Retardation of cerebral dopamine turnover after morphine withdrawal and its enhanced acceleration by acute morphine administration in rats

Abstract

To clarify the effects of withdrawal from chronic morphine treatment on cerebral dopamine (DA) turnover, we have measured the alpha-methyl-p-tyrosine (alpha MT)-induced depletion of DA in five brain areas of male Wistar rats given morphine twice daily for 40 or 60 days. After the last morphine dose (50 or 70 mg/kg) the rats were withdrawn for 1, 2 or 4 days. In order to study the development of tolerance some of the rats were challenged with 10 mg/kg of morphine. Withdrawal of morphine retarded the alpha MT-induced DA depletion in the limbic forebrain and after long enough chronic treatment in the striatum, too. The challenge dose of morphine accelerated the cerebral DA depletion slightly less in rats withdrawn for 1 day from 60-day chronic morphine treatment than in rats treated chronically with saline, but it enhanced the DA depletion more in rats withdrawn from morphine for 2 and 4 days than in chronic saline rats. This enhancement was clearest in rats withdrawn for 4 days from 60-day treatment. Thus withdrawal from morphine seems to sensitize the rats to the DA depletion accelerating effect of morphine. Our results show that repeated administration of morphine creates no marked tolerance to the DA depletion accelerating effect of morphine. In contrast, the dopaminergic neurones of the chronically treated rats seem to depend on continuous morphine administration for their normal functioning. Furthermore, the retarded DA turnover after discontinuation of morphine treatment seems to sensitize the dopaminergic neurones to the DA depletion accelerating effect of morphine.(ABSTRACT TRUNCATED AT 250 WORDS)

The fall of homovanillic acid and 5-hydroxyindoleacetic acid concentrations in brains of mice withdrawn from repeated morphine treatment and their restoration by acute morphine administration

“…Indeed, in several experiments it was found that chronic morphine treatment induces tolerance to the DA turnover enhancing effect of morphine (Fukui and Takagi, 1972;Smith et aL, 1972;De Simoni et aL, 1982). In contrast, we found that the DA depletion accelerating effect of morphine was even enhanced in rats withdrawn from 60-day morphine treatment (Attila and Ahtee, 1984), and a challenge dose of morphine clearly increased the cerebral 5-HIAA concentration in rats withdrawn from 8-week morphine treatment .…”

“…We earlier suggested Ahtee and Attila, 1980;Ahtee, 1983 and1984) that likely causes for reduced cerebral turnover of 5-HT and DA in rats on withdrawal from morphine are tolerant opiate receptors (Tseng et al, 1977) and reduced concentrations of endogenous opioid ligands (Przewtocki et al, 1979;Bergstr6m and Terenius, 1979). Opiate receptors could become tolerant before the endogenous opioid concentrations decrease but after the endogenous opioid concentrations decrease the receptors might regain their sensitivity at least partially.…”

“…There is evidence indicating that chronic opioid treatment attenuates the activity of the cerebral dopaminergic and 5-HTergic neurons in rats (Ahtee, 1973(Ahtee, , 1974Ahtee, 1983 and1984), although acute administration of morphine and related drugs increases the turnover of cerebral dopamine (DA) and 5-hydroxytryptamine (5-HT), and naloxone antagonizes these effects in rats (Garcia-Sevilla et aL, 1978;Ahtee and Carlsson, 1979). The attenuated activity of central dopaminergic neurons during opioid withdrawal does not fit together with the evidence indicating that DA is involved in the behaviourally reinforcing effects of opioids (Schwartz and Marchok, 1974).…”

Characterization of the decrease of extracellular striatal dopamine induced by intrastriatal morphine administration

“…The stereotypies induced by morphine and other m-opioids in rats treated repeatedly with opioids have been linked to the activation of the striatal dopaminergic system (Morelli et al, 1989). Indeed, we have shown that the e ect of morphine on striatal DA transmission is augmented during withdrawal from chronic morphine treatment (Ahtee et al, 1989;Attila & Ahtee, 1984;Honkanen et al, 1994). Therefore, we investigated whether tolerance develops to the inhibitory component of morphine on striatal DA release, which in turn might contribute to the sensitization of DA release in the withdrawal from repeated opioid treatment.…”

“…This sensitization is more apparent in the mesolimbic dopaminergic system (for a review see Kalivas & Stewart, 1991), but the nigrostriatal system also sensitizes during repeated morphine treatment. Thus, during withdrawal from repeated morphine administration, acute challenge with morphine increases the release of DA considerably more than in naõÈ ve animals (Ahtee, 1974;Attila & Ahtee, 1984;Honkanen et al, 1994). Also behavioural e ects of opioids linked to the activation of the nigrostriatal dopaminergic system undergo sensitization during repeated morphine administration (Ahtee, 1974;Babbini & Davis, 1972).…”