Nicotinic receptor agonists exhibit anxiolytic-like effects on the elevated plus-maze test

doi:10.1016/0014-2999(93)90498-7

European Journal of Pharmacology

Volume 238, Issue 1, 6 July 1993, Pages 1-8

https://doi.org/10.1016/0014-2999(93)90498-7 Get rights and content

Abstract

The effects of nicotinic receptor agonists on the elevated plus-maze test of anxiety were investigated in CD1 mice after intraperitoneal injections. Nicotine and lobeline, but not cytisine, exhibited a significant increase in the time spent by the mice in the open arms, a measure of anxiolytic activity. Nicotine also increased the total number of arm entries, a measure of general activity, but this effect was secondary to its anxiolytic-like properties. Nicotinic receptor antagonists on their own did not modify the behavior of mice in the maze. The effect of nicotine was mediated by central nicotinic receptors as it was blocked by the centrally-acting nicotinic antagonists mecamylamine and chlorisondamine, but not by hexamethonium (a peripherally acting blocker). Cotinine, the major metabolite of nicotine, was evaluated at different times after systemic injections and had no effect in the plus-maze. The anxiolytic-like profile induced by nicotinic receptor stimulation was not associated with potentiation of alcohol effects, a liability associated with the benzodiazepine therapy. This study demonstrates the anxiolytic-like properties of nicotine and lobeline in mice, and suggests that central nicotinic receptors are involved in the expression of emotional behavior.

References (37)

D.J. Anderson et al.
Neuronal nicotinic receptor binding in rat brain: a comparison of three radioligands
Soc. Neurosci. Abstr.
(1991)
D. Balfour et al.
Studies on the possible role of brain 5-HT systems and adrenocortical activity in behavioural responses to nicotine and diazepam in an elevated X-maze
Psychopharmacology
(1986)
S. Banerjee et al.
[³H]-Mecamylamine binding to rat brain membranes: studies with mecamylamine and nicotine analogues
Biochem. Pharmacol.
(1990)
J.D. Brioni
The role of GABA during the multiple consolidation of memory
Drug Dev. Res.
(1993)
J.D. Brioni et al.
Nicotinic receptor agonists facilitate retention of avoidance training: participation of dopaminergic mechanisms
Behav. Neural Biol
(1993)
P.B.S. Clarke
Chronic central nicotinic blockade after a single administration of the bisquaternary ganglion-blocking drug chlorisondamine
Br. J. Pharmacol.
(1984)
A.C. Collins et al.
Mecamylamine blockade of nicotine responses: evidence for two brain nicotinic receptors
Pharmacol. Biochem. Behav.
(1986)
B. Costall et al.
The actions of nicotine and cocaine in a mouse model of anxiety
Pharmacol. Biochem. Behav.
(1989)
J. Crawley et al.
Preliminary report of a simple animal behavior model for the anxiolytic effects of benzodiazepines
Pharmacol. Biochem. Behav.
(1980)
M.W. Decker et al.
The role of interactions between the cholinergic system and other neuromodulatory systems in learning and memory
Synapse
(1991)

E.S. Deneris et al.

Pharmacological and functional diversity of neuronal nicotinic acetylcholine receptors

Trends Pharmacol. Sci.

(1991)

S. File et al.

A test of anxiety that distinguishes between the action of benzodiazepines and those of other minor tranquilizers and of stimulants

Pharmacol. Biochem. Behav.

(1979)

I. Geller et al.

The effects of meprobamate, barbiturates, d-amphetamine and promazine on experimentally induced conflict in the rat

Psychopharmacologia

(1960)

D.G. Gilbert et al.

Effects of smoking nicotine on anxiety, heart rate and lateralization of EEG during a stressful movie

Psychophysiology

(1989)

G.H. Hall

Pharmacological responses to the intracerebral administration of nicotine

Pharmacol. Ther.

(1982)

J. Hughes et al.

Development of a class of selective cholecystokinin type B receptor antagonists having potent anxiolytic activity

P. Jacob et al.

Recent studies of nicotine metabolism in humans

Pharmacol. Biochem. Behav.

(1988)

B. Jones et al.

The potential anxiolytic activity of GR38032F, a 5-HT₃ receptor antagonist

Br. J. Pharmacol.

(1988)

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Nicotinic receptor agonists exhibit anxiolytic-like effects on the elevated plus-maze test

Abstract

Neuronal nicotinic receptor binding in rat brain: a comparison of three radioligands

Soc. Neurosci. Abstr.

Studies on the possible role of brain 5-HT systems and adrenocortical activity in behavioural responses to nicotine and diazepam in an elevated X-maze

Psychopharmacology

[3H]-Mecamylamine binding to rat brain membranes: studies with mecamylamine and nicotine analogues

Biochem. Pharmacol.

The role of GABA during the multiple consolidation of memory

Drug Dev. Res.

Nicotinic receptor agonists facilitate retention of avoidance training: participation of dopaminergic mechanisms

Behav. Neural Biol

Chronic central nicotinic blockade after a single administration of the bisquaternary ganglion-blocking drug chlorisondamine

Br. J. Pharmacol.

Mecamylamine blockade of nicotine responses: evidence for two brain nicotinic receptors

Pharmacol. Biochem. Behav.

The actions of nicotine and cocaine in a mouse model of anxiety

Pharmacol. Biochem. Behav.

Preliminary report of a simple animal behavior model for the anxiolytic effects of benzodiazepines

Pharmacol. Biochem. Behav.

The role of interactions between the cholinergic system and other neuromodulatory systems in learning and memory

Synapse

Pharmacological and functional diversity of neuronal nicotinic acetylcholine receptors

Trends Pharmacol. Sci.

A test of anxiety that distinguishes between the action of benzodiazepines and those of other minor tranquilizers and of stimulants

Pharmacol. Biochem. Behav.

The effects of meprobamate, barbiturates, d-amphetamine and promazine on experimentally induced conflict in the rat

Psychopharmacologia

Effects of smoking nicotine on anxiety, heart rate and lateralization of EEG during a stressful movie

Psychophysiology

Pharmacological responses to the intracerebral administration of nicotine

Pharmacol. Ther.

Development of a class of selective cholecystokinin type B receptor antagonists having potent anxiolytic activity

Recent studies of nicotine metabolism in humans

Pharmacol. Biochem. Behav.

The potential anxiolytic activity of GR38032F, a 5-HT3 receptor antagonist

Br. J. Pharmacol.

[³H]-Mecamylamine binding to rat brain membranes: studies with mecamylamine and nicotine analogues

The potential anxiolytic activity of GR38032F, a 5-HT₃ receptor antagonist