Asti Jackson

Effects of Menthol on Nicotine Pharmacokinetic, Pharmacology and Dependence in Mice

Although menthol, a common flavoring additive to cigarettes, has been found to impact the addictive properties of nicotine cigarettes in smokers little is known about its pharmacological and molecular actions in the brain. Studies were undertaken to examine whether the systemic administration of menthol would modulate nicotine pharmacokinetics, acute pharmacological effects (antinociception and hypothermia) and withdrawal in male ICR mice. In addition, we examined changes in the brain levels of nicotinic receptors of rodents exposed to nicotine and menthol. Administration of i.p. menthol significantly decreased nicotine’s clearance (2-fold decrease) and increased its AUC compared to i.p. vehicle treatment. In addition, menthol pretreatment prolonged the duration of nicotine-induced antinociception and hypothermia (2.5 mg/kg, s.c.) for periods up to 180 min post-nicotine administration. Repeated administration of menthol with nicotine increased the intensity of mecamylamine-precipitated withdrawal signs in mice exposed chronically to nicotine. The potentiation of withdrawal intensity by menthol was accompanied by a significant increase in nicotine plasma levels in these mice. Western blot analyses of α4 and β2 nAChR subunit expression suggests that chronic menthol impacts the levels and distribution of these nicotinic subunits in various brain regions. In particular, co-administration of menthol and nicotine appears to promote significant increase in β2 and α4 nAChR subunit expression in the hippocampus, prefrontal cortex and striatum of mice. Surprisingly, chronic injections of menthol alone to mice caused an upregulation of β2 and α4 nAChR subunit levels in these brain regions. Because the addition of menthol to tobacco products has been suggested to augment their addictive potential, the current findings reveal several new pharmacological molecular adaptations that may contribute to its unique addictive profile.

The interaction between alpha 7 nicotinic acetylcholine receptor and nuclear peroxisome proliferator-activated receptor-α represents a new antinociceptive signaling pathway in mice

Abstract Recently, &agr;7 nicotinic acetylcholine receptors (nAChRs), primarily activated by binding of orthosteric agonists, represent a target for anti‐inflammatory and analgesic drug development. These receptors may also be modulated by positive allosteric modulators (PAMs), ago‐allosteric ligands (ago‐PAMs), and &agr;7‐silent agonists. Activation of &agr;7 nAChRs has been reported to increase the brain levels of endogenous ligands for nuclear peroxisome proliferator‐activated receptors type‐&agr; (PPAR‐&agr;), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), in a Ca2+‐dependent manner. Here, we investigated potential crosstalk between &agr;7 nAChR and PPAR‐&agr;, using the formalin test, a mouse model of tonic pain. Using pharmacological and genetic approaches, we found that PNU282987, a full &agr;7 agonist, attenuated formalin‐induced nociceptive behavior in &agr;7‐dependent manner. Interestingly, the selective PPAR‐&agr; antagonist GW6471 blocked the antinociceptive effects of PNU282987, but did not alter the antinociceptive responses evoked by the &agr;7 nAChR PAM PNU120596, ago‐PAM GAT107, and silent agonist NS6740. Moreover, GW6471 administered systemically or spinally, but not via the intraplantar surface of the formalin‐injected paw blocked PNU282987‐induced antinociception. Conversely, exogenous administration of the naturally occurring PPAR‐&agr; agonist PEA potentiated the antinociceptive effects of PNU282987. In contrast, the cannabinoid CB1 antagonist rimonabant and the CB2 antagonist SR144528 failed to reverse the antinociceptive effects of PNU282987. These findings suggest that PPAR‐&agr; plays a key role in a putative antinociceptive &agr;7 nicotinic signaling pathway. Graphical abstract Figure. No Caption available. HighlightsThe &agr;7 nAChR and PPAR‐&agr; crosstalk is investigated using a mouse model of tonic pain.The PPAR‐&agr; antagonist blocks the antinociceptive effects of &agr;7 nAChR full agonist.The cannabinoid receptors are not involved in the effects of &agr;7 nAChR full agonist.Palmitoylethanolamide potentiates the antinociceptive effects of &agr;7 nAChR full agonist.PPAR‐&agr; plays a key role in a putative antinociceptive &agr;7 nicotinic signaling pathway.

Reversal of Nicotine Withdrawal Signs Through Positive Allosteric Modulation of α4β2 Nicotinic Acetylcholine Receptors in Male Mice

Introduction Nicotine withdrawal symptoms are important factors in determining the relapse rate to tobacco smoking and drugs that diminish these symptoms would potentially have a higher success rate as smoking cessation aids. Unlike US Food and Drug administration approved smoke cessation aids (nicotine and varenicline) which act as nicotinic acetylcholine receptors (nAChRs) agonists, desformylflustrabromine (dFBr) acts as a nAChR positive allosteric modulator with higher selectivity to the α4β2 nAChR. In animal studies, dFBr was well tolerated and reduced intravenous nicotine self-administration. In this study, we use behavioral test in mouse model of spontaneous nicotine withdrawal to assess the effect of dFBr on nicotine withdrawal symptoms. Methods Spontaneous nicotine withdrawal in nicotine-dependent ICR male mice was established 18-24 h after termination (minipump removal) of 14 days infusion of nicotine. After that (day 15), spontaneous signs of nicotine withdrawal were examined in the following order: anxiety-like behaviors, somatic signs, and then hyperalgesia using previously published behavioral protocols. Fifteen minutes before withdrawal signs testing, mice received a subcutaneous acute injection of vehicle or dFBr at the doses of 0.02, 0.1, and 1 mg/kg to determine the effect of dFBr on nicotine withdrawal symptoms. Results dFBr produced dose-dependent reversal of nicotine withdrawal signs in mouse model of spontaneous nicotine withdrawal. Implications Positive allosteric modulators of nAChR such as dFBr reduce nicotine withdrawal symptoms supporting the potential clinical use of this novel class of nAChR-based therapeutics as smoking cessation aid.

Assessment of nicotine withdrawal-induced changes in sucrose preference in mice

ABSTRACT Anhedonia, induced by nicotine withdrawal, may serve as an important affective sign that reinforces tobacco use and smoking relapse rates in humans. Animal models provide a way to investigate the underlying neurobiological factors involved in the decrease in responding for positive affective stimuli during nicotine withdrawal and may aid in drug development for nicotine dependence. Thus, we explored the use of the sucrose preference test to measure nicotine withdrawal‐induced reduction in response for positive affective stimuli in mice. C57BL/6J and knockout (KO) mice were chronically exposed to different doses of nicotine through surgically implanted subcutaneous osmotic minipumps for 14 days and underwent spontaneous nicotine withdrawal on day 15. A sucrose preference time course was performed and the results were compared to another well‐established affective sign of nicotine withdrawal, the reduction in time spent in light side, using the Light Dark Box test. Subsequently, our results demonstrated a time‐dependent and dose‐related reduction in sucrose preference in nicotine withdrawn male C57BL/6J mice, indicative of a decrease in responding for positive affective stimuli. Furthermore, the sucrose preference reduction during nicotine withdrawal was consistent with decrease in time spent in the light side of the Light Dark Box test. We also found the reduction for positive affective stimuli and time spent in the light side was not present in nicotine withdrawn &bgr;2 and &agr;6 KO mice, suggesting that these nicotinic subunits are involved in the affective signs of nicotine withdrawal. Thus, this report highlights the potential utility of the sucrose preference test as a useful measure of the decrease in responding for positive affective stimuli during spontaneous nicotine withdrawal. HIGHLIGHTSNicotine withdrawal induces attenuation in responding for positive affective stimuli.Spontaneous nicotine withdrawal produces reduction in sucrose preference.&bgr;2 and &agr;6 nAChR subunits play a role in affective behaviors of nicotine withdrawal.Sucrose preference test is a useful model for nicotine withdrawal‐induced affective behavior.

N -Oleoyl-glycine reduces nicotine reward and withdrawal in mice

ABSTRACT Cigarette smokers with brain damage involving the insular cortex display cessation of tobacco smoking, suggesting that this region may contribute to nicotine addiction. In the present study, we speculated that molecules in the insular cortex that are sensitive to experimental traumatic brain injury (TBI) in mice might provide leads to ameliorate nicotine addiction. Using targeted lipidomics, we found that TBI elicited substantial increases of a largely uncharacterized lipid, N‐acyl‐glycine, N‐oleoyl‐glycine (OlGly), in the insular cortex of mice. We then evaluated whether intraperitoneal administration of OlGly would alter withdrawal responses in nicotine‐dependent mice as well as the rewarding effects of nicotine, as assessed in the conditioned place preference paradigm (CPP). Systemic administration of OlGly reduced mecamylamine‐precipitated withdrawal responses in nicotine‐dependent mice and prevented nicotine CPP. However, OlGly did not affect morphine CPP, demonstrating a degree of selectivity. Our respective in vitro and in vivo observations that OlGly activated peroxisome proliferator‐activated receptor alpha (PPAR‐&agr;) and the PPAR‐&agr; antagonist GW6471 prevented the OlGly‐induced reduction of nicotine CPP in mice suggests that this lipid acts as a functional PPAR‐&agr; agonist to attenuate nicotine reward. These findings raise the possibility that the long chain fatty acid amide OlGly may possess efficacy in treating nicotine addiction. HighlightsN‐oleoyl‐glycine (OlGly) levels increase in the insular cortex of TBI mice.OlGly attentuates precipitated withdrawal in nicotine‐dependent mice.OlGly prevents nicotine conditioned place preference (CPP).OlGly induces reduction of nicotine CPP via PPAR‐&agr; mechanism of action.OlGly may possess efficacy in treating nicotine addiction.