EXTRANEURONAL NORADRENALINE IN THE PREFRONTAL CORTEX OF MORPHINE-DEPENDENT RATS - TOLERANCE AND WITHDRAWAL MECHANISMS

The changes in extracellular concentrations of noradrenaline (NA) in t he prefrontal cortex of morphine-dependent rats were studied by microd ialysis following an acute morphine challenge and during naloxone-prec ipitated withdrawal. Animals were implanted with morphine- or placebo- containing pellets for 5 days. In control rats a challenge dose of mor phine (5 mg/kg s.c.) induced a maximum decrease in NA output of about 45% of pre-drug levels. In contrast, morphine challenge had no effect on extraneuronal NA concentrations in morphine-implanted animals. In c ontrol animals, naloxone (2 mg/kg i.p.) produced no behavioral effect nor changed NA levels. However, in morphine-dependent animals naloxone suddenly increased extraneuronal NA by 175% of baseline dialysate lev els in the first sample after the injection and precipitated a morphin e-withdrawal symptomatology that paralleled the changes in NA output. Thus, chronic morphine treatment in rats results in the development of tolerance to the acute inhibitory effect of morphine on extraneuronal NA and is associated with a stimulation of prefrontocortical NA outpu t during naloxone-precipitated withdrawal.