Brain Research, 583 (1992) 127-136 © 1992 Elsevier Science Publishers B.V. All rights reserved 0006-8993/92/$05.00 BRES 17859 The effects of lesions of the habenular nuclei on the development of sensitization to the behavioral activational effects of repeatedly administered morphine in the rat D. Funk and J. Stewart Centerfor Studies in Behauioral Neurobiology, Departmentof PsychoLogy, Concordia University, Montreal, Que. (Canada) (Accepted 4 February 1992) Key words: Habenular nucleus; Morphine; Sensitization; Dopamine; Locomotor activity; Stereotyped behavior; Rat 127 The effects of lesions of the habenular nuclei on the development of sensitization to the behavioral activational effects of morphine (MOR), administered repeatedly either systemically or directly into the ventral tegmental area (VTA) were examined. Lesions of the habenular nuclei blocked the early-appearing sedative effects and enhanced the later-appearing locomotor activational effects seen after systemic injections of MOR (10 mgy'kg, i.p.), Habenular lesions did not potentiate the development of sensitization to the locomotor-activational effects seen with the repeated, systemic administration of MOR. The bilateral injection of MOR (5.0 JLg/O.5 JLlfside) directly into the VTA of animals with habenular lesions resulted in the performance of stereotyped behaviors that appeared as early as the second MOR exposure and remained at high levels with repeated MOR treatment. The stereotyped behavior shown by lesioned animals did not appear to interfere with the acute locomotor activational effects of intra-VTA MOR nor the development of sensitization to these effects when it was administered repeatedly. These results are in agreement with previous research suggesting that by disinhibiting the dopamine (DA) systems, habenular lesions enhance the acute behavioral activational effects of MOR. The results also suggest that the habenular nuclei do not control the changes in the response of the DA systems underlying the development of sensitization to the locomotor-activating effects of MOR when administered repeatedly. INTRODUCTION In the rat, the behavioral activational effects of morphine (MOR) have been shown to sensitize with repeated administration", MOR increases locomotor activity, at least in part, by activating the mesolimbic dopamine (DA) system through indirect actions on the cell bodies of DAergic neurons located in the ventral tegmental area (VTA)5,9,10,21,24. In keeping with this, injections of MOR directly into the VTA elicit large increases in locomotor activity17. When MOR is ad- ministered repeatedly and intermittently, either sys- temically or directly into the VTA, this locomotor activation sensitizes, or becomes more pro- nounced 1 8,45,46. This phenomenon is accompanied by an increase in the ability of MOR to stimulate the mesolimbic DA system. The mechanisms whereby the repeated administration of MOR come to elicit this sensitized response is not known!", The mesolimbic DA system can influence neural substrates underlying locomotor activity and motivated behavior through its projections to the nucleus accum- bens (NAcc) and caudate-putamen (CPU)26,48. The DA systems, in turn, receive regulatory inputs from several regions of the brain. One such area, the lateral habe- nular nucleus (LHb) of the epithalamus, has been shown to exert an inhibitory influence on the activity of the DA systems. With this in mind, it was hypothesized that the LHb might participate in the regulation of the sensitized response of the DA systems seen when MOR is administered repeatedly. The LHb and the medial habenula are key links in the proposed dorsal diencephalicconduction system, a descending pathway that connects a number of fore- Correspondence: J. Stewart, Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, 1455 DeMaison- neuve Blvd. West, Montreal, Que., Canada H3G IM8. Fax: (1) (514) 848-2817.