Vol. 287, Issue 3, 839-846, December 1998

Effects of 5-Hydroxytryptamine₂ Receptor Antagonism on the Behavioral Activation and Immediate Early Gene Expression Induced by Dizocilpine

Michael F. O'Neill, Caroline A. Hicks, Gillian Shaw, Tirumaran Parameswaran, Geraldine P. Cardwell and Michael J. O'Neill

Eli Lilly and Company Ltd., Windlesham, Surrey, UK

The noncompetitive N-methyl-D-aspartate (NMDA) antagonists dizocilpine and phencyclidine cause behavioral changes in animals that can be blocked by antipsychotic agents, implicating NMDA receptors in the expression of schizophrenic symptoms. In the present study, we examined the effects of dizocilpine (0.1-3.0 mg/kg s.c.) on locomotor activity and on the expression of c-fos and hsp-70 immediate-early genes (IEGs) in mice. Results indicate that dizocilpine increases locomotor activity and selectively increases the expression of c-fos and hsp-70 in the posterior cingulate cortex. Haloperidol (0.01-0.1 mg/kg) and clozapine (0.6-1.25 mg/kg) block both the locomotor response and the increased IEG immunoreactivity induced by dizocilpine (0.6 mg/kg). The 5-HT₂ antagonists ritanserin (0.06-0.25 mg/kg), ketanserin (0.03-0.12 mg/kg) and amesergide (0.3-1.25 mg/kg) also significantly attenuated the locomotor response to dizocilpine. Haloperidol and clozapine suppressed the head weaving induced by dizocilpine, but ritanserin, as previously reported did not. Although some attenuation of the c-fos and hsp-70 immunoreactivity was seen with the 5-HT₂ antagonists it was less pronounced than that induced by haloperidol or clozapine. In conclusion, 5-HT₂ antagonists as well as antipsychotic compounds attenuate the locomotor response to dizocilpine in mice. Haloperidol and clozapine appear to be more effective, however, in attenuating the expression of c-fos and hsp-70 in the posterior cingulate gyrus than 5-HT₂ antagonists ritanserin, ketanserin or amesergide. We thus have seen a dissociation in the capacity of compounds to alter the effects on behavior and IEG expression after dizocilpine administration.