Cholinergic Receptor Blockade in the VTA Attenuates Cue-Induced Cocaine-Seeking and Reverses the Anxiogenic Effects of Forced Abstinence

Nunes, Eric J.; Bitner, Lillian; Hughley, Shannon M.; Small, Keri M.; Walton, Sofia N.; Rupprecht, Laura E.; Addy, Nii A.

doi:10.1016/j.neuroscience.2019.06.028

Cited by 23 publications

(17 citation statements)

References 84 publications

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“…Importantly, there is ample evidence for nicotine in modulating the development, strength, and recall of drug-associated memories across multiple classes of abused drugs and across multiple learning paradigms designed to measure the impact of the reinforcing and aversive effects of drug administration 19 – 23 . Specifically, acute nicotine pretreatment robustly increases the incentive properties of discrete drug-predictive cues 19 , 24 – 26 and this enhancement is likely dependent on nicotinic activity within the midbrain dopaminergic circuitry, particularly the ventral tegmental area 27 , 28 . There is emerging evidence that, unlike the effects seen on discrete stimuli, nicotine pretreatment may impair the strength of drug-associated contextual memories.…”

Section: Introductionmentioning

confidence: 99%

“…effects of drug administration [19][20][21][22][23] . Specifically, acute nicotine pretreatment robustly increases the incentive properties of discrete drug-predictive cues 19,[24][25][26] and this enhancement is likely dependent on nicotinic activity within the midbrain dopaminergic circuitry, particularly the ventral tegmental area 27,28 . There is emerging evidence that, unlike the effects seen on discrete stimuli, nicotine pretreatment may impair the strength of drug-associated contextual memories.…”

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confidence: 99%

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Systemic nicotine enhances opioid self-administration and modulates the formation of opioid-associated memories partly through actions within the insular cortex

Loney

King

Meyer

2021

Sci Rep

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Habitual use of nicotine containing products increases propensity to misuse prescription opioids and its prevalence is substantially increased in individuals currently involved in opioid-treatment programs. Nicotine enhances self-administration of many classes of drugs in rodents, though evidence for direct effects on opioids is lacking. We sought to measure the effects of nicotine pretreatment on the reinforcing efficacy of opioids in both self-administration and contextual conditioning paradigms. First, we measured the effect of systemic nicotine pretreatment on self-administration of two opioids. Additionally, we measured the degree to which systemic nicotine pretreatment impacts the formation of morphine-associated contextual memories in conditioned taste avoidance and place preference paradigms. Given the involvement of the insula in the maintenance of substance abuse, its importance in nicotine addiction, and findings that insular inactivation impairs contextual drug conditioning, we examined whether nicotine administered directly to the insula could recapitulate the effects of systemic nicotine. We demonstrate that systemic nicotine pretreatment significantly enhances opioid self-administration and alters contextual conditioning. Furthermore, intra-insula nicotine similarly altered morphine contextual conditioning by blocking the formation of taste avoidance at all three morphine doses tested (5.0, 10, and 20 mg/kg), while shifting the dose–response curve of morphine in the place preference paradigm rightward. In conclusion, these data demonstrate that nicotine facilitates opioid intake and is partly acting within the insular cortex to obfuscate aversive opiate memories while potentiating approach to morphine-associated stimuli at higher doses.

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Systemic nicotine enhances opioid self-administration and modulates the formation of opioid-associated memories partly through actions within the insular cortex

Loney

King

Meyer

2021

Sci Rep

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“…For example, nAChRs are upregulated within the accumbens following voluntary ethanol consumption (Larsson, Edström et al 2005). Moreover, nAChR inhibition also reduces cocaine place preference and cocaine sensitivity (Zachariou, Caldarone et al 2001) and nAChR antagonism within the ventral tegmental area attenuates cue-induced cocaine seeking (Nunes, Bitner et al 2019). While the role of nAChRs have been explored across multiple drugs of abuse, their involvement in nicotine use and addiction has been most prominently studied.…”

Section: Interactions Between Chis Ach Nachrs and Drug-motivated Bmentioning

confidence: 99%

Accumbens Cholinergic Interneurons Mediate Cue-Induced Nicotine Seeking and Associated Glutamatergic Plasticity

Leyrer‐Jackson

Holter

Overby

et al. 2020

eNeuro

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Nicotine, the primary addictive substance in tobacco, is widely abused. Relapse to cues associated with nicotine results in increased glutamate release within nucleus accumbens core (NAcore), modifying synaptic plasticity of medium spiny neurons (MSNs) which contributes to reinstatement of nicotine seeking. However, the role of cholinergic interneurons (ChIs) within the NAcore in mediating these neurobehavioral processes is unknown. ChIs represent less than 1% of the accumbens neuronal population and are activated during drug seeking and reward-predicting events. Thus, we hypothesized that ChIs may play a significant role in mediating glutamatergic plasticity that underlies nicotine seeking behavior. Using chemogenetics in transgenic rats expressing Cre under the control of the choline acetyltransferase (ChAT) promoter, ChIs were bi-directionally manipulated prior to cueinduced reinstatement. Following nicotine self-administration and extinction, ChIs were activated or inhibited prior to a cue reinstatement session. Following reinstatement, whole-cell electrophysiology from NAcore MSNs was used to assess changes in plasticity, measured via α-amino-3-hydroxy-5methyl-4-isoxazolepropionic acid (AMPA) / N-Methyl-D-Aspartate (NMDA) (A/N) ratios. Chemogenetic inhibition of ChIs inhibited cued nicotine seeking and resulted in decreased A/N, relative to control animals, whereas activation of ChIs was unaltered, demonstrating that ChI inhibition may modulate plasticity underlying cue-induced nicotine seeking. These results demonstrate that ChI neurons play an important role in mediating cue-induced nicotine reinstatement and underlying synaptic plasticity within the NAcore.

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“…For example, nAChRs are upregulated within the accumbens following voluntary ethanol consumption [39]. Moreover, nAChR inhibition also reduces cocaine place preference and cocaine sensitivity [47] and nAChR antagonism within the ventral tegmental area attenuates cue-induced cocaine seeking [48]. While the role of nAChRs has been explored across multiple drugs of abuse, their involvement in nicotine use and addiction has been most prominently studied.…”

Section: Interactions Between Chis Ach Nachrs and Drug-motivated Bmentioning

confidence: 99%

Accumbens cholinergic interneurons mediate cue-induced nicotine seeking and associated glutamatergic plasticity

Leyrer‐Jackson

Holter

Overby

et al. 2020

Preprint

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Nicotine, the primary addictive substance in tobacco, is widely abused. Relapse to cues associated with nicotine results in increased glutamate release within nucleus accumbens core (NAcore), modifying synaptic plasticity of medium spiny neurons (MSNs) which contributes to reinstatement of nicotine seeking. However, the role of cholinergic interneurons (ChIs) within the NAcore in mediating these neurobehavioral processes in unknown. ChIs represent less than 1% of the accumbens neuronal population yet are activated during drug seeking and reward-predicting events. Thus, we hypothesized that ChIs may play a significant role in mediating glutamatergic plasticity that underlies nicotine seeking behavior. Using chemogenetics transgenic rats that express Cre under the control of the choline acetyltransferase (ChAT) promoter, ChIs were bi-directionally manipulated prior to cueinduced reinstatement. Following nicotine self-administration and extinction training, ChIs were activated or inhibited prior to a cue reinstatement session. Following reinstatement, whole-cell electrophysiology from NAcore MSNs was used to assess changes in plasticity, measured via α amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) / N-Methyl-D-Aspartate (NMDA) (A/N) ratios. Chemogenetic inhibition of ChIs inhibited cued nicotine seeking and resulted in decreased A/N, whereas activation of ChIs had no effect, demonstrating that ChI inhibition prevents transient synaptic potentiation (t-SP) associated with cue-induced nicotine seeking. To assess potential underlying mechanisms, accumbens α 4 β 2 -and α 7 -containing nicotinic ACh receptors (nAChRs) were pharmacologically inhibited and MSN synaptic morphology was assessed following reinstatement.Inhibition of both nAChR subtypes prevented cue-induced nicotine seeking and t-SP (measured via changes in spine head diameter). Together, these results demonstrate that these neurons mediate cue-induced nicotine reinstatement and underlying synaptic plasticity within the NAcore.--250 words--3 Introduction:

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Cholinergic Receptor Blockade in the VTA Attenuates Cue-Induced Cocaine-Seeking and Reverses the Anxiogenic Effects of Forced Abstinence

Cited by 23 publications

References 84 publications

Systemic nicotine enhances opioid self-administration and modulates the formation of opioid-associated memories partly through actions within the insular cortex

Systemic nicotine enhances opioid self-administration and modulates the formation of opioid-associated memories partly through actions within the insular cortex

Accumbens Cholinergic Interneurons Mediate Cue-Induced Nicotine Seeking and Associated Glutamatergic Plasticity

Accumbens cholinergic interneurons mediate cue-induced nicotine seeking and associated glutamatergic plasticity

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