Clozapine inhibits catalepsy induced by olanzapine and loxapine, but prolongs catalepsy induced by SCH 23390 in rats

Abstract

Loxapine (0.3 mg/kg s.c.), olanzapine (10 mg/kg s.c.) and SCH 23390 (R-(+)-chloro-2, 3, 4, 5-tetrahydro-3-methyl-5-phenyl-1-H-3-benzazepine; 1 mg/kg, s.c.), but not clozapine (10 mg/kg, s.c.), induced catalepsy in rats. Co-administration of clozapine (1, 3 and 10 mg/kg s.c.) dose-dependently inhibited loxapine-induced catalepsy. Clozapine (10 mg/kg s.c.) also prevented the induction of catalepsy by olanzapine. In addition, clozapine abolished the catalepsy induced by loxapine when it was administered after the response had fully developed. In contrast, the duration of SCH 23390-induced catalepsy was prolonged by clozapine, indicating that its anti-catalepsy effects against olanzapine and loxapine are unlikely to be caused by muscle relaxation, sedation or stimulation. Since SCH 23390-induced catalepsy is reported to be blocked by scopolamine, dizocilpine (MK-801) or 8-hydroxy-dipropylamino-tetralin, it is unlikely that muscarinic blockade, NMDA ion channel blockade and 5-HT1A receptor agonism, respectively, are involved in clozapine's action, but the mechanism by which clozapine exerts this anti-cataleptic effect remains unknown.

Noradrenergic Modulation of Subthalamic Nucleus Activity: Behavioral and Electrophysiological Evidence in Intact and 6-Hydroxydopamine-Lesioned Rats

“…1) in agreement with previous studies (Antonelli et al, 1991;Wellman and Davies, 1992;Mathe et al, 1996). In contrast, the ␣2-AR antagonist idazoxan increased the spontaneous activity of both intact and lesioned rats (i.e., displaying an antiparkinsonian activity), in keeping with previous reports showing that several ␣2-AR antagonists increase motor activity under normal conditions and improve motor functions in experimental and human parkinsonism (Kalkman et al, 1997;Bezard et al, 1999;Villegier et al, 2003).…”

Antipsychotic drugs which elicit little or no Parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors

“…This separation of antipsychotic drugs into 'loose' and 'tight' binding to D2, relative to that for dopamine, is consistent with the findings by Kalkman et al 71 These authors were able to reverse catalepsy induced by olanzapine and loxapine (both more loosely bound than dopamine), but were not able to reverse that by Figure 3 The therapeutic concentrations of various antipsychotic drugs consistently occupy 75-76% of dopamine D2 receptors (data from Figure 2), but similar calculations for the dopamine D3 and dopamine D4 receptors did not reveal any constant percent occupancy for all the antipsychotic drugs. CPZ, chlorpromazine; Cloz., clozapine; Halo., haloperidol; Molin., molindone; Olan., olanzapine; Raclo., raclopride; Remox., remoxipride; Sulp., S-Sulpiride; Thior., thioridazine; Flupen., cis-flupentixol; per., perphenazine.…”

The Role of Inhaled Loxapine in the Treatment of Acute Agitation in Patients with Psychiatric Disorders: A Clinical Review

“…Preclinical behavioural studies have demonstrated that loxapine may induce catalepsy in rats to the same extent as olanzapine, and these effects may be abolished by clozapine administration, but only when it is administered after the catalepsy is fully developed [33]. In discriminative stimulus comparisons, loxapine may only induce minimal generalization, similarly to haloperidol, whereas clozapine has been demonstrated to induce full dose-related generalization in the absence of response suppression [34].…”