Pergamon PharmacologyBiochemistry and Behavior,Vol. 48, No. 4, pp. 1041-1045, 1994 Copyright©1994Elsevier Science Ltd Printed in the USA.All rightsreserved 0091-3057/94 $6.00 + .00 0091-3057(94)E0051-I BRIEF COMMUNICATION Electrical Stimulation of the Dorsal Raphe Nucleus as a Discriminative Stimulus: Generalization to ( +_)-DOI DAVID J. MOKLER, l MARK DIXON AND LYNDA STAMBAUGH Department of Pharmacology, University of New England, College of Osteopathic Medicine, Biddeford, ME 04005 Received 6 July 1993 MOKLER, D. J., M. DIXON AND L. STAMBAUGH. Electrical stimulation of the dorsal raphe nucleus as a discrimi- native stimulus: Generalization to (+)-DOI. PHARMACOL BIOCHEM BEHAV 48(4) 1041-1045, 1994.- Electrical stim- ulation of the dorsal raphe nucleus of Sprague-Dawley rats was used as the cue for discrimination using a taste aversion paradigm. Rats were trained to associate saccharin drinking during electrical stimulation of the dorsal raphe nucleus with LiC1 injection after the session as the aversive unconditioned stimulus. In sessions without stimulation, rats were allowed to consume saccharin and received a saline injection after the session. Suppression of saccharin consumption during electrical stimulation was learned within 12 trials. Rats trained in the reverse discrimination, i.e., sessions with no electrical stimulation paired with LiC1 injection, showed a similar learning curve. Animals injected prior to the session with the hallucinogenic 5-HT2 agonist ( + )-DOI associated DOI with electrical stimulation of the dorsal raphe nucleus. Thus, animals may be trained to discriminate electrical stimulation of the dorsal raphe nucleus. Furthermore, animals generalize from activation of 5-HT2 receptors to electrical stimulation of the dorsal raphe nucleus. Electrical stimulation Dorsal raphe nucleus DOI 5-HT2 agonist Discrimination Rats 5-Hydroxytryptamine CURRENT hypotheses for the actions of indolealkylamine and phenylalkylamine hallucinogens suggest an interaction with 5-hydroxytryptamine (5-HT) systems of the brain. Data supporting this hypothesis are a) binding of hallucinogenic drugs to 5-HT receptors particularly the 5-HT 2 subtype (14, 17,22,28,33), and b) antagonism of the behavioral effects of these hallucinogenic drugs with antagonists such as ketanserin and pirenpirone which are selective for the 5-HT 2 receptors (16,26,27,32,33,40). The dorsal raphe nucleus of the midbrain is one of the major nuclei of 5-hydroxytryptamine (5-HT) cells that project to the forebrain. Electrical stimulation of the dorsal raphe nucleus (DRN) activates ascending 5-hydroxytryptamine (5- HT) neurons. This stimulation has been shown to increase the tissue levels of the 5-HT metabolite 5-HIAA (1,20), increase the turnover of 5-HT in forebrain regions (9,35,37), and in- crease the levels of extracellular 5-HT as determined by in vivo microdialysis (36). Animals can be trained to discriminate electrical stimula- tion of the DRN. Using a classical operant drug discrimination paradigm, Hirschhorn et al. (18) trained rats to discriminate nonaversive stimulation of the DRN. Animals were trained to a stimulus of 200-300 #A biphasic stimulation. After learning this discrimination, rats were tested for generalization to LSD or morphine. Rats generalized from the hallucinogen LSD (100 #g/kg) to electrical stimulation of the DRN. The purpose of this investigation was to further examine the discrimination of DRN stimulation and to extend these results to the 5-HT 2 agonist DOI. DOI is an agonist at 5-HT 2 receptor (2,8,10,12,13,22,31,40,41). DOI binds to 5-HT2A and 5-HT2c receptors in the forebrain, produces behavioral effects that are blocked by the 5-HT2A antagonist ketanserin, and To whom requests for reprints should be addressed. 1041