High affinity α3β4 nicotinic acetylcholine receptor ligands AT-1001 and AT-1012 attenuate cocaine-induced conditioned place preference and behavioral sensitization in mice

Khroyan, Taline V.; Yasuda, Dennis; Toll, Lawrence; Polgar, Willma E.; Zaveri, Nurulain T.

doi:10.1016/j.bcp.2015.08.083

Cited by 23 publications

(19 citation statements)

References 53 publications

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“…Work from Fowler and Kenny demonstrated that α5-KO (α5-expressing nAChRs are enriched in the vMHb-IPN pathway) mice show escalations of nicotine self-administration through a blunting of the aversive properties of nicotine and not an increase in the rewarding aspects of the drug (Fowler & Lu Qun 2011;Tuesta et al 2011). Conversely, pharmacological antagonism of β4-expressing nAChR (also enriched in the vMHb-IPN pathway) inhibits the self-administration of morphine and cocaine and blocks the formation of cocaine CPP (Glick et al 2006;McCallum & Glick 2009;Khroyan et al 2015). It is likely that a balance between α5 and β4 subunits is more influential in regulating drug response than a single subunit (Frahm et al 2011; ChAT-Cre DIO-mCherry-infused mice acquire cocaine-induced CPP (2-way ANOVA, main effect of conditioning, F 1,9 = 30.56, p = 0.0004), with no differences between CNO-primed (n = 6) and Veh-primed (n = 5) animals (no effect main effect of CNO-priming (F 1,9 = 0.4273, p = 0.5297).…”

Section: Discussionmentioning

confidence: 99%

Medial habenula cholinergic signaling regulates cocaine‐associated relapse‐like behavior

et al. 2018

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Propensity to relapse, even following long periods of abstinence, is a key feature in substance use disorders. Relapse and relapse-like behaviors are known to be induced, in part, by re-exposure to drug-associated cues. Yet, while many critical nodes in the neural circuitry contributing to relapse have been identified and studied, a full description of the networks driving reinstatement of drug-seeking behaviors is lacking. One area that may provide further insight to the mechanisms of relapse is the habenula complex, an epithalamic region composed of lateral and medial (MHb) substructures, each with unique cell and target populations. Although well conserved across vertebrate species, the functions of the MHb are not well understood. Recent research has demonstrated that the MHb regulates nicotine aversion and withdrawal. However, it remains undetermined whether MHb function is limited to nicotine and aversive stimuli or if MHb circuit regulates responses to other drugs of abuse. Advances in circuit-level manipulations now allow for cell-type and temporally specific manipulations during behavior, specifically in spatially restrictive brain regions, such as the MHb. In this study, we focus on the response of the MHb to reinstatement of cocaine-associated behavior, demonstrating that cocaine-primed reinstatement of conditioned place preference engages habenula circuitry. Using chemogenetics, we demonstrate that MHb activity is sufficient to induce reinstatement behavior. Together, these data identify the MHb as a key hub in the circuitry underlying reinstatement and may serve as a target for regulating relapse-like behaviors.

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Section: Discussionmentioning

confidence: 99%

Medial habenula cholinergic signaling regulates cocaine‐associated relapse‐like behavior

et al. 2018

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“…We have previously shown that AT-1001 does not exhibit reinforcing properties per se and does not induce reinstatement of nicotine seeking in extinguished rats [32, 36]. We have also shown that AT-1001 does not induce a conditioned place preference or aversion in mice [51]. …”

Section: Discussionmentioning

confidence: 99%

The α3β4 nAChR partial agonist AT-1001 attenuates stress-induced reinstatement of nicotine seeking in a rat model of relapse and induces minimal withdrawal in dependent rats

Yuan

Malagon

Yasuda

et al. 2017

Behavioural Brain Research

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The strong reinforcing effects of nicotine and the negative symptoms such as anxiety experienced during a quit attempt often lead to relapse and low success rates for smoking cessation. Treatments that not only block the reinforcing effects of nicotine but also attenuate the motivation to relapse are needed to improve cessation rates. Recent genetic and preclinical studies have highlighted the involvement of the α3, β4, and α5 nicotinic acetylcholine receptor (nAChR) subunits and the α3β4 nAChR subtype in nicotine dependence and withdrawal. However, the involvement of these nAChR in relapse is not fully understood. We previously reported that the α3β4 nAChR partial agonist AT-1001 selectively decreases nicotine self-administration in rats without affecting food responding. In the present experiments, we examined the efficacy of AT-1001 in attenuating reinstatement of nicotine-seeking behavior in a model of stress-induced relapse. Rats extinguished from nicotine self-administration were treated with the pharmacological stressor yohimbine prior to AT-1001 treatment and reinstatement testing. We also examined whether AT-1001 produced any withdrawal-related effects when administered to nicotine-dependent rats. We found that AT-1001 dose-dependently reduced yohimbine stress-induced reinstatement of nicotine seeking. When administered to nicotine-dependent rats at the dose that significantly blocked nicotine reinstatement, AT-1001 elicited minimal somatic withdrawal signs in comparison to the nicotinic antagonist mecamylamine, which is known to produce robust withdrawal. Our data suggest that α3β4 nAChR-targeted compounds may be a promising approach for nicotine addiction treatment because they can not only block nicotine’s reinforcing effects, but also decrease motivation to relapse without producing significant withdrawal effects.

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“…In this latter study, the involvement of α6β2-containing nAChRs was confirmed pharmacologically by the blockade of cocaine reward with the intracerebral administration of the selective nAChR antagonist α-conotoxin MII. Other nAChR-regulated brain circuits may also be involved in cocaine reward, since the high affinity α3β4 nAChR functional antagonists, AT-1001 and AT-1012, can also attenuate cocaine place preference (183). A less selective α3β4 nAChR antagonist, 18-methoxycoronaridine, has also been shown to inhibit the self-administration of both cocaine and methamphetamine (184,185).…”

Section: Concurrent Use Of Nicotine and Psychostimulantsmentioning

confidence: 99%

Mechanisms and genetic factors underlying co-use of nicotine and alcohol or other drugs of abuse

Cross

Lotfipour

Leslie

2016

The American Journal of Drug and Alcohol Abuse

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Concurrent use of tobacco and alcohol or psychostimulants represents a major public health concern, with use of one substance influencing consumption of the other. Co-abuse of these drugs leads to substantial negative health outcomes, reduced cessation, and high economic costs, but the underlying mechanisms are poorly understood. Epidemiological data suggest that tobacco use during adolescence plays a particularly significant role. Adolescence is a sensitive period of development marked by major neurobiological maturation of brain regions critical for reward processing, learning and memory, and executive function. Nicotine exposure during this time produces a unique and long-lasting vulnerability to subsequent substance use, likely via actions at cholinergic, dopaminergic, and serotonergic systems. In this review, we discuss recent clinical and preclinical data examining the genetic factors and mechanisms underlying co-use of nicotine and alcohol or cocaine and amphetamines. We evaluate the critical role of nicotinic acetylcholine receptors throughout, and emphasize the dearth of preclinical studies assessing concurrent drug exposure. We stress important age and sex differences in drug responses, and highlight a brief, low-dose nicotine exposure paradigm that may better model early use of tobacco products. The escalating use of e-cigarettes among youth necessitates a closer look at the consequences of early adolescent nicotine exposure on subsequent alcohol and drug abuse.

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High affinity α3β4 nicotinic acetylcholine receptor ligands AT-1001 and AT-1012 attenuate cocaine-induced conditioned place preference and behavioral sensitization in mice

Cited by 23 publications

References 53 publications

Medial habenula cholinergic signaling regulates cocaine‐associated relapse‐like behavior

Medial habenula cholinergic signaling regulates cocaine‐associated relapse‐like behavior

The α3β4 nAChR partial agonist AT-1001 attenuates stress-induced reinstatement of nicotine seeking in a rat model of relapse and induces minimal withdrawal in dependent rats

Mechanisms and genetic factors underlying co-use of nicotine and alcohol or other drugs of abuse

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