Vol. 273, No. 1 Printed in USA. ABSTRACT 327 0022-3565/95/2731-0327$03.OO/O ‘FitE Jousru. OF PHARMACOLOGY um Expiw.tneru. Taapnrrics Copyright C 1995 by The American Society for Pharmacology and Experimental Therapeutics .JPET 273:327-336, 1995 Behavioral and Neurochemical Effects of Opiolds in the Paramedian Midbrain Tegmentum Including the Median Raphe Nucleus and Ventral Tegmental Area1 MARK A. KLITENICK2 and DAVID WIRTSHAFTER Department of Psychology, University of Illinois at Chicago, Chicago, Illinois Accepted for publication December 13, 1994 Injections of morphine into the median raphe nucleus (MA) of rats produced a dose-dependent, naloxone sensitive increase in locomotor activity. Dose-dependent increases in activity also could be produced by intra-MR injections of the mu-opioid agonist Tyr-D-Ala-Giy-MePhe-Gly(oi)-enkephalin (DAMGO) and the delta-opioid agonist D-Pen2,D-Pen5-enkephalin (DPDPE), but not by the kappa-opioid agonist Dynorphin A (1-1 3). Map- ping studies demonstrated that DPDPE produced larger re- sponses when injected into the MR than into a number of adjacent structures, whereas the effective zone for obtaining responses with DAMGO appeared to extend forward into the caudal portion of the ventral tegmental area. The induction of hyperactivity by DPDPE and DAMGO was unaltered in animals with large depletions of forebrain serotonin produced by injec- tions of 5,7-dihydroxytryptamine, suggesting that these effects were not mediated through serotonergic mechanisms. Post- mortem assays indicated that serotonin turnover in the hip- pocampus was reduced slightly after intra-MR injections of DPDPE, but no effects were observed after injections of DAMGO or Dynorphin A (1-13). Injections of either DPDPE or DAMGO into the MA resulted in a large increase in dopamine turnover in the nucleus accumbens. Finally, intra-MA injections of DAMGO or Dynorphin A(1-13), but not DPDPE, stimulated ingestive behavior in nondepnved animals, although the effects were substantially smaller than those seen after injections of muscimol. These results demonstrate that pronounced behav- ioral and neurochemical effects can be produced by stimulation of opioid receptors within the MA and that the pattern of these effects depends upon which opioid receptor subtype is stimu- lated. Many studies have demonstrated that marked behavioral effects can be produced by manipulations of the MR. Electro- lytic or excitotoxic lesions of the MR have been shown to produce dramatic increases in locomotor activity (Jacobs et at., 1974; Geyer et at., 1976; Lorens, 1978; Asin et at., 1979; Wirtshafter and Asin, 1982; Asin and Fibiger, 1983), ar’1 similar effects have been observed after intra-MR microin- jections of the inhibitory GABAA agonist muscimol (Sainati and Lorens, 1982; Klitenick et at. , 1985; Wirtshafter et at., 1987, 1988; Wirtshafter and Trifunovic, 1992). Intra-MR in- jections of GABA agonists also result in large increases in food and water intake by nondeprived animals (Klitenick and Received for publication May 3, 1994. 1 This research was supported in part by National Institutes of Health Grant NS21359 (D. W.) and a National Research Service Award DA-05391 (M. A. K). 2 Present address: Department of Psychiatry, Division of Neurological Sci- ences, University ofBritish Columbia, 2255 Wesbrook Mall, Vancouver, B.C., V6T lZ3, Canada. Wirtshafter, 1986, 1988, 1989). Injections of muscimol into the MR result in much larger effects on both locomotor ac- tivity and ingestive behavior than do injections into sur- rounding structures such as the DR, the VTA or the CMR (Sainati and Lorens, 1982; Paris and Lorens, 1987; Klitenick and Wirtshafte , 1988; Wirtshafter and Klitenick, 1989), sug- gesting that these behavioral effects indeed result from an action of muscimol in the MR, or its immediate vicinity, rather than through diffusion of the a ug to a distant site. Although intra-MR injections of muscimol have been shown to reduce hippocampal 5-HT turnover (Forchetti and Meek, 1981; Nishikawa and Scatton, 1985a,b; Wirtshafter et at., 1986), neither the hyperactivity nor the increases in inges- tive behavior produced by intra-MR muscimol injections ap- pear to be mediated entirely through serotonergic mecha- nisms (Paris and Lorens, 1987; Wirtshafter et at., 1987; Wirtshafter and Trifunovic, 1992). Although a substantial number of studies have now exam- ABBREViATiONS: MA, median raphe nucleus; GABA, r-aminobutyric acid; DA, dorsal raphe nucleus; VIA, ventral tegmental area;CMA, pontine region lying caudal to the MA; 5-HT, 5-hydroxytryptamine (serotonin); DAMGO, Tyr-D-Ala-Gly-MePhe-Gly(ol)-enkephalin; DPDPE, D-Pen2,D-Pen5- enkephalin; DYN, Dynorphin A (1-13); DA, dopamine; RVTA, rostral VIA; CVTA, caudal VTA; 5,7-DHT, 5,7-dihydroxytryptamine; HPLC, high- performance liquid chromatography; DOPAC, dihydroxyindolacetic acid; 5-HIM, 5-hydroxyindolacetic acid; HVA, homovanillic acid; ANOVA, analysis of variance; 8-OH-DPAT, 8-hydroxy-2-(di-n-propylamino)tetralin hydrobromide. at Univ of Illinois at Chicago Library on March 6, 2011 jpet.aspetjournals.org Downloaded from