Effects of 5-hydroxytryptamine2 receptor antagonism on the behavioral activation and immediate early gene expression induced by dizocilpine.
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.
O'Neill
M F
MF
Eli Lilly and Company Ltd., Windlesham,Surrey, UK. oneill_michael_f@lilly.com
Hicks
C A
CA
Shaw
G
G
Parameswaran
T
T
Cardwell
G P
GP
O'Neill
M J
MJ
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D003024:Clozapine / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D006179:Gyrus Cinguli / Q000187:drug effects* / Q000378:metabolism; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis; D006220:Haloperidol / Q000494:pharmacology; D017874:Immediate-Early Proteins / Q000096:biosynthesis* / Q000235:genetics; D007150:Immunohistochemistry; D007650:Ketanserin / Q000494:pharmacology; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D016713:Ritanserin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*
D014150:Antipsychotic Agents; D018691:Excitatory Amino Acid Antagonists; D018840:HSP70 Heat-Shock Proteins; D017874:Immediate-Early Proteins; D016760:Proto-Oncogene Proteins c-fos; D012702:Serotonin Antagonists; D016713:Ritanserin; D016291:Dizocilpine Maleate; D007650:Ketanserin; D003024:Clozapine; D006220:Haloperidol