Janice M. Hitchcock

Selectivity of action of typical and atypical antipsychotic drugs as antagonists of the behavioral effects of 1-[2,5-dimethoxy-4-iodophenyl]-2-aminopropane (DOI)

1. There has been considerable research in the field of schizophrenia over the past few years with emphasis on the discovery of better drugs, particularly those with 5-HT2 antagonist activity. 2. In an effort to enhance identification of such compounds and to further understand the contribution of 5-HT2 activity to the effects of antipsychotic drugs, a series of conventional, atypical and purported antipsychotic compounds were assessed as antagonists of DOI-induced behaviors in rats. 3. DOI (1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride) is an hallucinogen having high affinity and selectivity as an agonist at 5-HT2A/2C receptors. Over a 30-min period after injection, DOI (0.3-10.0 mg/kg; i.p.) produced dose-related behavioral effects including head-and-body shakes, forepaw tapping and skin-jerks. Effects of the antipsychotic drugs and other compounds (30 min pretreatment; i.p.) were examined against a fixed dose of DOI (3.0 mg/kg). 4. In a dose-dependent manner, M100907 (MDL 100,907), risperidone, haloperidol, clozapine, iloperidone, olanzapine, amperozide, remoxipride, ritanserin and the neurotensin agonist NT1 (N alpha MeArg-Lys-Pro-Trp-Tle-Leu) antagonized each of the three behavioral effects of DOI. Drugs attenuating the head-and-body shakes were equally effective in blocking both forepaw tapping and skin-jerks indicating that these behaviors are mediated by similar mechanisms. The following compounds had either inconsistent or no effect on the DOI-induced behaviors: SB 200646A, citalopram, imipramine, fluoxetine, morphine, CP 99994, diazepam, ondansetron and SKF 97541. 5. The data show that antipsychotic agents, as a drug class, effectively block the effects of DOI. These actions are selective, as a series of nine non-antipsychotic and centrally-acting drugs were generally inactive in the procedure.

Neonatal hippocampal lesion model of schizophrenia in rats: Sex differences and persistence of effects into maturity

A neurodevelopmental model of schizophrenia in rats has recently been proposed employing neonatal hippocampal lesions. The present study further characterizes this model by investigating the long‐term effects of neonatal hippocampal lesions up to 100 days after birth, in male rats as well as female rats. Lesions were performed on postnatal day seven (PD 7).

Effects of depot drug formulations in procedures used to evaluate antipsychotic activity in rodents

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.