l-745870 and Psychotic-Disorders

Chronic methamphetamine (METH) treatment induces behavioral sensitization in rodents. During this process, hyperactivation of the mesolimbic dopamine system plays a central role, and dopamine D2-like receptor-based antipsychotics are known to alleviate the behavioral hyperactivity. The atypical antipsychotic, clozapine (Clz), acts partially as a dopamine D4 receptor (D4R) antagonist and mitigates hyperdopaminergic drug addiction and/or comorbid psychotic symptoms; however, it remains unclear whether D4R blockade contributes to the therapeutic effects of Clz. Here, we evaluated the potential role of D4R in regulating hyperdopaminergia-induced behavioral hyperactivity in METH behavioral sensitization and dopamine transporter (DAT) knockdown (KD) mice. Clz or a D4R-selective antagonist, L-745,870, were co-administered to mice with daily METH in a METH sensitization model, and Clz or L-745,870 were administered alone in a DAT KD hyperactivity model. Locomotor activity and accumbal D4R expression were analyzed. Clz suppressed both the initiation and expression of METH behavioral sensitization, as well as DAT KD hyperactivity. However, repetitive Clz treatment induced tolerance to the suppression effect on METH sensitization initiation. In contrast, D4R inhibition by L-745,870 had no effect on METH sensitization or DAT KD hyperactivity. Accumbal D4R expression was similar between METH-sensitized mice with and without Clz co-treatment. In sum, our results suggest the mesolimbic D4R does not participate in behavioral sensitization encoded by hyperdopaminergia, a finding which likely extends to the therapeutic effects of Clz. Therefore, molecular targets other than D4R should be prioritized in the development of future therapeutics for treatment of hyperdopaminergia-dependent neuropsychiatric disorders.

Topics: Amphetamine-Related Disorders; Animals; Antipsychotic Agents; Behavior, Animal; Central Nervous System Sensitization; Clozapine; Disease Models, Animal; Dopamine Agents; Locomotion; Methamphetamine; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Knockout; Mice, Transgenic; Psychotic Disorders; Pyridines; Pyrroles; Receptors, Dopamine D4

The effects of three selective D(4) antagonists [CP-293,019, L-745, 870, and Ro 61-6270] and two putative selective D(4) agonists [CP-226,269 and PD 168077] were compared with those of the generic D(2)-like [D(2L/S),D(3), D(4)] antagonist haloperidol to identify any characteristic "ethogram," in terms of individual topographies of behavior within the natural rodent repertoire, as evaluated using ethologically based approaches. Among the D(4) antagonists, neither L-745,870 (0.0016-1.0 mg/kg) nor Ro 61-6270 (0.2-25.0 mg/kg) influenced any behavior; whereas, CP-293,019 (0.2-25.0 mg/kg) induced episodes of nonstereotyped sniffing, sifting, and vacuous chewing; there were no consistent effects on responsivity to the D(2)-like agonist RU 24213. Among the putative D(4) agonists, CP-226, 269 (0.2-25.0 mg/kg) failed to influence any behavior; whereas, PD 168077 (0.2-25.0 mg/kg) induced nonstereotyped shuffling locomotion with uncoordinated movements, jerking, and yawning, which were insensitive to antagonism by CP-293,019, L-745,870, or haloperidol. These findings fail to indicate any "ethogram" for selective manipulation of D(4) receptor function at the level of the interaction between motoric and psychological processes in sculpting behavioral topography over habituation of exploration through to quiescence and focus attention on social, cognitive, or other levels of examination.

Topics: Animals; Behavior, Animal; Brain; Brain Mapping; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Habituation, Psychophysiologic; Male; Psychotic Disorders; Pyrazines; Pyridines; Pyrimidines; Pyrroles; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, Dopamine D4

Previous studies have shown D2-like dopamine receptor involvement in the regulation of phospholipid methylation (PLM), while others have documented impaired methionine and folate metabolism in schizophrenia. Utilizing [14C]formate labeling in cultured neuroblastoma cell lines, we now show that D4 dopamine receptors (D4R) mediate the stimulatory effect of dopamine (DA) on PLM. The effect of DA was potently blocked by highly D4R-selective antagonists and stimulated by the D4R-selective agonist CP-226269. DA-stimulated PLM was dependent upon the activity of methionine cycle enzymes, but DA failed to increase PLM in [3H]methionine labeling studies, indicating that a methionine residue in the D4R might be involved in mediating PLM. A direct role for MET313, located on transmembrane helix No. 6 immediately adjacent to phospholipid headgroups, was further suggested from adenosylation, site-directed mutagenesis and GTP-binding results. A comparison of PLM in lymphocytes from schizophrenia patients vs control samples showed a four-fold lower activity in the schizophrenia group. These findings reveal a novel mechanism by which the D4R can regulate membrane composition. Abnormalities in D4R-mediated PLM may be important in psychiatric illnesses such as schizophrenia.

Topics: Amino Acid Sequence; Aminopyridines; Animals; Benzazepines; Binding Sites; Carbon Radioisotopes; CHO Cells; Clozapine; Cricetinae; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Formates; Guanosine 5'-O-(3-Thiotriphosphate); Humans; Methionine; Mutagenesis, Site-Directed; Neuroblastoma; Phospholipids; Phosphorylation; Piperidines; Psychotic Disorders; Pyridines; Pyrroles; Raclopride; Receptors, Dopamine D2; Receptors, Dopamine D4; Recombinant Proteins; S-Adenosylmethionine; Salicylamides; Schizophrenia; Transfection; Tumor Cells, Cultured