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.
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Kingdom of Saudi Arabia; Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, United States of America.
Shakir D
SD
Alsharari
Department of Molecular Neuroscience, Krasnow Institute for Advanced Study, George Mason University, Fairfax, Virginia, United States of America.
Justin R
JR
King
Department of Molecular Neuroscience, Krasnow Institute for Advanced Study, George Mason University, Fairfax, Virginia, United States of America.
Jacob C
JC
Nordman
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, United States of America.
Pretal P
PP
Muldoon
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, United States of America.
Asti
A
Jackson
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Department of Pharmacology and Toxicology, and Psychiatry, University of Toronto, Toronto, Ontario, Canada.
Andy Z X
AZ
Zhu
Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Department of Pharmacology and Toxicology, and Psychiatry, University of Toronto, Toronto, Ontario, Canada.
Rachel F
RF
Tyndale
Department of Molecular Neuroscience, Krasnow Institute for Advanced Study, George Mason University, Fairfax, Virginia, United States of America.
Nadine
N
Kabbani
Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia, United States of America.
M Imad
MI
Damaj
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006930:Hyperalgesia / Q000150:complications / Q000188:drug therapy; D007036:Hypothermia, Induced; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008610:Menthol / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008813:Mice, Inbred ICR; D009538:Nicotine / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D059225:Nociception / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000378:metabolism; D013375:Substance Withdrawal Syndrome; D013997:Time Factors; D014029:Tobacco Use Disorder / Q000150:complications / Q000188:drug therapy*
D011978:Receptors, Nicotinic; D008610:Menthol; D009538:Nicotine