C Pharmacology & Toxicology 2001, 88, 59–66. Copyright C Printed in Denmark . All rights reserved ISSN 0901-9928 The Toxicity Profile of a Single Dose of Paroxetine: An Alternative Approach to Acute Toxicity Testing in the Rat Pauline M. Ryan 1,2 , John P. Kelly 1 , Philip L. Chambers 2 and Brian E. Leonard 1 1 Department of Pharmacology, National University of Ireland, Galway and 2 Department of Pharmacology and Therapeutics, University of Dublin, Trinity College, Ireland (Received July 7, 2000; Accepted September 13, 2000) Abstract: In this study we have examined the effect of a single administration of the selective serotonin reuptake inhibitor, paroxetine (120–300 mg kg ª1 , orally) in a recently developed rodent model of acute toxicity testing. Reduced body-weight, food consumption, water consumption and body temperature were observed in all paroxetine-treated groups, which were reversible within 7 days. Five days after administration, a dose-dependent increase in red blood cells, haemoglobin and haematocrit was observed with the 3 higher dose levels of paroxetine, which was significant in the 240 and 300 mg kg ª1 treatment groups (P0.05). Hyperactivity was apparent in the first 24 hr following treatment, as was evidence of the serotonin syndrome. When the animals were sacrificed (11 days after drug administration), an increase in liver weight was observed in the highest dose. These results are in agreement with those previously observed with paroxetine at the preclini- cal and clinical levels. They demonstrate that this rodent model, because of its multi-parameter nature, is a useful method for examining the consequences of a single high dose of an antidepressant drug. It has been acknowledged for the past 20 years that antide- pressant drugs are increasingly becoming one of the most frequently ingested substances during accidental poisoning or suicide attempts (Morgan et al. 1975; Hawton & Black- stock 1977; Starkey & Lawson 1980; Cassidy & Henry 1987; Henry 1992; Henry et al. 1995). It is expected that the intro- duction of safer antidepressants such as the selective sero- tonin reuptake inhibitors, such as paroxetine and atypical drugs, such as moclobemide and mianserin may alter pre- scribing habits (Buckley et al. 1993). However, despite the introduction of these alternatives, older tricyclic antide- pressants such as dothiepin and amitriptyline remain amongst the most widely prescribed antidepressants (Buckley et al. 1993). Thus, the full impact of these agents on mortality rate is yet to be realised. Paroxetine is an example of a selective serotonin reuptake inhibitor that was introduced in 1991. As a class of drugs the selective serotonin reuptake inhibitors are less toxic, in- duce fewer adverse effects and are safer in overdose when compared to the older tricyclic antidepressants such as ami- triptyline (Edwards et al. 1989; Rechlin et al. 1994). Phar- macologically, paroxetine is a potent and selective serotonin inhibitor of the neuronal reuptake of serotonin (5-HT) (Leonard 1992). There is experimental evidence to show that the selective serotonin reuptake inhibitors (SSRIs) fa- cilitate central serotonergic transmission by reducing the ac- tivity of somatodendritic inhibitory 5-HT 1A receptors and Author for correspondence: John P. Kelly, Neuropharmacology, National University of Ireland, Galway, Irland (fax π353 91 525300, e-mail jkell/iol.ie). enhancing the functional activity of postsynaptic 5-HT 2A receptors in limbic regions of the brain (Leonard 1992). An important issue in preclinical evaluation of drugs is their effects in overdose situations. This is probably most appropriate with antidepressants, many of which are the most commonly used agents in overdose (Morgan et al. 1975; Hawton & Blackstock 1977; Starkey & Lawson 1980; Cassidy & Henry 1987; Henry et al. 1995). In recent years the LD 50 test, the traditional method of assessing acute toxicity, has been criticized on both economic and ethical grounds (Zbinden & Flury-Roversi 1981; Bass et al. 1982; Tatersall 1982). Numerous alternatives to the LD 50 test have been devised with the objective of providing more de- tailed information on the nature of the toxicity as well as reducing the number of animals used. These have included the up-and-down procedure (Bruce 1985) and the fixed dose method (van den Heuval et al. 1987), which under OECD Guideline 420 has been adopted by many regulatory au- thorities. Another method for examining acute toxicity in a nonlethal dose range and involves the monitoring of a var- iety of physiological and behavioural parameters (Tambori- ni et al. 1990). In this study, we have assessed the acute toxicity profile of paroxetine using an adaptation of the model introduced by Tamborini et al. (1990). The model was adapted specifi- cally for the assessment of antidepressant drugs, by de- tecting and characterizing the toxic signs induced following large but non-lethal doses. In practice, the range of toxic effects of a new drug is not known. For this reason, general indices of body-weight gain, food and water intake and body temperature are carefully observed and recorded.