Withdrawal from repeated morphine sensitises mice to the striatal dopamine release enhancing effect of acute morphine

Abstract

The effects of morphine withdrawal and challenge on the alpha-methyl-rho-tyrosine (alpha MT)-induced depletion of dopamine (DA) as well as on DA metabolism and 3H-SCH 23390 and 3H-spiperone binding were studied in the striata of male mice. Morphine was given s.c. 3 times daily for 5 days followed by 1 to 3 days' withdrawal. The alpha MT-induced DA depletion was retarded in mice withdrawn for 1 day from repeated morphine. At this time point the striatal concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) fell, too. In mice withdrawn for 3 days from morphine neither DA depletion nor DOPAC or HVA concentrations differed from those of control mice. In control mice acute morphine challenge accelerated the DA depletion at the dose 10 mg/kg but not at the dose 30 mg/kg. Both doses elevated striatal DOPAC and HVA. In mice withdrawn from repeated morphine for 1 day acute morphine partially counteracted the withdrawal-induced retardation of DA depletion and elevated striatal DOPAC and HVA clearly less than in control mice. However, in mice withdrawn for 3 days 10 mg/kg of morphine clearly enhanced DA depletion and its effect on striatal HVA was significantly augmented. In these mice as in controls the 30 mg/kg dose did not alter striatal DA depletion and elevated HVA less than in controls. Acute morphine did not alter striatal 3-methoxytyramine (3-MT) concentration in control mice but at the dose 10 mg/kg increased it in mice withdrawn for 3 days.(ABSTRACT TRUNCATED AT 250 WORDS)

The involvement of noradrenergic transmission in the morphine‐induced locomotor hyperactivity in mice withdrawn from repeated morphine treatment

“…All in all our results suggest that in our control mice acute morphine increases the functional utilization of DA; and the morphine‐induced changes of HVA, DOPAC and 3‐MT concentrations in the striata we found in morphine‐withdrawn mice can be interpreted as an enhanced turnover and release of DA (see Introduction). Thus, as in our earlier studies ( Airio et al ., 1994 ; Airio & Ahtee, 1997 ), mice were sensitized to the acute morphine‐induced increase of striatal DA turnover and release after 5 day repeated morphine treatment followed by 3 day withdrawal.…”

“…In mice 1 day withdrawal from repeated morphine treatment induces modest regional changes of the NA turnover in the forebrain area and the lower brain stem but not in the hypothalamus ( Airio et al ., 1995 ) while after longer withdrawal periods the α‐methyl‐ p ‐tyrosine‐induced depletion of cerebral NA or the cortical MOPEG concentration are not altered ( Etemadzadeh, 1993 ; Funada et al ., 1993 ; Airio & Ahtee, 1997 ). Furthermore, the striatal DA metabolism and turnover are weakened in mice after 1 day but no longer after 3 day withdrawal from repeated morphine treatment ( Ahtee et al ., 1987 ; Airio et al ., 1994 ; Airio & Ahtee, 1997 ). In agreement with our earlier findings in the present experiments the cerebral NA or free MOPEG concentrations were not altered in any brain area of mice withdrawn for 3 days from the repeated morphine treatment.…”

“…Furthermore, acute morphine decreased the striatal 3‐MT concentration in the control mice, but not in the morphine‐withdrawn mice. Although the main effect of systemic morphine on cerebral DA in mice is to increase DA synthesis and turnover ( Ahtee et al ., 1987 ; Attila et al ., 1987 ; Etemadzadeh, 1993 ; Airio et al ., 1994 ; Funada et al ., 1994 ), acute morphine administration has been reported to decrease the striatal 3‐MT concentration in certain mouse strains including NMRI mice ( Racagni et al ., 1979 ; Airio and Ahtee, 1997 ). Further, using in vivo microdialysis it has been shown in rats that morphine when given locally inhibits the release of striatal DA ( Rossetti et al ., 1990 ; Piepponen et al ., 1995 ).…”

“…The coupling between morphine‐induced changes in locomotor activity and in cerebral NA and DA metabolism suggests that the morphine‐induced sensitization of locomotor activity is expressed in mice only when they are sensitized to the striatal DA turnover and release increasing effect of acute morphine and when morphine increases the NA turnover and release. As the morphine‐induced changes in striatal DA metabolism are similar in mice and rats ( Ahtee et al ., 1987 ; Attila et al ., 1987 ; Airio et al ., 1994 ; Airio & Ahtee, 1997 ) it is suggested that, as in rats, the sensitization of morphine‐induced locomotor hyperactivity in morphine‐withdrawn mice is brought about by hyperactive dopaminergic systems. However, in the withdrawn mice this effect can be masked by tolerance of their cerebral noradrenergic systems.…”

“…In rats on withdrawal from opioids acute opioid challenge accelerates striatal and limbic dopamine (DA) turnover and release more than in naïve controls ( Clouet & Ratner, 1970 ; Ahtee, 1973 ; Attila & Ahtee, 1983 ; 1984 ; Acquas & DiChiara, 1992 ; Ahtee et al ., 1989 ; 1990 ). Similar sensitization to morphine‐induced increase of striatal DA turnover and release during withdrawal has been found in mice ( Ahtee et al ., 1987 ; Airio et al ., 1994 ; Airio & Ahtee, 1997 ).…”