REPEATED AND CHRONIC MORPHINE ADMINISTRATION CAUSES DIFFERENTIAL LONG-LASTING CHANGES IN DOPAMINERGIC NEUROTRANSMISSION IN RAT STRIATUM WITHOUT CHANGING ITS DELTA-OPIOID AND KAPPA-OPIOID RECEPTOR REGULATION

Repeated, once daily morphine treatment (14 days) as well as chronic m orphine administration (6 days) caused a rebound reduction in the elec trically evoked release of [H-3]dopamine from superfused rat striatal slices 1 day after the last subcutaneous injection. Interestingly, whe reas [3H]dopamine release remained significantly reduced for at least 3 weeks following morphine withdrawal in chronically treated (tolerant /dependent) rats, neurotransmitter release from dopaminergic nerve ter minals gradually increased above control values following cessation of repeated morphine administration. Postsynaptically, dopamine D-1 rece ptor-stimulated adenylate cyclase appeared to be sensitized 1-3 days b ut was unchanged 3 weeks after chronic morphine treatment. In contrast , such an enhanced postsynaptic dopamine D-1 receptor efficacy did not occur 1-3 days following repeated morphine administration, but appear ed to develop slowly resulting in a profound increase of dopamine-sens itive adenylate cyclase 3 weeks after the last injection. The inhibito ry effect of dynorphin A-(1-13) on [H-3]dopamine release, as well as t hat of [Met(5)]enkephalin on dopamine D-1 receptor-stimulated adenylat e cyclase appeared to be unchanged subsequent to repeated or chronic m orphine treatment. These data indicate that, long after cessation of d rug treatment, chronic morphine treatment causes a reduction whereas r epeated morphine administration gradually induces an enhancement of op ioid receptor-regulated dopaminergic neurotransmission due to local ad aptive changes within the rat striatum. Such distinct long-lasting alt erations of dopaminergic neurotransmission induced by different tempor al patterns of morphine administration in projection areas of mesencep halic dopaminergic neurons may be related to the enduring effects of d rug abuse such as behavioural sensitization and drug craving.