Acute nicotine induces anxiety and disrupts temporal pattern organization of rat exploratory behavior in hole-board: a potential role for the lateral habenula

Abstract

Nicotine is one of the most addictive drugs of abuse. Tobacco smoking is a major cause of many health problems, and is the first preventable cause of death worldwide. Several findings show that nicotine exerts significant aversive as well as the well-known rewarding motivational effects. Less certain is the anatomical substrate that mediates or enables nicotine aversion. Here, we show that acute nicotine induces anxiogenic-like effects in rats at the doses investigated (0.1, 0.5, and 1.0 mg/kg, i.p.), as measured by the hole-board apparatus and manifested in behaviors such as decreased rearing and head-dipping and increased grooming. No changes in locomotor behavior were observed at any of the nicotine doses given. T-pattern analysis of the behavioral outcomes revealed a drastic reduction and disruption of complex behavioral patterns induced by all three nicotine doses, with the maximum effect for 1 mg/kg. Lesion of the lateral habenula (LHb) induced hyperlocomotion and, strikingly, reversed the nicotine-induced anxiety obtained at 1 mg/kg to an anxiolytic-like effect, as shown by T-pattern analysis. We suggest that the LHb is critically involved in emotional behavior states and in nicotine-induced anxiety, most likely through modulation of monoaminergic nuclei.

Acute and Chronic Nicotine Exposures Differentially Affect Central Serotonin 2A Receptor Function: Focus on the Lateral Habenula

“…Our data on the LHb further support the significant involvement of this small epithalamic area [28,29] and the 5-HT 2A R system [17,35] and their interaction in nicotine effects in the brain and, in general, in drug dependency. Nicotine's modulation is a complex phenomenon and, apart from the rewarding effect mediated by increasing DAergic transmission [7], this alkaloid modulates different neurotransmitter systems.…”

“…Of particular interest in studying drug addiction is the lateral habenula (LHb), a small epithalamic structure that conveys negative motivational signals [25], which might be an essential hub in nicotine/5-HT 2A R interaction. Indeed, the LHb can be directly activated by nicotine [26][27][28], and its lesion prevented nicotine-induce anxiety [29]. The LHb is heavily modulated by the serotonergic system and expresses several 5-HTR subtypes [30,31].…”

Nicotine produces long-term increases in cocaine reinforcement in adolescent but not adult rats

“…This dose has been shown to produce blood levels similar to those following smoking in humans. In addition, doses at or near 0.4 mg/kg nicotine are commonly used doses for preclinical behavioral studies of nicotine (Ahsan et al, 2014; Buffalari et al, 2016; Casarrubea et al, 2015). …”

Wellbeing of Alcohol-preferring Rats Euthanized with Carbon Dioxide at Very Low and Low Volume Displacement Rates

“…Rearing can be an indirect measure of anxiety in a novel environment (that is, induction chamber and gas exposure). 6,23 Because carbon dioxide is heavier than room air, the time spent in the bipedal stance, effectively avoiding the bottom of the chamber, was hypothesized to be indicative of the distress experienced by the rats. 4 The proportions of these measurements (number of rears and time spent at or above 5 in.…”