Abstract
The effects of morphine withdrawal and challenge on the a-methyl-p-tyrosine (αMT)-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The αMT induced DA depletion was retarded in mice withdrawn for 1 day from repeated morphine.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 In mice withdrawn for 3 days from morphine neither DA depletion nor DOPAC or HVA concentrations differed from those of control mice.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 In mice withdrawn from repeated morphine for 1 day acute morphine partially counteracted the withdrawal-induced retardation of DA depletion and elevated striatal DOPAC and HVA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 However, in mice withdrawn for 3 days 10 mg/kg of morphine clearly enhanced DA depletion and its effect on striatal HVA was significantly augmented.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not alter striatal 3-methoxytyramine (3-MT) concentration in control mice but at the dose 10 mg/kg increased it in mice withdrawn for 3 days. Morphine withdrawal did not significantly affect striatal 3H-SCH 23390 binding, but slightly decreased 3H-spiperone binding in mice withdrawn for 3 days indicating a down-regulation of D2 receptors.
Our results by using three different indices of DA release (DA depletion after aMT, HVA and 3-MT) show that long enough withdrawal from repeated morphine treatment augments the morphine-induced release of striatal DA in mice. We propose that the striatal DA release in mice is regulated by two opposite opioid sensitive mechanisms with different dose-dependencies and different tolerance development.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Acquas E, Di Chiara G (1992) Depression of mesolimbic dopamine transmission and sensitization to morphine during opiate withdrawal. J Neurochem 58:1620–1625
Acquas E, Carboni E, Di Chiara G (1991) Profound depression of mesolimbic dopamine release after morphine withdrawal in dependent rats. Eur J Pharmacol 193:133–134
Ahtee L (1973) Catalepsy and stereotyped behaviour in rats treated chronically with methadone: relation to brain homovanillic acid content. J Pharm Pharmacol 25:649–651
Ahtee L (1974) Catalepsy and stereotypies in rats treated with methadone; relation to striatal dopamine. Eur J Pharmacol 27:221–230
Ahtee L (1978) Effects of drugs affecting extrapyramidal motor functions on catalepsy and stereotypies induced by narcotic analgesics. In: Adler ML, Manara L, Samanin R (eds) Factors affecting the action of narcotics. Raven Press, New York, pp 479–494
Ahtee L, Attila P, Lauhakangas V, Solkinen A, Sipilä J (1987) 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. J Neural Transmission 68:63–78
Ahtee L, Attila LMJ, Carlson KR, Haikala H (1989) Changes in brain monoamine metabolism during withdrawal from chronic oral self-administration of morphine and in response to a morphine challenge dose in the withdrawn state. J Pharmacol Exp Ther 249: 303–310
Ahtee L, Attila LMJ, Carlson KR (1990) Augmentation of morphine-induced changes in brain monoamine metabolism after chronic naltrexone treatment. J Pharmacol Exp Ther 255:803–808
Attila LMJ, Ahtee L (1983) Cerebral dopamine and noradrenaline turnover and effects of morphine test dose in rats withdrawn from 20 days' morphine treatment. Med Biol 61:249–257
Attila LMJ, Ahtee L (1984) Retardation of cerebral dopamine turnover after morphine withdrawal and its enhanced acceleration by acute morphine administration in rats. Naunyn-Schmiedeberg's Arch Pharmacol 327:201–207
Attila LMJ, Etemadzadeh E, Ahtee L (1987) Differences in the effects of morphine on the a-methyl-p-tyrosine-induced depletion of dopamine and noradrenaline in various areas of the mouse brain. Pharmacol Toxicol 61:26–32
Babbini M, Davis WM (1972) Time-dose relationships for locomotor activity effects of morphine after acute or repeated treatment. Br J Pharmacol 46:213–224
Bailey JL (1967) Techniques in protein chemistry, 2nd edn. Elsevier, New York
Bhargava HN (1983) Binding of 3H-spiroperidol to striatal membranes of rats treated chronically with morphine. Neuropharmacol 22:1357–1361
Bhargava HN, Gulati A (1990) Modification of brain and spinal cord dopamine D1 receptors labeled with 3H-SCH 23390 after morphine withdrawal from tolerant and physically dependent rats. J Pharmacol Exp Ther 252:901–907
Brase DA, Loh HH, Way EL (1977) Comparison of the effects of morphine on locomotor activity, analgesia and primary and protracted physical dependence in six mouse strains. J Pharmacol Exp Ther 201:368–374
Brodie BB, Costa C, Dlabac A, Neff NH, Smookler HH (1966) Application of steady state kinetics to the estimation of synthesis rate and turnover time of tissue catecholamines. J Pharmacol Exp Ther 154:493–498
Broekkamp CLE, Phillips AG, Cools AR (1979) Stimulant effects of enkephalin microinjection into the dopaminergic A10 area. Nature 278:560–562
Brunello N, Volterra A, Di Giulio AM, Cuomo V, Racagni G (1984) Modulation of opioid system in C57 mice after repeated treatment with morphine and naloxone: Biochemical and behavioral correlates. Life Sci 34:1669–1678
Carlson KR, Cooper DO (1985) Morphine dependence and protracted abstinence: Regional alterations in CNS radioligand binding. Pharmacol Biochem Behav 23:1059–1063
Carroll BJ, Sharp PT (1972) Monoamine mediation of the morphine-induced activation in mice. Br J Pharmacol 46:124–139
Christie MJ, Overstreet DH (1979) Sensitivity of morphine tolerant rats to muscarinic and dopaminergic agonists: Relation to tolerance or withdrawal. Psychopharmacology 65:27–34
Clouet DH, Ratner M (1970) Catecholamine biosynthesis in brains of rats treated with morphine. Science 168:854–855
De la Baume S, Patey G, Marçais H, Protais P, Costentin J, Schwartz J-C (1979) Changes in dopamine receptors in mouse striatum following morphine treatments. Life Sci 24:2333–2342
Fernandes M, Kluve S, Coper H (1977) Quantitative assessment of tolerance to and dependence on morphine in mice. Naunyn-Schmiedeberg's Arch Pharmacol 297:53–60
Fog R (1970) Behavioural effects in rats of morphine and amphetamine and of combination of the two drugs. Psychopharmacology 16:305–312
Haikala H (1987) Use of a novel type of rotating disc electrode and a flow cell with laminar flow pattern for the electrochemical detection of biogenic monoamines and their metabolites after Sephadex gel chromatographic purification and high-performance liquid chromatographic isolation from rat brain. J Neurochem 49:1033–1041
Havemann U, Kuschinsky K (1982) Neurochemical aspects of the opioid-induced ‘catatonia’. Neurochem Int 4:199–215
Joyce EM, Iversen SD (1979) The effect of morphine applied locally to mesencephalic dopamine cell bodies on spontaneous motor activity in the rat. Neurosci Lett 14:207–212
Kalivas PW Duffy P (1987) Sensitization to repeated morphine injection in the rat: Possible involvement of A10 dopamine neurons. J Pharmacol Exp Ther 241:204–212
Kehr W (1976) 3-Methoxytyramine as an indicator of impulse-induced dopamine release in rat brain in vivo. Naunyn-Schmiedeberg's Arch Pharmacol 293:209–215
Kondo Y, Iwatsubo K (1980) Diminished responses of nigral dopaminergic neurons to haloperidol and morphine following lesions in the striatum. Brain Res 181:237–240
Maisonneuve IM, Keller RW Jr, Glick SD (1991) Interactions between ibogaine, a potential anti-addictive agent, and morphine: an in vivo microdialysis study. Eur J Pharmacol 199:35–42
Martin JR, Takemori AE (1986) Chronically administered morphine increases dopamine receptor sensitivity in mice. Eur J Pharmacol 121:221–229
Oliverio A, Castellano C, Puglisi-Allegra S (1983) Psychopharmacogenetics of opioids. Trends Pharmacol Sci 4: 350–352
Racagni G, Bruno F, Iuliani E, Paoletti R (1979) Differential sensitivity to morphine-induced analgesia and motor activity in two inbred strains of mice: Behavioral and biochemical correlations. J Pharmacol Exp Ther 209:111–116
Scatchard G (1949) The attractions of proteins for small molecules and ions. Ann NY Acad Sci 51:660–672
Spanagel R, Shippenberg TS (1993) Modulation of morphine-induced sensitization by endogenous kappa opioid systems in the rat. Neurosci Lett 53:232–236
Spanagel R, Herz A, Bals-Kubik R, Shippenberg TS (1991) β-Endorphin-induced locomotor stimulation and reinforcement are associated with an increase in dopamine release in the nucleus accumbens. Psychopharmacology 104:51–56
Stinus L, Koch GF, Ling N, Bloom FE, Le Moal M (1980) Locomotor activation induced by infusion of endorphins into the ventral tegmental area: Evidence for opiate-dopamine interactions. Proc Natl Acad Sci USA 77:2323–2327
Westerink BHC, Spaan SJ (1982a) Estimation of the turnover of 3-methoxytyramine in the rat striatum by HPLC with electrochemical detection: Implications for the sequence in the cerebral metabolism of dopamine. J Neurochem 38:342–347
Westerink BHC, Spaan SJ (1982b) On the significance of endogenous 3-methoxytyramine for the effects of centrally acting drugs on dopamine release in the rat brain. J Neurochem 38: 680–686
Wood PL (1993) Interrelationships of opioid, dopaminergic, cholinergic, and GABAergic pathways in the central nervous system. In: Herz A (ed) Handbook of experimental pharmacology, vol 104/I; Opioids I. Springer, Berlin Heidelberg, pp 624–643
Author information
Authors and Affiliations
Additional information
Correspondence to: L. Ahtee at the above address
Rights and permissions
About this article
Cite this article
Airio, J., Attila, M., Leikola-Pelho, T. et al. Withdrawal from repeated morphine sensitises mice to the striatal dopamine release enhancing effect of acute morphine. Naunyn-Schmiedeberg's Arch Pharmacol 350, 548–554 (1994). https://doi.org/10.1007/BF00173025
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00173025