Stimulation of nicotinic receptors in the lateral septal nucleus increases anxiety Abdel-Mouttalib Ouagazzal,* Paul J. Kenny and Sandra E. File Psychopharmacology Research Unit, Neuroscience Research Centre, GKT School of Biomedical Science, King's College London, Hodgkin Building, Guy's Campus, London SE1 9RT, UK Keywords: anxiety, lateral septum, nicotinic receptors, rat Abstract The present study investigated the role of nicotinic receptors in the lateral septum in the modulation of anxiety. The effects of direct injections of nicotine into the lateral septum were ®rst investigated in two tests of anxiety, social interaction and elevated plus-maze tests.Intra-septalinjectionofnicotine(1and4 mg)inducedconsistentanxiogeniceffectsinbothtests.Thereversalofnicotiniceffects with mecamylamine was then studied in the social interaction test. Intra-septal injection of mecamylamine at a low dose (15ng) induced an anxiolytic effect, suggesting the presence of intrinsic cholinergic tone increasing anxiety. At higher doses (30±50ng), mecamylamine was without effect in the social interaction test, but blocked the anxiogenic effects of nicotine (4 mg). These ®ndings provide further evidence for the role of the lateral septum in the modulation of anxiety and suggest that cholinergic projections to this brain area facilitate anxiety through nicotinic receptors. Introduction Over the past few years there has been considerable interest in the role of acetylcholine in emotional behaviour. Early research in this topic has suggested that dysfunction of cholinergic transmission is involved in the pathophysiology of depression (Dilsaver, 1986; Overstreet etal., 1989). In line with this view, subsequent animal and human studies have shown that the cholinergic agonist, nicotine, can act as an antidepressant (Salõ Ân-Pascual etal., 1996; Salõ Ân-Pascual & Drucker-Colõ Ân, 1998; Semba etal., 1998; Tizabi etal., 1999). Supporting evidence for the role of cholinergic systems in anxiety has also been provided by numerous studies. For instance, systemic administration of nicotine was shown to produce anxiolytic effects in several experimental models of anxiety, including the black±white box (Costall etal., 1989), mirrored chamber (Cao etal., 1993) and fear-potentiated startle tests (Vale & Green, 1996). In the social interaction and elevated plus-maze tests, both anxiolytic and anxiogenic effects of nicotine have been reported (Brioni etal., 1994 File etal., 1998a; Ouagazzal etal., 1999). The role of muscarinic receptors in anxiety has also been demonstrated by studies showing that systemic administration of scopolamine produces anxiogenic effects in the black±white box and the elevated plus-maze tests (Falter etal., 1991; Rodgers & Cole, 1995; Smythe etal., 1996). Although there is strong evidence for the role of central cholinergic systems in the modulation of anxiety, there have been few attempts to explore the neuronal substrates underlying such modulation. Studies conducted to date have suggested an involvement of cholinergic systems in the amygdala and hippocampus in the modulation of fear- and anxiety-related behaviours (Hess & Blozovski, 1987; Ohta etal., 1991; Smythe etal., 1998; File etal., 1998a,b). In the dorsal hippocampus, we have found that acetylcholine has a dual in¯uence on anxiety as measured in the social interaction and the elevated plus- maze tests. When rats are tested under low light in a familiar arena (LF), which is the least anxiety-provoking test condition, the blockade of nicotinic receptors with mecamylamine induced anxiogenic effects while nicotine had no effects suggesting that endogenous acetylcholine reduces anxiety in the dorsal hippocampus. On the other hand, when rats are tested under high light in a familiar test arena (HF), a moderately anxiogenic condition, mecamylamine was silent, but nicotine induced anxiogenic effects (File etal., 1998a). In the elevated plus-maze test, the behavioural pro®le of mecamy- lamine and nicotine seems to depend on the previous experience of the animals with the maze. In rats naive to the plus-maze, both compounds were without any effects. In contrast, in rats with a previous experience of the plus-maze, mecamylamine had anxiogenic effects while nicotine induced anxiolytic effects (File etal., 1998b; Ouagazzal etal., 1999). On the whole, these experiments show that cholinergic modulation of anxiety is complex and may vary depending on the state and/or type of anxiety. As part of a project aimed at evaluating the role of central cholinergic systems in anxiety, the present study investigated the effects of pharmacological challenges to nicotinic receptors into the lateral septum in two animal tests of anxiety, the elevated plus-maze and social interaction tests. Substantial evidence suggests that the lateral septum is a possible site of anxiety modulation. The lateral septum shares its anatomical connections with a wide range of brain structures (e.g. hippocampus, amygdala, periaqueductal grey and hypothalamus) that are known to play a central role in fear and anxiety (Risold & Swanson, 1997). More importantly, a lesion of the lateral septum was found to affect fear and anxiety responses in several anxiety tests (Yadin etal., 1993; Menard & Treit, 1996). Correspondence: Dr A.-M. Ouagazzal, F. Hoffmann-La Roche, Pharma- ceuticals Division, Preclinical Studies, PRPN, CH-4070 Basel, Switzerland. E-mail: abdel-mouttalib.ouagazzal@roche.com *Present address: F. Hoffmann-La Roche, Pharmaceuticals Division, Preclinical Studies, PRPN, CH-4070 Basel, Switzerland. Received 1 April 1999, revised 25 June 1999, accepted 13 July 1999 European Journal of Neuroscience, Vol. 11, pp. 3957±3962, 1999 ã European Neuroscience Association