The noradrenergic locus coeruleus (LC) plays a role in opioid dependence and withdrawal. In the present study, using a multiple-electrode recording technique that allowed several LC neurons to be recorded simultaneously over long time periods, LC neuronal activities were recorded before and after intracerebroventricular injection of morphine (26 nmol) under halothane anesthesia. We found that morphine did not simply decrease firing rates of LC neurons, as reported in earlier studies, but that

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... induced persistent oscillatory discharges in 49% (87 of 178) of the LC neurons recorded. Cross-correlation analysis revealed that almost all LC neurons (86 of 87) that exhibited oscillatory discharges were synchronized with at least one other neuron. When stated in terms of simultaneously recorded neuron pairs, 59% (292 of 492) of the oscillatory neuron pairs discharged synchronously. The morphine-induced synchronous oscillation began at ϳ10 min after morphine injection, reached its peak in ϳ20-30 min, persisted throughout the recording periods (up to 110 min after morphine injection, the longest recording time), and were reversed by an opioid receptor antagonist naltrexone. These data suggest that although the overall firing rate of LC neurons was reduced by morphine, the morphine-induced synchronous oscillatory activity may summate temporally and spatially at LC axon terminals and facilitate release of noradrenaline. Noradrenaline is an important neuromodulator and has been shown to induce and facilitate synaptic plasticity at LC target sites. We propose that the morphine-induced long-lasting synchronous oscillatory activity in the LC may be a neuronal signal that could induce synaptic plasticity leading to opioid addiction. The brain locus coeruleus (LC) is the largest cluster of noradrenergic neurons in the brain and projects broadly throughout the CNS (for review, see Foote et al., 1983) . The LC is enriched with opioid receptors (Temple and Zukin, 1987) and plays a role in several effects of opioids, such as opioid dependence and withdrawal (for review, see Nestler et al., 1994; Nestler and Aghajanian, 1997; . Systemic or intracoerulear administration of opioids, such as morphine, has been shown to have an inhibitory action on spontaneous LC neuronal activity (Korf et al., 1974; Bird and Kuhar, 1977; Aghajanian, 1978; Valentino and Wehby, 1988) . These earlier electrophysiological studies have focused on the effects of opioids on the activity of individual LC neurons. Several recent studies indicate that temporal relationships among the activities of LC neurons can also be modulated under certain circumstances. For example, synchronous membrane potential in the LC was found in explant tissue cultures or brain slices prepared from neonatal (Finlayson and Marshall, 1988; Christie et al., 1989; Christie and Jelinek, 1993) and adult rats (Travagli et al., 1995; Ishimatsu and Williams, 1996) . Synchronized LC firing was also observed in monkeys performing visual discrimination tasks (Usher et al., 1999) . The synchronous activities in the LC have been proposed to have important implications in development (trophic role) (Christie et al., 1989) and regulation of cognitive performance (Usher et al., 1999) . However, the effect of opioids on the temporal correlation between LC neurons has not been studied systemically in whole animals. In the present study, using a multiple-electrode recording technique that allowed several LC neurons to be recorded simultaneously over long time periods, we examined the effect of morphine, a classic opioid drug, on the temporal correlation between LC neurons. MATERIALS AND METHODS Surger y. All procedures were approved by the Institutional Animal C are and Use Committee at University of Mississippi Medical C enter. Adult male Sprague Dawley rats (250 -350 gm) were used in this study. A bundle of eight microwires (40 m / wire; N B Labs, Dennison, TX) was stereotaxically implanted into the LC under sodium pentobarbital (50 mg / kg, i.p.) anesthesia. A 21 gauge guide cannula was implanted into the lateral cerebral ventricle for drug injection. The microwire bundle and guide cannula were secured in place with four stainless steel screws