Raclopride-induced motor consolidation impairment in primates: role of the dopamine type-2 receptor in movement chunking into integrated sequences.

Results obtained in patients with schizophrenia have shown that antipsychotic drugs may induce motor learning deficits correlated with the striatal type-2 dopamine receptors (D(2)R) occupancy. Other findings suggest that the role of the striatum in motor learning could be related to a process of "chunking" discrete movements into motor sequences. We therefore hypothesized that a D(2)R blocking substance, such as raclopride, would affect motor learning by specifically disrupting the grouping of movements into sequences. Two monkeys were first trained to perform a baseline-overlearned sequence (Seq. A) drug free. Then, a new sequence was learned (Seq. B) and the overlearned sequence was recalled OFF-drug (Seq. A recall OFF-drug). The effect of raclopride was then assessed on the learning of a third sequence (Seq. C), and on the recall of the overlearned sequence (Seq. A recall ON-drug). Results showed that performance related to the overlearned sequence remained the same in the three experimental conditions (Seq. A, Seq. A recall OFF-drug, Seq. A recall ON-drug), whether the primates received raclopride or not. On the other hand, new sequence learning was significantly affected during raclopride treatment (Seq. C), when compared with new sequence learning without the effect of any drug (Seq. B). Raclopride-induced disturbances consisted in performance fluctuations, which persisted even after many days of trials, and prevented the monkeys from reaching a stable level of performance. Further analyses also showed that these fluctuations appeared to be related to monkeys' inability to group movements into single flowing motor sequences. The results of our study suggest that dopamine is involved in the stabilization or consolidation of motor performances, and that this function would involve a chunking of movements into well-integrated sequences.

Topiramate augments the antipsychotic-like effect and cortical dopamine output of raclopride.

Recent clinical studies have shown that the anticonvulsant drug topiramate may improve negative symptoms in schizophrenia when added to a stable regimen of neuroleptic medication. It has also been shown that addition of topiramate to neuroleptics might be beneficial in treatment-resistant schizophrenia. Clinically effective doses of antipsychotic drugs (APDs) have been found to suppress conditioned avoidance response behavior (CAR), a preclinical test of antipsychotic activity with high predictive validity, in rats. Therefore, we investigated the putative antipsychotic-like activity of topiramate when added to the selective dopamine (DA) D2 receptor antagonist raclopride, using the CAR model in the rat. Extrapyramidal side effect liability of the drug combination was evaluated in parallel by means of the catalepsy test. We also examined the effect of this drug treatment on DA release in the medial prefrontal cortex (mPFC) and the nucleus accumbens (NAC), using in vivo microdialysis in freely moving animals. Topiramate (40 mg/kg), while ineffective when given alone, significantly augmented the antipsychotic-like effect of raclopride (0.075 mg/kg) on CAR without any concomitant catalepsy. Addition of topiramate to rats treated with raclopride generated a large increase in DA output in the mPFC, whereas no additional effect on the raclopride-induced DA release in the NAC was obtained. These data support the adjunctive use of topiramate in schizophrenia to ameliorate negative symptoms and suggest that this treatment may increase the efficacy, but not the extrapyramidal side effect liability, of the APDs used.

Atropine reduces raclopride-induced muscle rigidity by acting in the ventral region of the striatum.

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.

Effects of (S)-ketamine on striatal dopamine: a [11C]raclopride PET study of a model psychosis in humans.

Administration of the N-methyl-D-aspartate (NMDA) antagonist S-ketamine in normals produces a psychosis-like syndrome including several positive and negative symptoms of schizophrenic disorders (Abi-Saab WM, D'Souza DC, Moghaddam B, Krystal JH. The NMDA antagonist model for schizophrenia: promise and pitfalls. Pharmacopsychiatry 1998;31:104-109). Given the clinical efficacy of dopamine (DA) D2 receptor antagonists in the treatment of positive symptoms, it is conceivable that S-ketamine-induced psychotic symptoms are partially due to a secondary activation of dopaminergic systems. To date, animal and human studies of the effects of NMDA antagonists on striatal DA levels have been inconsistent. The present study used positron emission tomography (PET) to determine whether a psychotomimetic dose of S-ketamine decreases the in vivo binding of [11C]raclopride to striatal DA D2 receptors in humans (n = 8). S-ketamine elicited a psychosis-like syndrome, including alterations in mood, cognitive disturbances, hallucinations and ego-disorders. S-ketamine decreased [11C]raclopride binding potential (BP) significantly in the ventral striatum (-17.5%) followed by the caudate nucleus (-14.3%) and putamen (-13.6%), indicating an increase in striatal DA concentration. The change in raclopride BP in the ventral striatum correlated with heightened mood ranging from euphoria to grandiosity. These results provide evidence that the glutamatergic NMDA receptor may contribute to psychotic symptom formation via modulation of the DA system.

Extrapyramidal side effects during chronic combined dopamine D1 and D2 antagonist treatment in Cebus apella monkeys.

Previous studies in non-human primates have shown that tolerance to dystonia occurs during chronic dopamine D1 (D1) but not D2 antagonism and induction/aggravation of oral dyskinesia (TD) during D2 but not D1 antagonism. We were therefore interested in determining the effects of combined chronic D1 + D2 antagonism on dystonia and dyskinesia. To this intent, 8 male Cebus apella monkeys were treated 10 weeks with gradually increasing doses of D1 antagonist (NNC 112) + a D2 antagonist (raclopride), followed by 2 weeks of treatment with the D2 antagonist alone. Due to previous neuroleptic exposure, 5 monkeys had TD and all were sensitized to dystonia. During the combined antagonist treatment, tolerance to dystonia occurred; the tolerance disappearing upon discontinuation of the D1 antagonist and continuation of the D2 antagonist alone. Parallel to these results, improvement of TD was seen during the combined antagonist treatment with worsening during the D2 antagonist alone. Both the combined antagonists and the D2 antagonist alone resulted in moderate/severe bradykinesia, with no tolerance. These findings indicate that supplementation of traditional D2 antagonism with a D1 antagonist would lessen the risk of dystonia and allow alleviation of preexisting TD, though parkinsonian side effects might still occur. The findings further indicate that separate dopaminergic mechanisms control dystonia/dyskinesia and parkinsonism.