Peptides. Vol. 6, pp. 67-73, 1985. '~ AnkhoInternational Inc. Printed in the U.S.A. 0196-9781/85$3.00 + .00 Effects of Intracranial Serf-Stimulation on Brain Opioid Peptides ' ELLIOT A. STEIN Department of Biology, Marquette University, Mihcaukee, Received I June 1984 WI 53233 STEIN, E. A. L'(fects ~?" intracranial se!f-stimulation on brain opioid peptides. PEPTIDES 6(1) 67-73, 1985.--The neurochemical system(s) underlying brain stimulation reward (ICSS) has been investigated for many years. The catechol- amine hypothesis is currently most accepted with predominant emphasis on the role of dopamine. The present report examines the role of three opioid peptides--Methionine and Leucine Enkephalin (ME and LE) and/:3-Endorphin (B-E) in this behavior. Peptide levels from piutitary, hypothalamus and whole brain were determined by independent RIAs and analyzed according to treatment: low, moderate and high ICSS responders, sham controls, animals receiving nonspecific stimulation, and naloxone--with and without ICSS. Not only did naloxone reduce ICSS from high responders by 74%, it also was able to reduce peptide levels--most notably for ME and/3E in most regions. Additionally, the effects of ICSS on endorphin levels was found to be related to the rate category of responding. Since endorphins are known to interact with dopamine systems, it is therefore considered likely that the endogenous opioid peptides play an important role in ICSS either directly or indirectly via their influence on catecholamine systems. Beta-endorphin Leucine enkephalin Methionine enkephalin Brain stimulation reward Naloxone THE positive reinforcing effects of intracranial self- stimulation (ICSS) first reported by Olds and Milner [23] are believed by most investigators to result from activation of central nervous system pathways which are normally in- volved in signalling information regarding the reinforcing properties of various sensory stimuli. That is, food, water, sexual stimuli and perhaps the euphoric properties of a number of drugs of abuse are believed to activate many of the same pathways recruited by the electrical stimuli of ICSS [39,42]. Considerable research effort over the years has de- lineated a remarkable map of both pathways as well as nuclei which support this behavior [39]. In addition, the elucidation of the neural mechanisms involved in this behavior has also been addressed [39]. The neurochemical basis of ICSS, i.e., which neuro- transmitters and where along the putative reward pathways they are released, has also been intensely investigated. The catecholamine hypothesis, one of the first espoused, has dominated much of the current research in this area [11, 13, 34]. Early investigators pointed to the critical role of norepi- nephrine (NE) in this behavior, although many of the pharamcologic agents used in these studies were subse- quently found to alter dopamine (DA) transmission as well. Subsequent pharmacologic and anatomic studies have impli- cated DA as an important component in this system [42]. Other neurotransmitter systems have also been demon- strated to alter ICSS behavior [27]. None of these putative neurotransmitters, however, can account for all the experi- mental findings to date. Recently, the endogenous opioid peptides (EOP) have also been implicated in the mediation of reward behavior for 'Supported in part by grant DA 02234 to E.A.S. both natural rewards (i.e., food and water) [8] as well as artificial rewards (i.e., drugs of abuse and ICSS) [1,35]. For example, endogenous opioids have been implicated in play- ing a role in consummatory behavior since opiate receptor blockers like Naloxone and Naltrexone have repeatedly been demonstrated to inhibit both food [17,191 and water [8,19] intake in deprived animals. Additionally, Dum et al. [9] recently demonstrated changes in opiate receptor bind- ing and /3-Endorphin levels in hypothalamus after rats re- ceived a highly palatable food, suggesting a role for this neu- rochemical system somewhere in the reward process. Rats will also self-administer opiates and opioid peptides directly into a number of specific subcortical sites including lateral ventricles [1, 32, 37], ventral tegmentum [4], nucleus accum- bens septi [25] and lateral hypothalamus [26]. Opiates can also modify ICSS behavior as well. Morphine has been shown to exert a biphasic effect upon ICSS with initial depression followed by an enhancement (higher rates or lower thresholds) of the behavior [5, 10, 22]. However, studies with opiate antagonists have not yielded consistent results. Naloxone (Nx) has been reported to either not alter 114, 18, 29, 37, 40], mildly depress I2,331 or significantly re- duce [12, 35, 41] ICSS behavior. It is not clear at this time why this variability exists. Among the factors to explain this discrepancy is the variety of stimulation sites and tech- niques employed, with the possibility of activating different neuronal and neurochemical pathways. Recently, evidence has been presented indicating that as the work requirements for obtaining ICSS increase, so does the effectiveness of Nx to block the behavior [12,41]. To further address the issue of opioid involvement in ICSS, the present study investigated 67