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

Rationale: Inhibition of glutamatergic N-methyl-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 antagonist, MK-801, in male CD-I mice. Results: MK-801 (0.02-1.28 mg kg; ED50 0.2 mg kg; s.c.) induced a dose-dependent 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 alpha (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 alpha (1) adrenoceptor antagonist, prazosin (2 mg kg; i.p.), reduced the MK-801-induced response. Conclusions: It therefore appears that presynaptic noradrenergic alpha (2) and postsynaptic alpha (1) adrenoceptor stimulation exert opposing effects on the behavioural expression of MK-801 in mice.