Nicotinic–serotonergic interactions in brain and behaviour

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Abstract

This review focuses on nicotinic–serotonergic interactions in the central nervous system (CNS). Nicotine increases 5-hydroxytryptamine (5-HT) release in the cortex, striatum, hippocampus, dorsal raphé nucleus (DRN), hypothalamus, and spinal cord. As yet, there is little firm evidence for nicotinic receptors on serotonergic terminals and thus nicotine's effects on 5-HT may not necessarily be directly mediated, but there is strong evidence that the 5-HT tone plays a permissive role in nicotine's effects. The effects in the cortex, hippocampus, and DRN involve stimulation of 5-HT1A receptors, and in the striatum, 5-HT3 receptors. The 5-HT1A receptors in the DRN play a role in mediating the anxiolytic effects of nicotine and the 5-HT1A receptors in the dorsal hippocampus and lateral septum mediate its anxiogenic effects. The increased startle and anxiety during nicotine withdrawal is mediated by 5-HT1A and 5-HT3 receptors. The locomotor stimulant effect of acute nicotine is mediated by 5-HT1A receptors and 5-HT2 receptors may play a role in the expression of a sensitised response after chronic nicotine treatment. Unfortunately, the role of 5-HT1A receptors in mediating nicotine seeking has not yet been investigated and would seem an important area for future research. There is also evidence for nicotinic–serotonergic interactions in the acquisition of the water maze, passive avoidance, and impulsivity in the five-choice serial reaction task.

Introduction

Most of the research on nicotine has focused on its effects on the dopaminergic system. However, because of the predominantly presynaptic localisation of the nicotinic receptors (nAChRs), nicotine induces the release of several other neurotransmitters, including acetylcholine (ACh), noradrenaline, serotonin [5-hydroxytryptamine (5-HT)], GABA, and glutamate Wonnacott, 1997, Wonnacott et al., 1989, Role and Berg, 1996, Vizi and Lendvai, 1999. There is no direct evidence for presynaptic nicotinic receptors located on serotonergic nerve terminals, but as reviewed in this article, there is considerable evidence that nicotine does affect serotonergic neurotransmission. There are also several behavioural effects of nicotine that seem to be mediated by effects on the serotonergic system.

Although it is not the detailed subject of this review, it should be remembered that there is a complex bidirectional interaction between the cholinergic and serotonergic systems and that nicotine can influence the release of both ACh and serotonin. Thus, for example, in the dorsal hippocampus, stimulation of presynaptic nicotinic autoreceptors stimulates ACh release, through a nicotinic receptor that does not contain an α7 subunit, whereas serotonergic stimulation of 5-HT1B heteroreceptors decreases ACh release (Vizi and Kiss, 1998). Likewise, stimulation of the 5-HT1B autoreceptors in the dorsal hippocampus decreases 5-HT release, whereas stimulation of nicotinic receptors increases 5-HT release Lendvai et al., 1996, File et al., 2000b, Kenny et al., 2000b. Thus, as the serotonergic tone in this brain region is increased, the cholinergic tone is decreased, and vice versa. ACh release in the cortex is also decreased by 5-HT, acting through 5-HT3 receptors in the cortex Maura et al., 1992, Giovannini et al., 1998. Likewise, ACh release in the striatum is inhibited by serotonin acting at 5-HT1A receptors (Rada et al., 1993). Thus, in several brain regions, there are likely to be mutually inhibitory effects between the cholinergic and serotonergic systems and any effects of nicotine will be the result of the balance of its effects on these two systems.

A number of different subtypes of nAChR exist, each with individual pharmacological and physiological profiles and distinct anatomical distribution in the brain. To date, nine individual subunits have been identified and cloned in the human brain. Studies have revealed that multiple subtypes of functional neuronal nAChRs can be formed from various combinations of nAChRs subunits, although evidence exists to suggest that nAChRs expressed in vivo may be functionally categorised into four groups Zoli et al., 1998, Alkondon and Albuquerque, 1993 and the predominant forms in the central nervous system (CNS) are the α4β2 and α4α5β2 subtypes. Deficits in α4β2 receptors have been associated with autism and schizophrenia and age-related neurodegenerative disorders have been predominantly associated with α4-containing receptors (Court et al., 2000).

Section snippets

Cortex

Systematically administered nicotine (0.2 mg/kg sc) and the (α4β2) nicotinic receptor agonist RJR-2403 significantly increased cortical 5-HT release in awake, behaving rats Summers and Giacobini, 1995, Summers et al., 1996, whereas a higher dose (1.2 mg/kg sc) and other nonselective agonists like 5-fluoronicotine, noranhydroecgonine, and pyridyl-methylpyrrolidine were without any effect Summers and Giacobini, 1995, Summers et al., 1995. Ribeiro et al. (1993) found that nicotine (1.6 mg/kg sc)

Dorsal raphé nucleus

The DRN has been identified as an important neuroanatomical substrate mediating nicotine's anxiolytic effect. Low doses of nicotine (2.5–10 ng) administered directly into the DRN induced an anxiolytic effect in the social interaction test of anxiety (Cheeta et al., 2001a). This is similar to the pattern previously observed when the specific 5-HT1A receptor agonist 8-OH-DPAT was administered to this region Higgins et al., 1988, Hogg et al., 1994, Picazo et al., 1995. The anxiolytic effects of

Locomotor stimulation

Acute doses of nicotine can cause small increases in locomotor activity, but the stimulant effects are much greater after a period of chronic administration when there is sensitisation to this response (e.g., Benwell and Balfour, 1992, Clarke et al., 1988). The stimulant effects are probably mediated by activation of postsynaptic dopamine receptors in the nucleus accumbens Benwell and Balfour, 1992, Clarke et al., 1988. Systemic administration of 8-OH-DPAT (0.5 mg/kg sc) potentiated the

Conclusions

There is good evidence that nicotine increases 5-HT release in several brain regions, although there is as yet little evidence that this is the result of a direct effect of nicotine on presynaptic heteroreceptors on 5-HT terminals. However, it is clear that the 5-HT tone plays a crucial permissive role in the expression of nicotine's effects and this can be seen at the level of 5-HT release and on nicotine's effects on cognition. This is important because it means that results from in vitro

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