The genetically dystonic ( dt sz ) hamster is an autosomal recessive mutant that shares several features with paroxysmal dystonia, i.e., a subcategory of inherited idiopathic dystonia in humans. Because the serotonin (5-HT) system has been suggested to be involved in dystonia, we examined the functional responsiveness of the 5-HT system in dystonic hamsters by administering various 5-HT agonists and antagonists selective for different receptor subtypes and observing the effects on dystonic attacks as well as the behavioural responses associated with drug administration. Paradoxically, marked prodystonic effects (i.e., increased severity and/ or decreased latency of dystonic attacks) were seen with both the selective 5-HT 1A receptor agonist 8-hydroxy-2(di- n-propylamino) tetralin (8-OH-DPAT) and the selective and “silent” 5-HT 1A receptor antagonist, N-tert-butyl-3[4-(2-methoxy-phenyl) piperazin-1-yl]-2-phenylpropionamide [(+)-WAY-100135], whereas other 5-HT 1A receptor antagonists, i.e., methyl 4[4-(4-[1,1,3-trioxo-2H-1,2-benzoiosothiazol-2-yl]butyl)-1-piperazinyl]1-H-indole-2-carboxylate (SDZ 216-525) and N 1-bromoacetyl- N 8-3′-(4-indolyloxy)-2′-hydroxypropyl-(Z)-1,8-diamino- p-methane (pindobind-5-HT 1A) did not alter dystonia to any comparable extent. Because among these 5-HT 1A receptor antagonists, (+)-WAY-100135 is the only drug known to be not only silent at postsynaptic but also presynaptic (somatodendritic) 5-HT 1A receptors, the marked prodystonic effect of this drug could relate to increased 5-HT release as a result of the blockade of somatodendritic 5-HT 1A receptors. The only 5-HT A receptor antagonist that exerted antidystonic effects in hamsters was pindolol, which, however, could be related to its β-adrenoceptor blocking action. The 5-HT 1A receptor partial agonist ipsapirone exerted moderate prodystonic activity. Prodystonic activity was also determined for the mixed 5-HT 1A/5-HT 2 receptor agonist 5-methoxy- N, N-dimethyltryptamine, although this drug was less potent in this regard than 8-OH-DPAT. The 5-HT 2 receptor agonist l-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) exerted prodystonic effects in mutant hamsters, which, however, were also seen after the administration of the 5-HT 2 receptor antagonist ritanserin. Collectively, the results of this study demonstrate that dystonia in genetically dystonic hamsters can be affected by pharmacologie manipulation of 5-HT receptors. The data may also indicate that dystonia is not a potential clinical application for selective 5-HT 1A or 5-HT 2 receptor antagonists.