Quetiapine (Seroquel) shows a pattern of behavioral effects similar to the atypical antipsychotics clozapine and olanzapine: studies with tremulous jaw movements in rats

Abstract

Rationale: Previous studies demonstrated that clozapine and olanzapine suppressed tacrine-induced jaw movements at lower doses than those required for suppression of lever pressing. Objective: The present studies were undertaken to evaluate the novel atypical antipsychotic quetiapine using the jaw movement model. Methods: The effect of acute quetiapine on the suppression of tacrineinduced tremulous jaw movements was examined. To determine the relative potency of this effect compared with other behavioral effects of quetiapine, suppression of lever pressing also was studied. In other studies, rats received quetiapine for 14 consecutive days to study the effects of repeated injections of this drug. Results: Acute quetiapine injections decreased tacrine-induced jaw movements and lever pressing. The ratio of the ED 50 for suppression of jaw movements divided by the ED 50 for suppression of lever pressing was used as an index of liability to produce motor side effects, and the present results demonstrate that quetiapine has a ratio similar to that previously shown for clozapine and olanzapine. In the repeated-administration studies, quetiapine failed to induce jaw movements. On day 14, quetiapine reduced tacrine-induced tremulous jaw movements, and in a parallel experiment quetiapine significantly suppressed lever pressing on days 1-14. Repeated injections of quetiapine reduced tacrine-induced jaw movements over a dose range lower than that required for suppression of lever pressing. Conclusions: On tests of jaw movement activity and lever pressing after both acute and repeated drug administration, quetiapine showed a profile somewhat similar to clozapine and olanzapine. A theoretical model is offered suggesting that atypical antipsychotics that act on 5-HT or muscarinic receptors have intrinsic antiparkinsonian actions that work in opposition to the motor effects produced by dopamine antagonism.

A 5-HT2A receptor inverse agonist, ACP-103, reduces tremor in a rat model and levodopa-induced dyskinesias in a monkey model

“…The rank order binding potency of antipsychotics for blocking tremulous jaw movements (i.e., risperidone, olanzapine, clozapine, quetiapine, thioridazine; Trevitt et al, 1997,Trevitt et al, 1999; Betz et al, 2005) is consistent with the rank order of affinity of these drugs for binding to 5-HT 2A receptors (Richelson and Souder, 2000; Seeman et al, 1997; Weiner et al, 2001), suggesting that 5-HT 2A receptors mediate this behavioral effect. This observation is consistent with the present data showing that ACP-103 could suppress tacrine-induced tremulous jaw movements.…”

“…5-HT 1A agonists have been shown to suppress tacrine-induced tremulous jaw movements (Zazpe et al, 2006). Atypical antipsychotics that act on 5-HT receptors, including clozapine, olanzapine and quetiapine, have all been reported to block tremulous jaw movements induced by pilocarpine, physostigmine or tacrine (Chesler and Salamone, 1996; Stewart et al, 1988; Trevitt et al, 1997,Trevitt et al, 1999; Betz et al, 2005; Zazpe et al, 2006). Similarly, several 5-HT 2 receptor family antagonists, including seganserin, ritanserin and ketanserin, have been reported to decrease haloperidol-induced vacuous chewing in rats (Naidu and Kulkarni, 2001).…”

Differential effects of antipsychotic medications on polyunsaturated fatty acid biosynthesis in rats: Relationship with liver delta6-desaturase expression

“…Drug doses were selected based on prior studies finding that they produce therapeutically-relevant plasma concentrations in rats following oral administration (Andersson et al, 2002; McNamara et al, 2009b; Terry et al, 2005). Doses of quetiapine were selected based on prior findings of significant effects on behavioral and neurochemical variables within this dose range (Migler et al, 1993; Tarazi et al, 2002), and to avoid significant sedative effects observed at higher doses (≥40 mg/kg, Betz et al, 2005). Drugs were administered through the rat’s drinking water to avoid daily injection stress and surgical implantation of mini-pumps, to mimic oral administration in human patients, and to permit maintenance of drug dose in accordance with age-related increases in body weight.…”

Atypical antipsychotic medications increase postprandial triglyceride and glucose levels in male rats: Relationship with stearoyl-CoA desaturase activity

“…Doses of risperidone, olanzapine, and haloperidol were selected based on prior studies finding production of therapeutically-relevant plasma concentrations in rats following chronic oral administration (Andersson et al, 2002; McNamara et al, 2009a; Terry et al, 2005). Doses of quetiapine were selected based on prior behavioral and neurochemical studies finding significant effects within this dose range (Migler et al, 1993; Tarazi et al, 2002), and to avoid sedative effects observed at higher doses (≥40 mg/kg, Betz et al, 2005) which could impair food and fluid intake. Drugs were administered through the rat’s drinking water to avoid daily injection stress and surgical implantation of mini-pumps, to mimic oral administration in human patients, and to permit maintenance of drug dose in accordance with age-related increases in body weight and fluid intake.…”