Modulation of MK-801-induced behaviour by noradrenergic agents in mice

Abstract

Rationale: Inhibition of glutamatergic Nmethyl-D-aspartate (NMDA) receptors following the administration of NMDA receptor antagonists results in psychotic-like behaviour. Whereas it is known that pharmacological manipulation of dopaminergic and serotonergic pathways affect this drug-induced psychosis, a role for noradrenaline has not yet been clearly defined. Objectives: Thus, in the present study, we assessed a possible role for noradrenaline in the behavioural response to the non-competitive NMDA receptor anatgonist, MK-801, in male CD-I mice. Results: MK-801 (0.02-1.28 mg/kg; ED 50 0.2 mg/kg; s.c.) induced a dosedependent increase in locomotor, stereotypic and ataxic behaviours. Pre-treatment with the noradrenaline re-uptake inhibitors, desipramine (10 mg/kg; i.p.) and reboxetine (20 mg/kg; i.p.), attenuated the locomotor, stereotypic and ataxic response to MK-801 (0.2 mg/kg; s.c.). The noradrenergic system was lesioned with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4, 50 mg/kg; i.p., 7 and 4 days prior to challenge) to reduce noradrenaline concentrations in the cortex by 70%-80%. Whereas DSP-4 lesioning had little effect on the response to MK-801, it completely reversed the attenuating effects of reboxetine. Pre-treatment with the α 2 adrenoceptor agonist, clonidine (0.2 mg/kg; i.p.), and the antagonist, yohimbine (2 mg/kg; i.p.), attenuated and potentiated the response to MK-801, respectively. Pre-treatment with the α 1 adrenoceptor antagonist, prazosin (2 mg/kg; i.p.), reduced the MK-801-induced response. Conclusions: It therefore appears that presynaptic noradrenergic α 2 and postsynaptic α 1 adrenoceptor stimulation exert opposing effects on the behavioural expression of MK-801 in mice.

Bimodal effects of MK-801 on locomotion and stereotypy in C57BL/6 mice

“…It has also been proposed that rearing is mediated by noradrenergic pathways, in contrast to horizontal locomotion, which more reflects the action of the mesolimbic dopamine system (Miyamoto et al 1984;Masuo et al 1995). Consistent with this idea are experiments in CD-I mice showing that noradrenaline tends to antagonize MK-801 effects (Harkin et al 2001), which would predict the inhibitory effects we observed on rearing. Several other drugs have differential effects on horizontal versus vertical locomotion.…”

α1-Adrenergic receptors mediate the locomotor response to systemic administration of (±)-3,4-methylenedioxymethamphetamine (MDMA) in rats

“…Other studies have shown that systemic administration of prazosin can attenuate the locomotor response to cocaine, the NMDA receptor antagonist MK-801, and the DA reuptake inhibitor GBR 12783 (Arnt 1995;Dickinson et al 1988;Drouin et al 2002a;Harkin et al 2001;Mathe et al 1996;Snoddy and Tessel 1985;Svensson et al 1995;Wellman et al 2002). Thus, the experiments described herein tested the hypothesis that activation of α 1 -adrenoceptors in the prefrontal cortex and ventral tegmental area of the rat modulate the locomotor response to MDMA.…”

Characterization of the effects of receptor-selective ligands in rats discriminating the novel antipsychotic quetiapine

“…Although the clinical significance of a 1 -adrenoceptor blockade for the therapeutic properties of quetiapine and other antipsychotics remains unclear, a 1 -adrenoceptor antagonists are active in several models predictive of clinical activity (Brunello et al 1995). They improve functioning in models of cognitive deficits in schizophrenia Geyer 1997, 1999;Carasso et al 1998) and attenuate hyperactivity elicited by amphetamine, dizocilpine and phencyclidine (Harkin et al 2001;Drouin et al 2002).…”