J. Airio et L. Ahtee, The involvement of noradrenergic transmission in the morphine-induced locomotor hyperactivity in mice withdrawn from repeated morphine treatment, BR J PHARM, 126(7), 1999, pp. 1609-1619
1 Our previous studies suggest that in addition to the cerebral dopaminergi
c systems the noradrenergic ones have a crucial role in the morphine-induce
d behavioural sensitization in mice. Therefore the effects of alpha(2)-adre
noceptor antagonist, idazoxan (1 and 3 mg kg(-1), i.p.) on morphine-induced
locomotor hyperactivity as well as on morphine-induced changes in cerebral
noradrenaline (NA) and striatal dopamine (DA) metabolism were studied in m
ice withdrawn for 3 days from 5 day repeated morphine treatment. The concen
trations of NA, free 3-methoxy-4-hydroxyphenylethylene glycol (MOPEG), DA,
3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 3-meth
oxytyramine (3-MT) were determined.
2 Acute morphine (10 mg kg(-1), s.c.) increased locomotor activity in contr
ol and in morphine-withdrawn mice; idazoxan alone did not alter the activit
y. Idazoxan pretreatment did not alter the locomotor hyperactivity induced
by acute morphine in control mice but potentiated it in morphine-withdrawn
mice.
3 Acute morphine elevated MOPEG less but increased DOPAC and HVA more clear
ly in morphine-withdrawn mice than in controls, and decreased 3-MT only in
controls. Idazoxan alone did not alter the NA or DA metabolite concentratio
ns in control mice, but elevated MOPEG as well as DOPAC in morphine-withdra
wn mice.
4 In control mice idazoxan enhanced acute morphine's elevating effect on MO
PEG. In withdrawn mice idazoxan counteracted the tolerance so that acute mo
rphine elevated MOPEG in these mice to about similar level as in controls.
5 Idazoxan pretreatment abolished the HVA increasing effect of acute morphi
ne both in control and withdrawn mice. In control mice idazoxan enhanced mo
rphine's elevating effect on DOPAC and abolished morphine's decreasing effe
ct on 3-MT. Idazoxan did not alter morphine's effects on DOPAC or 3-MT conc
entrations in withdrawn mice.
6 Our results show that in morphine-withdrawn mice idazoxan pretreatment re
veals the morphine-induced locomotor sensitization. This most probably occu
rs by overcoming the tolerance towards the acute morphine-induced increase
of cerebral NA turnover and release. It is suggested that in mice the cereb
ral noradrenergic in addition to the dopaminergic systems are major determi
nants of the behavioural sensitization to morphine.