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The effects of chronically ablating the serotoninergic inputs to various regions of the rat brain on the ability to solve a feature-negative discrimination was measured. After intracerebroventricular administration of the specific neurotoxin 5,7-dihydroxytryptamine, the rats exhibited an impaired capacity to solve such a discrimination, irrespective of whether auditory or visual stimuli were used. Further behavioural analysis revealed that this effect was not due to a reduced capacity to form excitatory associations, since both groups responded equally to reinforced stimuli. By contrast, the lesion more likely resulted in a failure to endow the non-reinforced stimuli with inhibitory properties. This suggestion was supported by the observation that, in a retardation test, the conditioned inhibitor aroused less inhibition in the lesioned group than in vehicle-injected controls. Furthermore, the conditioned inhibitor failed to pass a summation test in lesioned animals, again indicating that their hampered ability to master the discrimination was the result of an impairment in the formation of inhibitory associations. It is concluded that destruction of central 5-hydroxytryptamine-containing pathways impairs the functioning of brain areas underlying inhibitory associative learning.

The use of long‐acting depot antipsychotics results in an increase in compliance and significantly decreases rates of relapse and rehospitalization of schizophrenic patients. However, the assessment of activity of such drugs in small animals is not as straightforward as the evaluation of acutely active drugs. Previous studies have investigated the effects of depot formulations by assessing their activity in preclinical methods that examine their striatal dopaminergic components alone. These methods are currently used to examine the extrapyramidal side‐effects of antipsychotic agents. In the light of recent drug developments, however, it is possible that such procedures may no longer be appropriate for testing antipsychotics which produce fewer side effects and which have a broader range of action including nondopaminergic components. Accordingly, the present study aimed to further investigate the activities of clinically used depot antipsychotics by using procedures that are considered more predictive of antipsychotic activity rather than extrapyramidal side‐effect liability. Along with acutely active analogs, flupenthixol decanoate, fluphenazine decanoate, and haloperidol decanoate were examined in the following procedures with rats or mice: antagonism of 1[2,5‐dimethoxy‐4‐iodophenyl]‐2‐aminopropane (DOI) ‐induced behaviors and amphetamine‐stimulated locomotion. Effects of the depot formulations in both procedures were determined at time points ranging from 24 h to 14 days after administration. In general, some antipsychotic‐related effects were observed with the drugs particularly at earlier time points; effects at 14 days were minimal. The results from this study demonstrate that depot formulations of antipsychotic drugs have effects in rodents, but factors possibly related to injection volume, test procedure, and species could limit the duration of action in small laboratory animals. Drug Dev. Res. 47:27–36, 1999. © 1999 Wiley‐Liss, Inc.