raclopride and Muscle-Rigidity

Extrapyramidal side-effects (EPSE) of antipsychotic medication are related to the occupancy of dopamine D2 receptors and there appears to be a threshold of D2 occupancy below which clinically EPSE are unlikely to occur. It is unclear whether there are motor changes produced by 'subthreshold' levels of D2 occupancy that are not detectable by clinical examination. This study was designed to investigate whether a number of electromechanical instrumental techniques could detect 'subthreshold' motor changes and whether these changes correlate with dopamine D2 occupancy as measured by [11C]-raclopride PET scan. Twenty medication naïve patients were studied before and during treatment with low dose haloperidol. Instrumental techniques detected an asymmetrical worsening in motor function with drug treatment despite the failure of the group to experience significant EPSE. These changes did not correlate with D2 occupancy and measurements of rigidity, tremor, and bradykinesia did not closely inter-correlate.

Topics: Adult; Carbon Radioisotopes; Cerebellum; Corpus Striatum; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Female; Haloperidol; Humans; Hypokinesia; Male; Motor Activity; Muscle Rigidity; Raclopride; Receptors, Dopamine D2; Schizophrenia; Schizophrenia, Paranoid; Tomography, Emission-Computed; Tremor

Adenosine A2A receptor agonists produce a hypokinetic state (catalepsy) that is believed to reflect antagonistic interaction of A2A and dopamine D2 receptors in the basal ganglia. In addition to catalepsy, pharmacological blockade of D2 receptors produces rigidity. However there are conflicting data about the effect of A2A agonists on muscle tone, with some reports indicating an increase, while other data suggest that A2A catalepsy is dominated by muscle hypotonia. We investigated the effect on resistance to imposed movements of systemic cataleptic doses of the selective A2A agonist CGS21680 (5 mg/kg), and compared it with the effect of the D2 antagonist raclopride (5 mg/kg), in rats. Total resistance is made up of elastic and viscous components. The elastic component is velocity independent, and is referred to as "stiffness," whereas viscosity, which dampens responses to imposed movements, is velocity dependent. Using a method for quantifying total joint resistance that enabled separate identification of stiffness and viscosity, we found that during catalepsy evoked by either drug there was a clear increase in joint rigidity. Both CGS21680 and raclopride significantly increased joint stiffness, the velocity independent component of rigidity that is most affected in Parkinsonism. In contrast, the effect of CGS21680 on the velocity-dependent viscosity component was less robust than for raclopride, and did not reach significance, possibly reflecting an interaction with sedative effects via extrastriatal receptors. The effect of CGS21680 and raclopride on joint stiffness is thus consistent with previous findings suggesting functional antagonism of A2A and D2 receptors in the basal ganglia.

Topics: Adenosine; Adenosine A2 Receptor Agonists; Animals; Biomechanical Phenomena; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Hindlimb; Joints; Male; Muscle Rigidity; Muscle Tonus; Phenethylamines; Raclopride; Rats; Rats, Wistar; Receptors, Adenosine A2

Parkinson-like extrapyramidal motor side effects associated with the use of antipsychotic drugs, such as increased muscle rigidity, are thought to result from blockade of striatal dopamine D2 receptors. While anticholinergic medications (muscarinic receptor antagonists) ameliorate extrapyramidal side effects, the mechanisms underlying their effectiveness remain unclear. We investigated the site of action of atropine, a non-selective muscarinic receptor antagonist, in reducing increased muscle rigidity, assessed as increases in tonic electromyographic (EMG) activity, induced by the selective dopamine D2 receptor antagonist, raclopride. Atropine significantly reduced raclopride-induced EMG increases in rat hindlimb muscles, when injected into the ventral striatum, but not the dorsal striatum or the substantia nigra. Atropine's site of action was localised to a small area of muscarinic receptors within the ventral part of the striatum, using quantitative autoradiography. These findings provide new information about the regulation of motor control by muscarinic receptor antagonists and additional evidence about the functional heterogeneity of the striatum.

Topics: Animals; Atropine; Basal Ganglia; Brain Mapping; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Electromyography; Injections, Intraventricular; Injections, Subcutaneous; Male; Muscarinic Antagonists; Muscle Rigidity; Raclopride; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Time Factors

The aim of the present study was to investigate the relationship between effects on muscle tone and D2 receptor occupancy of two typical antipsychotic drugs, raclopride and chlorpromazine, and the atypical drug, clozapine. Increased muscle tone (i.e., muscle rigidity), was measured as increases in tonic electromyographic (EMG) activity of the antagonistic muscles of the rat hind limb. D2 dopamine receptor occupancy was assessed in the striatum and substantia nigra, areas involved in the regulation of muscle tone. Raclopride and chlorpromazine produced dose-dependent increases in EMG activity associated with D2 occupancy of 68%-80% in the striatum and 67%-76% in the nigra. No significant increases in EMG were observed with clozapine which showed low D2 occupancy. The results are consistent with those from human studies showing extrapyramidal side effects were associated with striatal D2 occupancy of > 70%.

Topics: Animals; Antipsychotic Agents; Autoradiography; Brain Chemistry; Chlorpromazine; Clozapine; Dose-Response Relationship, Drug; Electromyography; Hindlimb; Male; Muscle Rigidity; Muscle Tonus; Raclopride; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Salicylamides

We have used PET to study striatal D1 and D2 receptor binding in 10 patients with either the choreic or akinetic-rigid variants of Huntington's disease and in three patients with other causes of chorea. Background rigidity and bradykinesia in choreic patients were scored with a four-point scale. PET studies showed a severe and parallel reduction of both striatal D1 and D2 receptor binding in Huntington's disease patients irrespective of their predominant phenotype (mean reduction 60%). Huntington's disease patients with rigidity showed more pronounced reduction of striatal D1 and D2 binding compared with those without rigidity. A case of chorea associated with systemic lupus erythematosus had normal D2 binding. These results suggest that the presence of chorea per se may not be determined by alterations in striatal dopamine receptor binding, but that rigidity in Huntington's disease is associated with severe striatal D1 and D2 receptor loss.

Topics: Adult; Aged; Basal Ganglia; Benzazepines; Carbon Radioisotopes; Caudate Nucleus; Chorea; Dopamine; Female; Humans; Huntington Disease; Lupus Erythematosus, Systemic; Male; Middle Aged; Motor Activity; Muscle Rigidity; Phenotype; Putamen; Raclopride; Receptors, Dopamine D1; Receptors, Dopamine D2; Salicylamides; Tomography, Emission-Computed