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

0Previous studies in non-human primates have shown that tolerance to dyston ia occurs during chronic dopamine D1 (D1) but not D2 antagonism and inducti on/aggravation of oral dyskinesia (TD) during D2 but not DI 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 a pella monkeys were treated 10 weeks with gradually increasing doses of D1 a ntagonist (NNC 112) + a D2 antagonist (raclopride), followed by 2 weeks of treatment with the D2 antagonist alone. Due to previous neuroleptic exposur e, 5 monkeys had TD and all were sensitized to dystonia. During the combine d antagonist treatment, tolerance to dystonia occurred; the tolerance disap pearing upon discontinuation of the D1 antagonist and continuation of the D 2 antagonist alone. Parallel to these results, improvement of TD was seen d uring the combined antagonist treatment with worsening during the D2 antago nist alone. Both the combined antagonists and the D2 antagonist alone resul ted in moderate/severe bradykinesia, with no tolerance. These findings indi cate 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 i ndicate that separate dopaminergic mechanisms control dystonia/dyskinesia a nd parkinsonism.