Pharmacological modulation of the α7 nicotinic acetylcholine receptor in a mouse model of mecamylamine-precipitated nicotine withdrawal.

Abstract

RATIONALE:

Recent preclinical data has implicated the α7 nicotinic acetylcholine receptor (nAChR) as a target in modulating nicotine reward. However, the role of the channel properties of the α7 nAChR in nicotine withdrawal is unknown.

OBJECTIVES:

This study aimed to investigate the impact of α7 nAChR pharmacological modulation on mecamylamine-precipitated nicotine withdrawal behaviors in mice by using positive allosteric modulators (PAMs).

METHODS:

The effect of the orthosteric α7 nAChR full agonist PNU282987 (1, 3, 9 mg/kg, s.c.), type I α7 PAM NS1738 (1 and 10 mg/kg; i.p.) and the type II α7 PAM PNU120596 (3 and 9 mg/kg, i.p.) on anxiety-like behavior, somatic signs, and hyperalgesia was measured in mice undergoing mecamylamine-precipitated nicotine withdrawal. Mice were infused with 24 mg/kg/day nicotine or saline for 14 days using s.c. osmotic minipumps. Nicotine withdrawal signs were precipitated upon administration of the non-selective nAChR antagonist mecamylamine (3.5 mg/kg, i.p.).

RESULTS:

Anxiety-like behavior in nicotine withdrawn mice was only attenuated by PNU282987 in a dose-related fashion. Somatic signs were reduced by PNU282987 and NS1738. PNU120596 was the only compound that reversed precipitated nicotine withdrawal-induced hyperalgesia.

CONCLUSIONS:

Taken together, our results suggest that modulation of the α7 nAChR can play important roles in mecamylamine-precipitated nicotine withdrawal behaviors in mice. In addition, the effects of PAMs in this study suggest that endogenous acetylcholine/choline tone is sufficient to attenuate some aspects of precipitated nicotine withdrawal. These findings highlight a beneficial effect of using α7 nAChR PAMs in some aspects of precipitated nicotine withdrawal.

• Authors: Asti Jackson, Roger L Papke, M Imad Damaj
• Journal: Psychopharmacology (Psychopharmacology (Berl)) Vol. 235 Issue 7 Pg. 1897-1905 (07 2018) ISSN: 1432-2072 [Electronic] Germany
• PMID: 29549391 (Publication Type: Journal Article)

Chemical References

• Benzamides
• Bridged Bicyclo Compounds
• Nicotinic Agonists
• Nicotinic Antagonists
• PNU-282987
• alpha7 Nicotinic Acetylcholine Receptor
• Mecamylamine
• Nicotine

Topics

• Animals
• Benzamides (administration & dosage)
• Bridged Bicyclo Compounds (administration & dosage)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Infusion Pumps
• Male
• Mecamylamine (administration & dosage)
• Mice
• Mice, Inbred ICR
• Nicotine (administration & dosage, adverse effects)
• Nicotinic Agonists (administration & dosage)
• Nicotinic Antagonists (administration & dosage)
• Substance Withdrawal Syndrome (etiology, physiopathology, psychology)
• alpha7 Nicotinic Acetylcholine Receptor (agonists, antagonists & inhibitors, physiology)