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It has been suggested that the neuroleptic-induced acute dyskinetic syndrome in monkeys may be a useful model of extrapyramidal dysfunction. Various drugs that have well-characterized effects on clinical extrapyramidal syndromes and on catecholaminergic, cholinergic, or GABAergic neurotransmission were assessed in dyskinesia-susceptible squirrel monkeys. Catecholamine depletors (alpha-methyl-p-tyrosine, tetrabenazine) induced the syndrome, as do dopamine (DA) receptor antagonists, and d-amphetamine reversed the effects of tetrabenazine. The haloperidol-induced syndrome was reversed by the indirectly acting DA agonists amantadine and L-dopa. Neither of the DA autoreceptor agonist TL-99 or 3-PPP elicited this syndrome, suggesting that these agents lack extrapyramidal involvement. Anticholinergics reversed haloperidol-induced dyskinesias and the cholinomimetic arecoline was capable of inducing dyskinesias. When coadministered repeatedly with haloperidol, benztropine suppressed the emergence of susceptibility to neuroleptic-induced dyskinesias. These results confirm that the acute dyskinetic syndrome in the monkey is characterized by DA deficiency and acetylcholine excess. Diazepam and baclofen, which have been reported to have some clinical benefit in tardive dyskinesia, suppressed haloperidol-induced acute dyskinesias without causing gross motor depression. Pharmacological manipulation of GABAergic pathways from striatum may constitute a fruitful approach to the treatment of dyskinetic motor disorders.

The collagen II gene is expressed primarily in chondrocytes. Its transcription is activated through the interaction of cell type-specific regulatory elements located in the promoter region and in the first intron. In this study, we found that a short promoter sequence including two GC boxes was required for efficient enhancer-mediated transcription. Gel-shift analysis, site mutations, and footprint analysis showed that one of the GC boxes bound functionally to an Sp1-related factor and that an oligonucleotide containing this GC box did interact with an enhancer-nuclear factor complex. Additionally, an enhancer-derived oligonucleotide was found to complex CIIZFP, a zinc-finger protein that binds to the enhancer within the first intron and Sp1, but only in presence of CIIZFP. Antibodies against Sp1 specifically inhibited the formation of this complex. Western/Southwestern analysis also showed that a protein complex including Sp1 was able to bind the enhancer and the promoter regions in non-denaturing conditions. This complex was dissociated by denaturation. These results suggest that the formation of a nuclear protein-mediated loop structure between the promoter and enhancer may regulate transcription of the collagen II gene transcription.