Menthol enhances nicotine-induced locomotor sensitization and in vivo functional connectivity in adolescence

Thompson, Matthew; Poirier, Guillaume L.; Dávila‐García, Martha I.; Huang, Wei; Tam, Kelly; Robidoux, Maxwell; Dubuke, Michelle L.; Shaffer, Scott A.; Colon-Perez, Luis M.; Febo, Marcelo; DiFranza, Joseph R.; King, Jean A.

doi:10.1177/0269881117719265

Cited by 20 publications

(7 citation statements)

References 98 publications

(116 reference statements)

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“…The enhancing effect of menthol on nicotine-induced dopamine release is consistent with a recent electrophysiological study that showed that menthol+nicotine increased the frequency of dopamine neuron firing more than nicotine alone (Henderson et al, 2017). In adolescent rats, functional magnetic resonance imaging indicated greater functional connectivity in reward circuitry (i.e., the ventral tegmental area and its dopaminergic projection terminal regions) with combined treatment with menthol (5.38 mg/kg) and nicotine (0.4 mg/kg) compared with nicotine alone (Thompson et al, 2017). Additionally, menthol was shown to alter dopamine neurotransmission in rodents by directly interacting with dopamine uptake (Umezu and Morita, 2003).…”

Section: Discussionmentioning

confidence: 99%

Menthol facilitates dopamine-releasing effect of nicotine in rat nucleus accumbens

Zhang

Harrison

Biswas

et al. 2018

Pharmacology Biochemistry and Behavior

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Menthol is a significant flavoring additive in tobacco products. Accumulating clinical evidence suggests that menthol may promote tobacco smoking and nicotine dependence. Our previous studies demonstrated that menthol enhanced nicotine reinforcement in rats. However, it is unclear whether menthol interacts with nicotine at the neurochemical level. The present study used intracranial microdialysis to examine whether and the ways in which menthol affects nicotine-induced dopamine release in rats in the nucleus accumbens core (NAc), a terminal field of brain reward circuitry. To make comparisons with our previous work that showed an enhancing effect of menthol on nicotine self-administration behavior, male Sprague-Dawley rats were first trained in 20 daily 1-h sessions to press a lever for intravenous nicotine self-administration (15 μg/kg/infusion). Dopamine levels were then measured in the right NAc using intracranial microdialysis coupled with high-performance liquid chromatography. Five minutes before microdialysis, the rats received an intraperitoneal injection of menthol (0, 1, 2.5, and 5 mg/kg), a subcutaneous injection of nicotine (0.2 mg/kg or its vehicle), or both. Menthol alone did not affect dopamine levels in dialysates, whereas nicotine alone elevated dopamine levels. Combined nicotine and menthol administration significantly increased dopamine levels compared with nicotine alone. These data indicate a facilitating effect of menthol on nicotine-induced dopamine release in the NAc. These findings shed light on our understanding of the neurobiological mechanisms that underlie the menthol-induced enhancement of nicotine reinforcement.

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Section: Discussionmentioning

confidence: 99%

Menthol facilitates dopamine-releasing effect of nicotine in rat nucleus accumbens

Zhang

Harrison

Biswas

et al. 2018

Pharmacology Biochemistry and Behavior

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“…In addition, accumulating evidence indicates that menthol also affects the central nervous system (CNS). In rodents, menthol is distributed throughout the brain after peripheral administration ( Pan et al., 2012 ; Thompson et al., 2018 ). Previous studies demonstrated that menthol affects neuronal activity via voltage-gated calcium (Ca) channels ( Swandulla et al., 1986 , 1987 ) and acts as an allosteric modulator of serotonin type 3 receptor expressed in neurons ( Ashoor et al., 2013 ).…”

Section: Introductionmentioning

confidence: 99%

“…Other studies reported that the γ-aminobutyric acid type A (GABA A ) receptor mediates some of the CNS effects of menthol ( Zhang et al., 2008 ; Tani et al., 2010 ). Moreover, it has been suggested that the CNS effects of menthol play a role in the development of nicotine dependence ( Alsharari et al., 2015 ; Henderson et al., 2016 , 2017 ; Thompson et al., 2018 ).…”

Section: Introductionmentioning

confidence: 99%

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Identification of novel target molecules of l-menthol

Umezu

2021

Heliyon

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The present study used a binding assay to identify novel target biomolecules of l -menthol ([−]-menthol) that promote mouse ambulation. Among 88 different ligands to specific biomolecules examined, 0.1 mM l -menthol inhibited the binding of 13 ligands with relatively high inhibition rates. The assays showed that l -menthol acts on calcium channels, sodium channels, γ-aminobutyric acid type A (GABA A ) receptor, GABA transporter, dopamine transporter, dopamine D4 receptor, adenosine A2a receptor, α2A-adrenergic receptor, histamine H2 receptor, bombesin receptor, angiotensin AT1 receptor, vasopressin V2 receptor, and leukotriene B4 receptor over a similar concentration range. The inhibition constant (K i ) for l -menthol inhibition of binding of [ 3 H]-WIN35,428 to the human recombinant dopamine transporter was 6.15 × 10 −4 mol/L. The K i for l -menthol inhibition of binding of [ 3 H]-ethynylbicycloorthobenzoate (EBOB), a ligand of GABA A receptor picrotoxin site, was 2.88 × 10 −4 mol/L. These results should aid future research by providing clues for investigating the mechanisms underlying l -menthol activities, including the ambulation-promoting effect. The present results suggest that the dopamine transporter, adenosine A2a receptor, dopamine D4 receptor, α2A-adrenergic receptor, and GABA A receptor are promising candidate molecules that are involved in the mechanisms underlying the psychostimulant-like effect of l -menthol.

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“…It has been suggested that these sensory properties serve as powerful cues that become associated with smoking and serve to influence smoking intensity as well as nicotine craving and relapse (Ahijevych and Garrett 2010;Kreslake et al 2008b;Perkins and Karelitz 2014). There is also mounting evidence suggesting that some of these effects may be mediated independent of sensory cues effects via pharmacological interactions of menthol and nicotine (Ashoor et al 2013a;Brody et al 2013;Hans et al 2012; Thompson et al 2018). For example, as compared to non-menthol cigarette smokers, menthol cigarette smokers have a higher density of nAChRs at subtypes that are associated with enhanced smoking intensity and relapse (i.e., α4β2; Brody et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Effect of menthol on nicotine intake and relapse vulnerability in a rat model of concurrent intravenous menthol/nicotine self-administration

et al. 2018

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Rationale: Epidemiological data suggest that menthol may increase vulnerability to cigarette/ nicotine use and relapse. While menthol's sensory properties are often attributed as the underlying cause of the enhanced vulnerability, an alternative possibility is that they are mediated via pharmacological interactions with nicotine.Objective: This study addressed the possibility that menthol enhances nicotine intake and relapse vulnerability via pharmacological interactions with nicotine using a concurrent intravenous menthol/nicotine self-administration procedure.Methods: Following acquisition, adolescent rats were given 23-hr/day access to nicotine (0.01 mg/kg/infusion), nicotine plus menthol (0.16, 0.32, or 0.64 mg/kg/infusion), or menthol alone (0.16, 0.32, 0.64 mg/kg/infusion) for a total of 10 days. Nicotine-seeking was assessed using an extinction/cue-induced reinstatement procedure following 10-days of forced abstinence. We also assessed the effect of menthol (0.32 mg/kg/infusion) on progressive-ratio responding for nicotine (0.01 mg/kg/infusion).Results: Menthol decreased PR responding for nicotine, but did not affect self-administration under extended access conditions. The low dose of menthol tended to decrease subsequent extinction responding, and was not different from menthol alone, whereas, the high dose decreased reinstatement responding. Although not significant, the highest levels of extinction responding were observed in a minority of rats in the moderate and high menthol-nicotine groups; rats in these groups also took longer to extinguish. Conclusions:Taken together, these results demonstrate that pharmacological interactions of menthol with nicotine reduce, rather than increase, nicotine's reinforcing effects and some measures of relapse vulnerability. Importantly, however, moderate and high menthol doses may increase some aspects of relapse vulnerability in a minority of individuals.

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Menthol enhances nicotine-induced locomotor sensitization and in vivo functional connectivity in adolescence

Cited by 20 publications

References 98 publications

Menthol facilitates dopamine-releasing effect of nicotine in rat nucleus accumbens

Menthol facilitates dopamine-releasing effect of nicotine in rat nucleus accumbens

Identification of novel target molecules of l-menthol

Effect of menthol on nicotine intake and relapse vulnerability in a rat model of concurrent intravenous menthol/nicotine self-administration

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