Dopamine antagonist properties of atypical neuroleptics may be revealed following mesolimbic denervation.

A mesolimbic denervation, caused by bilateral intra-accumbens 6-hydroxydopamine, increased the potency of apomorphine in two behavioural tests of dopamine agonist activity, climbing behaviour and circling (combinations of the accumbens denervation with unilateral electrolesion of the striatum). Of a number of neuroleptics tested, haloperidol, fluphenazine, sultopride, tiapride, sulpiride and thioridazine, only the latter two showed greater effectiveness than normal to antagonize the apomorphine responses after mesolimbic denervation. Sulpiride and thioridazine cause remarkably little change in 'normal' tests for antipsychotic activity; their effectiveness in the clinic may reflect a more unique ability to act on dopamine receptor mechanisms of changed sensitivity.