Psychopharmacology (1993) 112:111-115 Psychopharmacology © Springer-Verlag 1993 Effect of 5--HT3 receptor antagonists on the discriminative stimulus properties of morphine in rats Narges Joharchi, Edward M. Sellers, and Guy A. Higgins Clinical PsychopharmacologyProgram, Addiction Research Foundation, 33 Russell Street, Toronto, and Departments of Pharmacology and Medicine, University of Toronto, Toronto, Ontario, Canada Received December 18, t 992 / Final version March 9, t 993 Abstract. 5-HT3 receptor antagonists, e.g. MDL72222, ondansetron and ICS205-930, have been previously re- ported to block a morphine (1.5 mg/kg)-induced con- ditioned place preference in rats. This finding suggests that these drugs may modify the morphine discriminative stimulus which underlies place conditioning. To study this further we have examined the effects of MDL72222, ondansetron and ICS205-930 against a morphine dis- criminative stimulus using a two-choice, food reinforced, operant paradigm. In an attempt to provide consistency with previous place conditioning studies, a morphine training dose of 1.5 mg/kg was used in addition to a higher 3 mg/kg dose which was studied in separate ani- mals. Stimulus control of behaviour was attained at both morphine training doses, the characteristics of each being consistent with an effect at the mu opioid receptor. On- dansetron (0.001-1 mg/kg), MDL72222 (0.1-3 mg/kg), and ICS205-930 (0.001-1 mg/kg) all failed to consistent- ly antagonise the morphine cue at both training doses, although a mild attenuation was seen in the 1.5 mg/kg group following pretreatment with an intermediate dose of ondansetron and ICS205-930 (both 0.01 mg/kg). The present results therefore suggest hat 5-HT3 antagonists do not block a morphine discriminative state, at least in rats. Key words: Morphine drug discrimination - Rat- 5-HT3 receptor antagonists - Opioid - Naloxone Morphine, in common with a variety of related opioids, possesses discriminative stimulus properties in rats (Shannon and Holtzman 1976a, t977a; Colpaert 1977; Young et al. 1992). Thus animals may be trained in a two-choice situation to make an appropriate response Correspondence to." G.A. Higgins, Glaxo Unit of Behavioural Psychopharmacology, University of Hertfordshire, College Lane, Hatfield, Herts ALl0 9AB, UK depending on whether they have been injected with mor- phine or saline vehicle prior to testing. Because it seems that there is a good correlation between the stimulus properties of a variety of opioid drugs in animals, includ- ing rats, and their subjective effects in humans (Shannon and Holtzman 1976a, 1977a; Colpaert 1977; Preston and Jasinski 1991), the drug discrimination paradigm has become a valuable model with which to study these agents. This type of research is important, as the subjec- tive effects of opiates are thought to significantly contrib- ute to their abuse liability (Jaffe 1990; Preston and Jasin- ski 1991). By the use of the drug discrimination procedure, at the preclinical stage, novel drugs may be tested for their ability to either substitute for (generalise to), or antagonise, an opioid (e.g. morphine) cue. Drugs which block this cue may have potential as treatments for opiate abuse, since there would be a possibility that these agents may modify an opioid discriminative state in humans. Recently 5-HT3 receptor antagonists (e.g. ondan- setron, ICS205-930, MDL72222) have been reported to prevent the development of a morphine conditioned place preference in rats (Carboni et al. 1989; Higgins et al. 1992). One interpretation of this finding is that 5-HT3 receptor blockade might modify the morphine discrimi- native stimulus such that it can no longer elicit a place preference. Therefore in the present study we have attempted to extend these findings by investigating the effects of 5-HT3 antagonists in an operant, food rein- forced, drug discrimination paradigm using morphine as the training drug. Because the dose of training drug can be a critical factor in quantitative and qualitative assess- ments of stimulus generalisation and, more important to the present study, antagonism (Shannon and Holtzman 1979; Stolerman et ai. 1987; Young et al. 1992), we utilised two training doses of morphine in separate squads of rats. A 3 mg/kg training dose was used, as this has been reliably shown to produce accurate and stable discriminative control (Shannon and Holtzman 1976a, 1977a). A lower training dose of 1.5 mg/kg was also used because this was the dose of morphine used to induce a