Neurobiological mechanisms by which nicotine mediates different types of anxiety

Abstract

The effects of nicotine administration into the dorsal hippocampus and lateral septum provide further evidence that different neurochemical and neuroanatomical substrates control behaviour in different animal tests. Thus, in the social interaction test (a model of generalised anxiety disorder), bilateral administration of nicotine (1–4 μg) into both regions has anxiogenic effects in test conditions that generate moderate anxiety. The anxiogenic effects are mediated by a nicotine-evoked increase in 5-hydroxytryptamine (5-HT) release and are reversed by co-administration of the 5-HT_1A receptor antagonist, N-(2-(6-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridyl)-cyclohexane carboxamide trichloride (WAY 100,635). On trial 1 in the elevated plus-maze (which models the escape components of panic disorder), nicotine is without effect when administered to the dorsal hippocampus, but has anxiogenic effects after lateral septal administration. On trial 2 in the elevated plus-maze (a model of specific phobia), nicotine (1 μg) has anxiolytic effects when administered to the dorsal hippocampus, but is ineffective (4 and 8 μg) in the lateral septum.

Introduction

The term anxiety disorder encompasses a number of conditions, including generalised anxiety disorder (GAD), panic disorder and specific (or simple) phobias. Different pharmacological treatments are effective in treating these three types of anxiety disorder. Thus, benzodiazepines are very effective in treating GAD, with 5-HT_1A receptor agonists having a somewhat lower efficacy. In panic disorder, antidepressants are the most effective treatment, with benzodiazepines working only at high doses. In specific phobias, benzodiazepines are ineffective and, indeed, there is no really useful drug treatment for this disorder. This differing pattern of drug treatment suggests that these different anxiety disorders have different underlying neurobiological pathologies. It is not surprising, then, that factor analysis has provided evidence that measures obtained from different animal tests of anxiety measure quite independent factors, and thus the different animal tests are measuring different types, or states, of anxiety (File, 1992).

The hippocampus and septal nuclei are two regions of the limbic system that have long been implicated in the control of anxiety (Gray, 1982), but as will be seen in the following sections, these areas are not equally important in all animal tests of anxiety. Accumulating evidence from lesion studies and central drug administration has shown that different brain regions and neurotransmitters control behaviour in the different animal tests of anxiety Menard and Treit, 1996, Treit and Menard, 1997, Treit and Menard, 1999. The effects of nicotine after bilateral administration to the dorsal hippocampus and lateral septum highlight the differing roles of the nicotinic cholinergic systems in modulating behaviour in three different animal tests of anxiety. The social interaction test is a model of GAD File, 1980, File, 1997, trial 1 in the plus-maze measures the escape aspects of panic disorder Graeff et al., 1993a, Graeff et al., 1993b and trial 2 in the elevated plus-maze is a model of specific phobia File and Zangrossi, 1993, File et al., 1993, Fernandes and File, 1996.