Alteration in Regulation of Serotonin Release in Rat Dorsal Raphe Nucleus after Prolonged Exposure to Morphine 1 RUI TAO, ZHIYUAN MA and SIDNEY B. AUERBACH Department of Biological Sciences, Rutgers University, Piscataway, New Jersey Accepted for publication March 30, 1998 This paper is available online at http://www.jpet.org ABSTRACT Regulation of serotonin (5-HT) release may be altered during the development of opioid tolerance and dependency. To test this hypothesis, changes in extracellular 5-HT during prolonged administration of morphine were determined by microdialysis in the dorsal raphe nucleus (DRN) of freely behaving rats. Mor- phine or placebo pellets were implanted s.c. As compared to placebo, morphine pellets induced a sustained, 50% increase in DRN 5-HT and a significant elevation in hot plate latency during the 12-hr period after implantation. One week later DRN 5-HT had returned to control levels, and implanting additional morphine pellets had no effect on 5-HT or hot plate latency. One day after removing the pellets from rats exposed to mor- phine for 2 wk, acute challenge with morphine (20 mg/kg, s.c.) had a significantly smaller effect on 5-HT in the DRN as com- pared to the placebo treatment group. Administration of nal- trexone to rats implanted with morphine pellets for 2 wk in- duced signs of withdrawal and a significant decrease in DRN 5-HT. These results suggest that the regulation of 5-HT release is altered during the development of tolerance to morphine. Thus, DRN 5-HT may be one of the factors involved in the changes in physiology and behavioral state during opioid with- drawal. Some evidence suggests that a change in serotonergic neu- rotransmission is involved in opioid tolerance and depen- dency. Acute systemic administration of morphine enhanced 5-HT turnover in the mammalian CNS, but the increase in turnover was attenuated after prolonged opiate treatment and tissue levels of 5-HT were decreased during withdrawal (Yarbrough et al., 1973). Opioids do not directly stimulate serotonergic neuronal discharge (Auerbach et al., 1985; Chiang and Pan, 1985; Jolas and Aghajanian, 1997). Instead, similar to the indirect excitatory effect on dopaminergic cells (Johnson and North, 1992) opioids may disinhibit serotoner- gic neuronal activity. In support of this hypothesis, opioids suppressed GABA-mediated inhibitory postsynaptic currents recorded in vitro from serotonergic neurons in the rat DRN (Jolas and Aghajanian, 1997). Although, excitatory postsyn- aptic currents were similarly suppressed by opioids in vitro (Jolas and Aghajanian, 1997), GABA appears to be the pre- dominate tonic influence on serotonergic neurons in the rat DRN in vivo (Tao and Auerbach, 1994; Tao et al., 1997). Thus, the net short term effect of morphine may be an in- crease in 5-HT release in widespread areas of the forebrain (Tao and Auerbach, 1994, 1995). After prolonged administration of opioids, inhibitory influ- ences on monoaminergic neurons may be up-regulated. This hypothesis is suggested by the increase in GABA-mediated inhibition of dopaminergic neurons in the ventral tegmental nucleus during withdrawal from morphine (Bonci and Wil- liams, 1997). Similarly, after prolonged treatment with mor- phine, single neurons recorded in the ventrolateral PAG showed signs of adaptation (Chieng and Christie, 1996). Thus, there was a reduction in the direct inhibitory effect of opioids on PAG neurons in slices prepared from morphine- dependent rats. Conversely, naloxone-precipitated with- drawal was associated with increased neuronal discharge. There is no conclusive evidence that this subpopulation of opioid-sensitive PAG neurons is GABAergic or makes synap- tic contact with serotonergic neurons. Nevertheless, these results are consistent with the possibility that that GABA release in the adjacent DRN increases during withdrawal from morphine, which in turn could result in decreased se- rotonergic neuronal activity. Because 5-HT may be involved in adaptation to stress and drug addiction, it is of interest to determine if prolonged exposure to opioids alters serotonergic neuronal activity. However, earlier turnover and electrophysiological studies have provided conflicting evidence concerning this issue (re- viewed by Redmond and Krystal, 1984). To test the specific Received for publication November 28, 1997. 1 This work was supported by Grant RO1 MH51080A from the National Institutes of Health. ABBREVIATIONS: 5-HT, serotonin (5-hydroxytryptamine); 5-HIAA, 5-hydroxyindoleacetic acid; GABA, -aminobutyric acid; DRN, dorsal raphe nucleus; MRN, median raphe nucleus; aCSF, artificial cerebrospinal fluid; MPE, maximum possible effect; PAG, periaqueductal gray; CNS, central nervous system. 0022-3565/98/2861-0481$03.00/0 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 286, No. 1 Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics Printed in U.S.A. JPET 286:481–488, 1998 481 at ASPET Journals on November 7, 2016 jpet.aspetjournals.org Downloaded from