Interactions of the Novel Antipsychotic Aripiprazole (OPC-14597) with Dopamine and Serotonin Receptor Subtypes

Abstract

cells; C-6 cells; SchizophreniaSchizophrenia is a chronic psychiatric illness with two major types of symptoms-positive or psychotic symptoms, such as hallucinations and delusions, and negative or deficit symptoms, such as amotivation, apathy, and asociality. Approximately 1% of the population suffers from schizophrenia (Kaplan and Sadock 1988). The serendipitous discovery of chlorpromazine four decades ago not only provided the first efficacious therapeutic intervention, but also opened horizons into research about the etiology and therapy of this disease. It was soon hypothesized that chlorpromazine and similar drugs worked by being pharmacological antagonists of the neurotransmitter dopamine (Seeman et al. 1976;Creese et al. 1976), a hypothesis that ultimately provided the foundation for the commonly accepted division of dopamine receptors into two classes (Garau et al. 1978), now often called D 1 and D 2 (Kebabian and Calne 1979).During the past decade, molecular cloning studies have resulted in the identification of several genes coding for dopamine receptors. There now are at least two From the Departments of Pharmacology (CP, RBM) and Psychiatry (CPL, RBM), and Medicinal Chemistry (RBM), Curricula in Toxicology (CPL, RBM), and Neurobiology (MML, RBM), UNC Neuroscience Center (CPL, CP, MML, RBM), University of North Carolina School of Medicine, Chapel Hill, North Carolina; and Molecular Neuropharmacology Section (CM, DJ, JAS, AMG, DRS), National Institutes of Neurological Disorders and Stroke, Bethesda, Maryland.Address correspondence to: Dr. Cindy Lawler, CB #7250; UNC Neuroscience Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599-7250. Received April 17, 1998; revised August 27, 1998; accepted September 21, 1998. (Zhou et al. 1990;Monsma et al. 1990;Sunahara et al. 1990;Dearry et al. 1990) and D 1B (Tiberi et al. 1991) or D 5 (Sunahara et al. 1991], both of these linked functionally to stimulation of cAMP synthesis, and preferentially recognizing 1-phenyl-tetrahydrobenzazepines (e.g., SCH23390). The D 2 -like receptors come from at least three genes and include multiple splice variants. The D 2 -like receptors [D 2S (Bunzow et al. 1988), D 2L (Giros et al. 1989;Monsma et al. 1989), D 3 (Sokoloff et al. 1990, and D 4 ] sometimes are linked to inhibition of cAMP synthesis and have a different pharmacological specificity from the D 1 -like receptors (i.e., having much higher affinity for spiperone or sulpiride).The traditional view of antipsychotic drug efficacy posits a primary role for pharmacological antagonism of D 2 -like receptors. Despite the demonstrable effectiveness of dopamine D 2 receptor antagonists, however, a substantial number (up to 20%) of patients are considered unresponsive to these typical antipsychotics (Kane et al. 1988). Furthermore, the typical antipsychotics have significant and serious side effects that make them less than optimal therapeutic agents (see Peacock and Gerlach 1996). For example, they cause acute drug-induced parkinsonian symptoms (...

Aripiprazole, A Novel Atypical Antipsychotic Drug with a Unique and Robust Pharmacology

“…Thus, when rat D 2 -receptors were expressed in HEK293 cells using an assay buffer containing NaCl (50 mM Tris-HCl, pH ¼ 7.4, 50 mM NaCl, 5 mM MgCl 2 , 0.5 mM EDTA) affinities were 6.8-fold lower than that reported in rat striatal membranes, but a striking 62-fold lower than those values obtained using stably transfected CHO cells assayed in a Na-free buffer (Lawler et al, 1999). The large effect of sodium ions on the measured affinity of aripiprazole is likely due to the fact that sodium ions decrease agonist affinities for D 2 -family receptors (Neve, 1991;Neve et al, 1991Neve et al, , 2001.…”

“…Some prior studies have suggested that aripiprazole is a partial agonist at D 2 receptors (Burris et al, 2002), while others have proposed that the drug is 'functionally selective' at D 2 receptors (Lawler et al, 1999). The present experiments thus tested aripiprazole in several different systems, including many not previously studied.…”

“…Inhibition of forskolin-stimulated 3 0 ,5 0 -cyclic adenosine monophosphate (cAMP) production in stable D4 and 5-HT 1A receptor expressing cell lines was measured as previously reported (Lawler et al, 1999;Zhang et al, 1994). In brief, cells were grown in 24-well plates and growth media were replaced with fresh F12 medium containing 100 mM IBMX and 100 mM forskolin (all on ice) just prior to experimentation.…”

“…There has been a long-standing hypothesis that D 2 partial agonists would be of particular utility in schizophrenia (Tamminga, 2002), and the developers of aripiprazole have proposed that the novel and improved clinical profile of aripiprazole is caused by the partial agonist properties at D 2 -dopamine receptors that result in 'dopamine stabilization' (Burris et al, 2002;Inoue et al, 1996). Conversely, it has been suggested (Lawler et al, 1999) that aripiprazole is not simply a partial agonist, but a drug whose D 2 functional effects were dependent on the cellular location (and signaling proteins) of the targeted D 2 receptor, a phenomenon termed 'functional selectivity' Lawler et al, 1999;Mottola et al, 2002) or 'agonist trafficking' (Kenakin, 1995). Whatever the mechanism, aripiprazole has been shown to be effective in treating the positive and negative symptoms of schizophrenia with a low incidence of side effects including minimal short-term weight gain, low liability for inducing movement disorders, and reductions (rather than elevations) in plasma prolactin levels (Goodnick and Jerry, 2002;Kane et al, 2002).…”

“…Aripiprazole has high affinity for D 2 -and D 3 -dopamine and 5-HT 7 serotonin receptors (Lawler et al, 1999). There has been a long-standing hypothesis that D 2 partial agonists would be of particular utility in schizophrenia (Tamminga, 2002), and the developers of aripiprazole have proposed that the novel and improved clinical profile of aripiprazole is caused by the partial agonist properties at D 2 -dopamine receptors that result in 'dopamine stabilization' (Burris et al, 2002;Inoue et al, 1996).…”