The involvement of noradrenergic transmission in the morphine-induced locomotor hyperactivity in mice withdrawn from repeated morphine treatment

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on morphine-induced changes in cerebral noradrenaline (NA) and striatal dopamine (DA) metabolism were studied in m ice withdrawn for 3 days from 5 day repeated morphine treatment.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(3-MT) were determined. 2 Acute morphine (10 mg kg(-1), s.c.) increased locomotor activity in contr ol and in morphine-withdrawn mice; idazoxan alone did not alter the activit y. Idazoxan pretreatment did not alter the locomotor hyperactivity induced by acute morphine in control mice but potentiated it in morphine-withdrawn mice. 3 Acute morphine elevated MOPEG less but increased DOPAC and HVA more clear ly in morphine-withdrawn mice than in controls, and decreased 3-MT only in controls.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 In withdrawn mice idazoxan counteracted the tolerance so that acute mo rphine elevated MOPEG in these mice to about similar level as in controls. 5 Idazoxan pretreatment abolished the HVA increasing effect of acute morphi ne both in control and withdrawn mice.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 Idazoxan did not alter morphine's effects on DOPAC or 3-MT conc entrations in withdrawn mice. 6 Our results show that in morphine-withdrawn mice idazoxan pretreatment re veals the morphine-induced locomotor sensitization.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.