Stimulus properties of the "atypical" antipsychotic zotepine in rats: comparisons with clozapine and quetiapine.
The stimulus properties of the "atypical" antipsychotic zotepine were assessed in three studies in rats. In Study 1, the ability of zotepine to generalise to clozapine was studied. Two groups of rats were trained to discriminate clozapine at 2 and 5 mg/kg. Clozapine induced full generalisation in both groups, with the generalisation curves shifted significantly to the left in the low dose group. In generalisation tests clozapine did not suppress responding. Zotepine induced dose-related generalisation in both groups, with full generalisation in the low dose group and 50% maximal generalisation in the high dose group at the highest dose that could be tested. In contrast to clozapine, zotepine induced substantial (50% or more) substitution for clozapine only at doses which suppressed responding. In Study 2 zotepine was investigated in rats trained to discriminate quetiapine (10 mg/kg). Quetiapine induced full generalisation and zotepine only induced 54% generalisation at the highest dose that could be tested. Generalisation was accompanied by response suppression induced by both quetiapine and zotepine. In Study 3 an attempt was made to train a zotepine discrimination (1 mg/kg increased to 2 mg/kg). Even after 150 training sessions it proved impossible to obtain reliable discriminative responding with zotepine. These data suggest that: (i) The actions of zotepine in discrimination assays are similar to, but not identical with, those of clozapine and quetiapine; (ii) The differences among the actions of clozapine, quetiapine and zotepine may be related to either the unique ability of zotepine to block noradrenaline (NA) uptake, or to its more marked affinity for D(2) receptors; (iii) The finding that zotepine only mimicked quetiapine up to a level of 54% was unexpected, since quetiapine and clozapine generalise reciprocally and zotepine generalised fully to (low dose) clozapine. This finding may also be related either to zotepine's ability to inhibit NA uptake or its relatively high D(2) affinity; (iv) Although zotepine clearly possesses discriminative properties, it is not possible to train it as a reliable stimulus, in contrast to clozapine and quetiapine. This may be due to its more marked D(2) receptor affinity. Collectively, these data demonstrate both similarities and differences between zotepine and other novel atypical antipsychotics in drug discrimination assays.
Goudie
Andrew J
AJ
Psychology Department, Liverpool University, Eleanor Rathbone Building, Bedford Street North, L69 7ZA, Liverpool, UK. ajg@liverpool.ac.uk
Smith
Judith A
JA
Cole
Jon C
JC
D000818:Animals; D014150:Antipsychotic Agents / Q000378:metabolism / Q000494:pharmacology*; D003024:Clozapine / Q000378:metabolism / Q000494:pharmacology*; D003987:Dibenzothiazepines / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D000069348:Quetiapine Fumarate; D051381:Rats; D017208:Rats, Wistar; D011930:Reaction Time / Q000187:drug effects* / Q000502:physiology
D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D000069348:Quetiapine Fumarate; D003024:Clozapine