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


OBJECTIVE
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; 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 alpha2 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 alpha1 adrenoceptor antagonist, prazosin (2 mg/kg; i.p.), reduced the MK-801-induced response.


CONCLUSIONS
It therefore appears that presynaptic noradrenergic alpha2 and postsynaptic alpha1 adrenoceptor stimulation exert opposing effects on the behavioural expression of MK-801 in mice.
Harkin
A
A
Department of Pharmacology, National University of Ireland, Galway. andrew.harkin@nuigalway.ie
Morris
K
K
Kelly
J P
JP
O'Donnell
J M
JM
Leonard
B E
BE
D018663:Adrenergic Agents / Q000494:pharmacology; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001259:Ataxia / Q000139:chemically induced; D001596:Benzylamines / Q000494:pharmacology; D003000:Clonidine / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009025:Morpholines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D009638:Norepinephrine / Q000378:metabolism*; D011224:Prazosin / Q000494:pharmacology; D000077593:Reboxetine; D013239:Stereotyped Behavior / Q000187:drug effects* / Q000502:physiology
D018663:Adrenergic Agents; D018759:Adrenergic Uptake Inhibitors; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D001596:Benzylamines; D018691:Excitatory Amino Acid Antagonists; D009025:Morpholines; D016291:Dizocilpine Maleate; D000077593:Reboxetine; D003000:Clonidine; C012102:DSP 4; D003891:Desipramine; D009638:Norepinephrine; D011224:Prazosin