Perospirone, a Novel Antipsychotic Agent, Hyperpolarizes Rat Dorsal Raphe Neurons via 5-HT1A Receptor

Abstract

Abstract. To investigate the effect of cis-N-[4-[4-(1,2-benz-isozole-3-yl)-1-piperazinyl]butyl] cyclohexane-1,2-dicarboximide hydrochloride (perospirone), a novel antipsychotic agent with high affinities for D 2 / 5-HT 2 receptors, on the rat dorsal raphe (DR) neurons, an electrophysiological study was performed using the tight-seal whole-cell patch-clamp technique. Applications of perospirone at the concentration between 10 -9 and 10 -5 M hyperpolarized the membrane potential and inhibited spontaneous action potentials of the DR neurons in a concentrationdependent manner. This effect of perospirone on DR neurons is similar to that of typical 5HT 1A -receptor agonists, including 8-OH-DPAT or tandospirone. In addition, WAY100635, a 5-HT 1A -receptor antagonist, inhibited this perospirone-induced hyperpolarization of DR neurons, suggesting that perospirone physiologically acts on DR neurons as a 5HT 1A -receptor agonist. These results provide new profiles of perospirone as an antipsychotic drug.

Role of 5-HT1A receptors in the modulation of stress-induced lactate metabolism in the medial prefrontal cortex and basolateral amygdala

“…Perospirone exhibits a relatively high affinity for 5-HT 1A receptor (Ki=2.9 nM) in its binding character and is a 5-HT 1A partial agonist Kato et al 1990). In addition, perospirone physiologically acts on rat dorsal raphe neurons as a 5-HT 1A -receptor agonist (Shiwa et al 2003). A recent study showed that systemic or local administration of atypical antipsychotic drugs, e.g., clozapine and ziprasidone, enhanced dopamine release in the mPFC of wild-type but not 5-HT 1A knockout mice (DiazMataix et al 2005).…”

A pharmaco-EEG study on antipsychotic drugs in healthy volunteers

“…One of the following substances was applied orally in each session: chlorpromazine (50 mg), haloperidol (1 mg), olanzapine (1.25 mg), perospirone (4 mg; Kato et al 1990;de Paulis 2002;Shiwa et al 2003), quetiapine (33 mg), risperidone (0.5 mg), and placebo. Chlorpromazine and haloperidol are typical antipsychotics, and olanzapine, perospirone, quetiapine, and risperidone are atypicals (Stahl 2000).…”

“…Perospirone has been approved only in Japan. Its primary mode of action is through an antagonism of 5-HT 2A receptors and D 2 receptors; besides, it acts as an agonist of 5-HT 1A receptors (Kato et al 1990;de Paulis 2002;Shiwa et al 2003). Dosage was equivalent to of 1 mg haloperidol, which, according to previous pharmaco-EEG studies of our laboratory, was enough to have an effect on the brain electrical activity while assuring subject's safety (Saito et al 1983(Saito et al , 1993(Saito et al , 1998.…”

Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties

“…In addition to clozapine, other antipsychotics, such as ziprasidone and nemonapride, exhibit partial agonist properties at 5-HT 1A receptors (Assié et al 1997;NewmanTancredi et al 2005), as do the more recent antipsychotics, aripiprazole, and perospirone (Hagiwara et al 2008;Shiwa et al 2003;Stark et al 2007). Other compounds have undergone extensive clinical trials, including bifeprunox (phase III trials completed, Food and Drug Administration (FDA) nonapprovable; Jordan et al 2002Jordan et al , 2004Van Vliet et al 2000a, b), lurasidone (phase III trials completed, FDA approved; Ishibashi et al 2010) and cariprazine (phase II Grunder 2010;Kiss et al 2010).…”