5-(4-piperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine fumarate (JL13) displays clozapine-like activity in several behavioral models predictive of antipsychotic activity or neurological side effects (Ellenbroek & Liégeois, CNS Drug Rev 2003, 9:41–57), in spite of its weak antagonistic activity at dopamine (DA) D₂ receptors as determined by in vitro binding (Liégeois et al, J Med Chem 1994, 37:519-25) or electrophysiological studies (Seutin et al, Int J Neuropsychopharmacol 2000, 3:S128). In the current study we evaluated the long-term effects of JL13 on different DA receptors in rat forebrain regions and compared findings to rats treated with clozapine previously. Two groups (N = 7) of rats received control vehicle or JL13 (10.0 mg/kg/d) by osmotic minipumps implanted subcutaneously for 4 weeks. At the end of treatment, animals were sacrificed and their brains were processed for in vitro DA receptor autoradiography. Similar to clozapine, JL13 infusion increased labeling of D₂ receptors in medial prefrontal cortex (32%) and hippocampus (19%), and D₄ receptors in nucleus accumbens (by 61%), caudate-putamen (46%) and hippocampus (57%), while sparing D₂ receptors in basal ganglia. In addition, JL13 but not clozapine, increased D₁ binding in nucleus accumbens (26%) and caudate-putamen (23%). D₃ receptors remained unchanged after repeated treatment with clozapine and JL13. Clozapine-like effects of JL13 on DA receptor subtypes further support the development of this compound as a novel atypical antipsychotic agent.

Acknowledgment: 

Supported by MH-068359 and NARSAD (FIT). J.-F.L. is Senior Research Associate of the "Fonds National pour la Recherche Scientifique (F.N.R.S.)" of Belgium. A.G. is Research Fellow of the « Fonds pour la formation à la Recherche Industrielle et Agricole (F.R.I.A.) >>.