Original article 257 Effects of fluoxetine on hippocampal rhythmic slow activity and behavioural inhibition Robert G.K. Munn and Neil McNaughton Anxiolytics that act as GABA A agonists and those that act as 5-HT 1A receptor agonists all reduce the frequency of hippocampal rhythmic slow activity (RSA). Changes in RSA have been linked to changes in behavioural inhibition and therefore anxiety – but this has not been tested with specific serotonin reuptake inhibitors, which are antidepressant and anxiolytic; therefore we tested the effects of fluoxetine on RSA and behavioural inhibition. Fluoxetine (FLU; 10 and 20 mg/kg, intraperitoneally) produced a dose-related reduction in the frequency of reticular-elicited RSA. Groups of rats received, intraperitoneally, either (i) saline, or 5 mg/kg fluoxetine, or 10 mg/kg fluoxetine; or (ii) saline, or 20 mg/kg fluoxetine, or 6.6 mg/kg of the 5-HT 1A agonist buspirone (BUS) and were tested on a fixed interval 60-s schedule and a differential reinforcement of low rates 15-s schedule. FLU at 5 mg/kg produced effects similar to low doses of BUS and other anxiolytics. FLU (10 and 20 mg/kg) produced effects more like those reported earlier for higher doses of BUS. These results continue to link anxiolysis, RSA and behavioural inhibition, and suggest that serotonergic anxiolytics share some of the central actions of GABAergic anxiolytics, but at higher doses, administered acutely, have distinct side effects that can obscure their anxiolytic action in behavioural tasks. Behavioural Pharmacology 19:257–264  c 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins. Behavioural Pharmacology 2008, 19:257–264 Keywords: anxiety, behavioural inhibition, differential reinforcement of low rates, fixed interval, fluoxetine, hippocampus, rat, rhythmic slow activity, theta Department of Psychology, University of Otago, Dunedin, New Zealand Correspondence to Professor Neil McNaughton, Department of Psychology, University of Otago, PO Box 56, Dunedin, New Zealand E-mail: nmcn@psy.otago.ac.nz Received 7 September 2007 Accepted as revised 19 January 2008 Introduction ‘Classical’ anxiolytics (barbiturates, benzodiazepines, meprobamate, etc.) act as positive allosteric modulators and direct agonists at the GABA A -receptor (Korpi et al., 2002). By contrast, novel anxiolytics such as buspirone (BUS) act as agonists at 5-HT 1A receptors (Glaser and Traber, 1983; Peroutka, 1985; Eison and Temple, 1986; Gobert et al., 1999). Novel anxiolytics have little interaction with GABA (Eison and Temple, 1986), and therefore do not share the muscle-relaxant, sedative, addictive and anti-convulsant effects of classical anxioly- tics, demonstrating their pharmacological independence (Balster and Woolverton, 1982; Riblet et al., 1982). The clearest similarity between novel and classical anxiolytics, aside from their capacity to reduce anxiety in the clinic, is that all of those tested thus far reduce the frequency of reticular-elicited hippocampal RSA in a simple dose-dependent manner (McNaughton et al., 1986; McNaughton and Coop, 1991; for review see McNaughton et al., 2007). This action is independent of the pharmacological mechanism by which RSA alteration is achieved; and therefore it has been suggested that changes in hippocampal RSA are critical for some aspects of central anxiolytic action (Gray, 1982; Gray and McNaughton, 2000). Both lesion of the hippocampus (Jarrard and Becker, 1977; Sinden et al., 1986) and anxiolytic drugs (Richelle et al., 1962; Panickar and McNaughton, 1991) produce deficits involving a loss of behavioural inhibition in nonspatial operant tasks (Gray, 1982). It has therefore been hypothesized that loss of behavioural inhibition is the critical functional effect of reduced RSA in the hippocampus (Gray and McNaughton, 2000). Fluoxetine (FLU) (and its primary metabolite norflu- oxetine), are selective serotonin reuptake inhibitors (SSRIs) that exert their primary pharmacological effect by the blockade of the 5-HT reuptake transporter (Malagie´ et al., 1995; Herva ´s and Artigas, 1998). FLU is therefore pharmacologically similar to BUS, in that it can act as an agonist at 5-HT 1A receptors, albeit in a less direct and less receptor-subtype-specific manner. For instance, fluoxetine has been shown to have separate agonistic effects at 5-HT 2C receptors (Pa ¨lvima ¨ki et al., 1999). Like BUS, FLU is not only an antidepressant but also has a quite separate anxiolytic action (Davidson, 2001; Ball et al., 2005). To further challenge the link between clinical anxiolytic efficacy and hippocampal RSA, we recorded reticular stimulated hippocampal RSA over a 225-min period using two doses of fluoxetine and vehicle control. We predicted that, if hippocampal RSA is a reliable marker of anxiolytic efficacy, fluoxetine should decrease the frequency of reticular-elicited hippocampal RSA in a dose-dependent manner. 0955-8810  c 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.