Development Of Morphine Tolerance Dependence Research Articles

Modifications of striatal D2 dopaminergic postsynaptic sensitivity during development of morphine tolerance-dependence in mice

Alterations in the activity of striatal dopaminergic neurons have been implicated in the development of morphine tolerance-dependence in rodents. To further explore this possibility, we examined the activity of these neurons in mice exposed to morphine during 4 days (addiction group) and subsequently treated with naloxone (withdrawal group). The efficiency of opiate treatment was assessed behaviorally. Striatal dopaminergic activity was evaluated by measuring: a) the ratio between the amounts of L-3,4-dihydroxyphenylacetic acid (DOPAC), the main intraneuronal metabolite of dopamine (DA), and the neurotransmitter itself, as an index of presynaptic activity; and b) the number and affinity of D1 and D2 dopaminergic receptors, as well as the amount of their coupled second messenger, cyclic adenosine monophosphate (cAMP), as postsynaptic parameters. Spontaneous motor activity was decreased in chronically morphine-exposed mice. In these animals, the number of striatal D2 receptors also decreased, with no changes in their affinity, whereas the number and affinity of D1 receptors remained uncharged. This hyposensitivity of D2 receptors was paralleled by an increase in the amount of cAMP with a good statistical correlation between both parameters. Treatment with naloxone of morphine-exposed mice resulted in the typical jumping behavior indicative of opiate withdrawal. The differences in D2 receptors between placebo- and morphine-exposed mice disappeared after naloxone-induced opiate withdrawal, although this effect was due more to the inhibitory effect of naloxone on the density of these receptors in placebo-exposed mice rather than to a stimulatory effect in morphine-addicted mice. The morphine-induced increase in cAMP content also disappeared after naloxone treatment. No significant changes occured in the presynaptic activity in both states, as reflected by the absence of changes in the DOPAC/DA ratio. However, DA storage decreased after the induction of opiate withdrawal, which could be related to a repeated DA utilization during the naloxone-induced jumping behavior in morphine-addicted mice. In summary, our results provide neurochemical evidence of changes in striatal dopaminergic neurotransmission concomitant to the typical motor alterations produced during morohine tolerance-dependence. These changes were mainly produced at the postsynaptic level, by decreasing the number of D2 receptors and increasing the cAMP production, during the morphine addiction. These differences disappeared after the naloxone-induced morphine withdrawal, likely by an inhibitory effect of naloxone on D2 receptors in placebo-exposed mice. Moreover, a presynaptic effect could be suspected during the opiate withdrawal in view of the decrease in DA content observed in naloxone-treated morphine-exposed mice.