Effects of YM-43611, a Novel Dopamine D2-Like Receptor Antagonist, on Immediate Early Gene Expression in the Rat Forebrain

Abstract

The pharmacological characteristics of two benzamides, YM-43611, a potent and selective dopamine D 3 and D 4 antagonist, and YM-09151-2 (nemonapride), were compared with two reference antipsychotic agents, haloperidol and clozapine, in terms of modification of c-fos and related gene expression in the rat forebrain. After subcutaneous injection of YM-43611 (1 or 5 mg/kg), nemonapride (4 mg/kg), haloperidol (1 mg/kg), or clozapine (25 mg/kg), Fos immunocytochemistry was employed, and the distributions of Fos-like immunoreactive neurons were compared. As was the case for the two reference antipsychotics, the two benzamides enhanced c-Fos immunoreactivity in a number of forebrain regions. Specifically, like clozapine and nemonapride, YM-43611 significantly increased the number of immunoreactive cells in the nucleus accumbens shell and islands of Calleja. In contrast to clozapine and nemonapride, YM-43611 did not increase c-fos expression in the medial prefrontal cortex. Haloperidol and nemonapride elevated the number of positive cells in the striatum and nucleus accumbens core, whereas clozapine and YM-43611 did not. Clozapine increased the number of Fos-like immunoreactive cells in the lateral septal nucleus and the diagonal band nucleusThe mechanism by which neuroleptics induce therapeutic effects remains elusive. Early receptor binding studies demonstrated a strong correlation between clinical potency and antagonism of the classical dopamine D 2 receptor (Creese et al. 1976;Seeman et al. 1976). Although recent pharmacological successes have implicated the potential role of several of the newly discovered dopamine receptors (D 3 , D 4 , D 5 ), nondopamine receptors, including serotonergic, adrenergic, and cholinergic receptors, are believed to subserve a specialized function in both the therapeutic action and side effect profiles of antipsychotic drugs (Deutch et al. 1991).Immediate early genes (IEGs), such as c-fos , can be activated by a variety of physiological and pharmacological stimuli and mediate the synthesis of phosphoprotein Fos Herschman 1989 Presented at the 35th annual meeting of A.C.N.P., San Juan, December 1996.Received July 29, 1996; revised December 17, 1996; accepted December 18, 1996. 28 K. Kurokawa et al. N EUROPSYCHOPHARMACOLOGY 1997 -VOL . 17 , NO . 1 that haloperidol, a typical neuroleptic, and clozapine, an atypical antipsychotic, significantly increase neuronal c-fos and related gene expression in a number of forebrain regions (Dragunow et al. 1990;Deutch et al. 1992;Nguyen et al. 1992; Robertson and Fibiger 1992;MacGibbon et al. 1994;Fink-Jensen et al. 1995;Wan et al. 1995). These studies have indicated that typical and atypical antipsychotic drugs exert regionally distinct effects on neuronal IEG expression in the striatum, lateral septum, and islands of Calleja, although they exhibit quite similar actions on c-fos expression in the nucleus accumbens shell.In addition to remoxipride, two benzamide derivatives have been introduced as selective antagonists for the dopamine D 2 -l...

Examining dopamine D3 receptor occupancy by antipsychotic drugs via [3H]7-OH-DPAT ex vivo autoradiography and its cross-validation via c-fos immunohistochemistry in the rat brain

“…3a), whereas haloperidol (0.04 mg/kg) and L-741626 (2.5 mg/kg) both failed to cause significant changes in Fos-LI. Previous reports examining the effects of haloperidol concur with our findings (Hurley et al, 1996;Kovacs et al, 2001;Kurokawa et al, 1997); however one study using a higher dose found a small but significant increase after haloperidol treatment (Vahid-Ansari and Robertson, 1996). The robust increase in ICjM Fos-LI observed after treatment with SB-277011-A (Fig.…”

Clozapine- and Olanzapine-induced Fos Expression in the Rat Medial Prefrontal Cortex is Mediated by β-Adrenoceptors

“…The mechanisms underlying this action, although investigated intensively, remain to be established. Recent studies involving the Fos protein have demonstrated that clozapine induces a much larger increase in the number of neurons that exhibit Fos-like immunoreactivity (LI) in the medial prefrontal cortex (mPFC) than do typical neuroleptics (Deutch and Duman 1996; Fink-Jensen and Kristensen 1994; Fink-Jensen et al 1995;Guo et al 1995;Kurokawa et al 1997;Robertson and Fibiger 1992;Robertson et al 1994;Wan et al 1995). This regionally specific clozapine effect sets it apart from typical neuroleptics.…”