement/methods , Postoperative Complications/diagnosis , Postoperative Complications/prevention & control , Retrospective Studies , Treatment Outcome , Vagus Nerve/physiology
14.
J Exp Anal Behav ; 112(3): 254-272, 2019 11.
Article in English | MEDLINE | ID: mdl-31694068

ABSTRACT

Most delay discounting studies use tasks that arrange delay progressions in which the spacing between consecutive delays becomes progressively larger. To date, little research has examined delay discounting using other progressions. The present study assessed whether the form or steepness of discounting varied across different delay progressions. Human participants completed three discounting tasks with delay progressions that varied in the time between consecutive delays: a standard (increasing duration between delays), linear (equal duration between delays), and an inverse progression (decreasing duration between delays). Steepness of discounting was generally reduced, and remained so, following experience with the inverse progression. Effects of the delay progression on the best fitting equation were order-dependent. Overall the hyperbola model provided better fits, but the exponential model performed better with data from the inverse progression. Regardless, differences in which model fit best were often small. The finding that the best fitting model was dependent, in some cases, on the delay progression suggests that a single quantitative model of discounting may not be applicable to describe discounting across all procedural contexts. Ultimately, changes in steepness of discounting following experience with the inverse progression appeared similar to anchoring effects, whose mechanism will require further study to delineate.


Subject(s)
Delay Discounting , Female , Humans , Male , Models, Psychological , Reinforcement Schedule , Reward , Time Factors , Young Adult
15.
J Am Chem Soc ; 141(13): 5381-5391, 2019 04 03.
Article in English | MEDLINE | ID: mdl-30848592

ABSTRACT

Halogen bonding (XB) has recently emerged as a promising noncovalent activation mode that can be employed in catalysis. However, methodologies utilizing XB remain rare, and the hydrogen-bonding (HB) catalysis congeners are more widespread in comparison. Herein, we demonstrate a remarkable case whereby employment of XB catalysis in strain-release glycosylation generates O, N-glycosides in excellent anomeric selectivity exceeding HB activation. Deeper investigation unraveled XB catalyst dependencies on multiple stages of the mechanism and a hitherto unknown XB-glycosyl acceptor activation. We present a proof of concept to interrogate sp3-rich glycosidic chemical space for novel biological activity, by integrating XB-catalyzed construction of a glycosidic compound collection, and evaluating these analogues via cell-based phenotypic screens. We show that XB-catalyzed strain-release glycosylation defines a new class of glycosides that inhibit the hedgehog signaling pathway through a nonsmoothened mode of action, opening new opportunities to combat acquired cancer resistance.


Subject(s)
Glycosides/pharmacology , Hedgehog Proteins/antagonists & inhibitors , Catalysis , Glycosides/chemistry , Glycosylation , Halogens/chemistry , Molecular Conformation
16.
Behav Pharmacol ; 30(4): 363-369, 2019 06.
Article in English | MEDLINE | ID: mdl-30272586

ABSTRACT

Alcohol is the most commonly abused drug in the USA and many people suffer from alcohol use disorder. Many factors are associated with alcohol use disorder, but the causal role of comorbid nicotine use has not been extensively considered. Nicotine has reward-enhancing properties and may increase the value of alcohol. Monoamine oxidase inhibition increases nicotine self-administration and may increase the reward-enhancing effects of nicotine. We assessed the effect of nicotine and nicotine in combination with a commonly used monoamine oxidase inhibitor (tranylcypromine) on the value of alcohol using a progressive ratio schedule of reinforcement in rats. Nicotine administration increased the breakpoint for alcohol, but nicotine in combination with tranylcypromine decreased the breakpoint for alcohol. The current study adds to previous research showing that nicotine increases the value of alcohol. This finding has important implications for the etiology of addiction because of the comorbidity of smoking with many drugs of abuse. The finding that nicotine in combination with tranylcypromine reduces the value of alcohol warrants further investigation.


Subject(s)
Alcohol Drinking/drug therapy , Nicotine/pharmacology , Tranylcypromine/pharmacology , Alcohol Drinking/metabolism , Animals , Behavior, Addictive/drug therapy , Behavior, Addictive/metabolism , Conditioning, Operant/drug effects , Ethanol/metabolism , Male , Monoamine Oxidase Inhibitors/metabolism , Monoamine Oxidase Inhibitors/pharmacology , Nicotine/metabolism , Rats , Rats, Long-Evans , Reinforcement, Psychology , Reward , Self Administration , Tranylcypromine/metabolism
17.
Nat Commun ; 9(1): 4057, 2018 10 03.
Article in English | MEDLINE | ID: mdl-30282986

ABSTRACT

The utility of thiourea catalysis in selective glycosylation strategies has gained significant momentum lately due to its versatility in hydrogen bonding or anionic recognition activation modes. The use of these non-covalent interactions constitute a powerful means to construct glycosidic linkages as it mimics physiologically occurring glycosyltransferases. However, glycosyl donor activation through the currently employed catalysts is moderate such that, in general, catalyst loadings are rather high in these transformations. In addition, thiourea catalysis has not been well explored for the synthesis of furanosides. Herein, we demonstrate an ultra-low loadings stereoselective and stereospecific thiourea catalyzed strain-release furanosylation and pyranosylation strategy. Our ultra-low organocatalyzed furanosylation enables a multicatalytic strategy, which opens up a unique avenue towards rapid diversification of synthetic glycosides. In-situ NMR monitoring unravel insights into unknown reaction intermediates and initial rate kinetic studies reveal a plausible synergistic hydrogen bonding/Brønsted acid activation mode.


Subject(s)
Thiourea/chemistry , Catalysis , Glycosylation , Magnetic Resonance Spectroscopy , Substrate Specificity
18.
J Exp Anal Behav ; 110(3): 412-429, 2018 11.
Article in English | MEDLINE | ID: mdl-30203525

ABSTRACT

We examined the effects of outcome framing on delay discounting. In Experiment 1, participants completed four delay-discounting tasks. In one monetary task, money was framed in units of dollars ($50), and in the other, money was framed in units of handfuls of quarters (equal to $50). In one food task, food was framed in clear units of food (e.g., 100 M&Ms), and in the other, food was framed in units of servings (e.g., 10 servings of M&Ms). When money was framed in units of dollars, participants discounted less by delay compared to discounting of handfuls of quarters. When food was framed as clear units, participants also discounted less compared to how they discounted servings. In Experiment 2, participants completed two delay-discounting tasks for dollars and quarters (e.g., $50 or 200 quarters) to determine if the results of Experiment 1 were due to the differences in handling costs. In one delay-discounting task, money was framed in units of dollars. In the other delay-discounting task, money was framed in units of quarters. There was no difference in how participants discounted delayed money framed as dollars or quarters. Clear unit framing may result in less discounting by delay than fuzzy unit framing.


Subject(s)
Delay Discounting , Reward , Adult , Female , Food , Humans , Male
19.
PLoS One ; 13(8): e0202230, 2018.
Article in English | MEDLINE | ID: mdl-30110388

ABSTRACT

Alcohol is the most commonly used drug in the United States and alcohol abuse can lead to alcohol use disorder. Alcohol use disorder is a persistent condition and relapse rates following successful remission are high. Many factors have been associated with relapse for alcohol use disorder, but identification of these factors has not been well translated into preventative utility. One potentially important factor, concurrent nicotine use, has not been well investigated as a causal factor in relapse for alcohol use disorder. Nicotine increases the value of other stimuli in the environment and may increase the value of alcohol. If nicotine increases the value of alcohol, then nicotine use during and after treatment may make relapse more probable. In the current study, we investigated the effect of continuous nicotine exposure (using osmotic minipumps to deliver nicotine or saline, depending on group, at a constant rate for 28 days) on resurgence of alcohol seeking in rats. Resurgence is a type of relapse preparation that consists of three phases: Baseline, Alternative Reinforcement, and Resurgence Testing. During Baseline, target responses produced a dipper of alcohol. During Alternative Reinforcement, target responses were extinguished and responses on a chain produced a chocolate pellet. During Resurgence Testing, responses on the chain were also extinguished and a return to responding on the target lever was indicative of resurgence. Multilevel modeling was used to analyze the effect of nicotine on resurgence. Both the nicotine and saline group showed resurgence of alcohol seeking, but there was no difference in the degree of resurgence across groups. Future directions could involve testing alternative drug delivery techniques.


Subject(s)
Alcoholism/etiology , Nicotine/administration & dosage , Alcohol Drinking/psychology , Alcoholism/psychology , Animals , Behavior, Animal/drug effects , Conditioning, Operant , Disease Models, Animal , Drug Interactions , Drug-Seeking Behavior/drug effects , Ethanol/administration & dosage , Ethanol/adverse effects , Humans , Male , Nicotine/adverse effects , Rats , Rats, Long-Evans , Recurrence , Reinforcement, Psychology
20.
J Exp Anal Behav ; 109(1): 210-237, 2018 01.
Article in English | MEDLINE | ID: mdl-29380434

ABSTRACT

The present study examined persistence and relapse of reinforced behavioral variability in pigeons. Pigeons emitted four-response sequences across two keys. Sequences produced food according to a lag schedule, in which a response sequence was followed by food if it differed from a certain number of previous sequences. In Experiment 1, food was delivered for sequences that satisfied a lag schedule in both components of a multiple schedule. When reinforcement was removed for one component (i.e., extinction), levels of behavioral variability decreased for only that component. In Experiment 2, food was delivered for sequences satisfying a lag schedule in one component of a multiple schedule. In the other component, food was delivered at the same rate, but without the lag variability requirement (i.e., yoked). Following extinction, levels of behavioral variability returned to baseline for both components after response-independent food delivery (i.e., reinstatement). In Experiment 3, one group of pigeons responded on a lag variability schedule, and the other group responded on a lag repetition schedule. For both groups, levels of behavioral variability increased when alternative reinforcement was suspended (i.e., resurgence). In each experiment, we observed some evidence for extinction-induced response variability and for variability as an operant dimension of behavior.


Subject(s)
Conditioning, Operant , Reinforcement, Psychology , Retention, Psychology , Animals , Columbidae , Reinforcement Schedule
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