raclopride and Psychomotor-Agitation

Blockade of dopamine D2 receptors remains a common feature of all antipsychotics. It has been hypothesized that the extrastriatal (cortical, thalamic) dopamine D2 receptors may be more critical to antipsychotic response than the striatal dopamine D2 receptors. This is the first double-blind controlled study to examine the relationship between striatal and extrastriatal D2 occupancy and clinical effects. Fourteen patients with recent onset psychosis were assigned to low or high doses of risperidone (1 mg vs 4 mg/day) or olanzapine (2.5 mg vs 15 mg/day) in order to achieve a broad range of D2 occupancy levels across subjects. Clinical response, side effects, striatal ([11C]-raclopride-positron emission tomography (PET)), and extrastriatal ([11C]-FLB 457-PET) D2 receptors were evaluated after treatment. The measured D2 occupancies ranged from 50 to 92% in striatal and 4 to 95% in the different extrastriatal (frontal, temporal, thalamic) regions. Striatal and extrastriatal occupancies were correlated with dose, drug plasma levels, and with each other. Striatal D2 occupancy predicted response in positive psychotic symptoms (r=0.62, p=0.01), but not for negative symptoms (r=0.2, p=0.5). Extrastriatal D2 occupancy did not predict response in positive or negative symptoms. The two subjects who experienced motor side effects had the highest striatal occupancies in the cohort. Striatal D2 blockade predicted antipsychotic response better than frontal, temporal, and thalamic occupancy. These results, when combined with the preclinical data implicating the mesolimbic striatum in antipsychotic response, suggest that dopamine D2 blockade within specific regions of the striatum may be most critical for ameliorating psychosis in schizophrenia.

Topics: Adolescent; Adult; Antipsychotic Agents; Benztropine; Dopamine Antagonists; Double-Blind Method; Dyskinesia, Drug-Induced; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Muscarinic Antagonists; Neostriatum; Positron-Emission Tomography; Prolactin; Prospective Studies; Psychiatric Status Rating Scales; Psychomotor Agitation; Pyrrolidines; Raclopride; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Schizophrenic Psychology

The present study examined the roles of dopamine and D(1)- and D(2)-like dopamine receptors in ventrolateral orbital cortex (VLO)-evoked antinociception in rats with persistent inflammatory pain. Following formalin injection into the rat unilateral hindpaw pad, the effects of dopamine receptor agonist and antagonist microinjections into the VLO on nociceptive behavior were observed. Results demonstrated that VLO microinjection of the non-selective dopamine receptor agonist apomorphine (R(-)-apomorphine hydrochloride, 1.0, 2.5 and 5.0μg) depressed later-phase nociceptive behavior induced by formalin injection; this effect was attenuated by the D(2)-like dopamine receptor antagonist S(-)-raclopride(+)-tartrate salt (raclopride, 3.0μg), but not by the D(1)-like dopamine receptor antagonist R(+)-SCH-23390 hydrochloride (SCH-23390, 1.0μg). Apomorphine-induced antinociception was mimicked by microinjection of the D(2)-like dopamine receptor agonist (-)-quinpirole hydrochloride (2.0 and 5.0μg) into the same VLO site, and this effect was antagonized by raclopride (3.0μg). In addition, microinjection of the D(1)-like dopamine receptor agonist R(+)-SKF-38393 hydrochloride (5.0μg) had no effect on formalin-induced nociceptive behavior during the later phase. However, the D(1)-like dopamine receptor antagonist SCH-23390 (2.5, 5.0 and 10μg) depressed nociceptive behavior in a dose-dependent manner. These results suggested that dopamine mediated VLO-induced antinociception via different mechanisms in the persistent inflammatory pain model; D(2)-like receptors mediated dopamine-induced antinociception, while D(1)-like dopamine receptors exhibited tonic facilitatory action on nociceptive behavior, thereby blocking D(1)-like dopamine receptors could induce antinociception.

Topics: Animals; Behavior, Animal; Benzazepines; Dopamine Agonists; Dopamine Antagonists; Frontal Lobe; Male; Microinjections; Models, Animal; Pain Measurement; Psychomotor Agitation; Raclopride; Rats; Rats, Sprague-Dawley; Receptors, Dopamine

Pharmacological effects were recorded and time course for receptor binding in brain was followed by positron emission tomography after IV injection of the selective D1-dopamine receptor antagonist SCH 23390 in four healthy subjects in doses of 310-810 micrograms. Akathisia, the syndrome of motor restlessness, appeared after the three highest doses. The akathisia was transient and occurred only when [11C]SCH 23390 binding in the basal ganglia was at a high level with a central D1-dopamine receptor occupancy of 45-59%. The D2-dopamine receptor antagonist [11C]raclopride was injected IV into 20 healthy subjects and 13 schizophrenic patients. Akathisia appeared in 14 healthy subjects and 7 patients and coincided with maximal [11C]raclopride binding in the basal ganglia. The findings for [11C]raclopride and [11C]SCH 23390 are the first demonstration of a relationship between time courses for radioligand binding in the human brain and simultaneously induced pharmacological effects.

Topics: Adolescent; Adult; Akathisia, Drug-Induced; Benzazepines; Carbon Radioisotopes; Cerebellum; Dopamine Antagonists; Female; Humans; Male; Psychomotor Agitation; Putamen; Raclopride; Radioligand Assay; Receptors, Dopamine; Receptors, Dopamine D1; Receptors, Dopamine D2; Salicylamides; Schizophrenia; Time Factors; Tomography, Emission-Computed