Ž . Brain Research 854 2000 85–92 www.elsevier.comrlocaterbres Research report Microinjections of an opiate receptor antagonist into the bed nucleus of the stria terminalis suppress heroin self-administration in dependent rats John R. Walker ) ,1 , Serge H. Ahmed 1 , K. Noelle Gracy, George F. Koob DiÕision of Psychopharmacology, Department of Neuropharmacology, The Scripps Research Institute, 10550 North Torrey Pines Road, CVN-7 La Jolla, CA 92037 USA Accepted 26 October 1999 Abstract Recent anatomical evidence suggests that the shell of the nucleus accumbens, the bed nucleus of the stria terminalis, and the central nucleus of the amygdala, together referred to as the extended amygdala, may play a role in opiate dependence. The bed nucleus of the stria terminalis and the shell of the nucleus accumbens have a moderately high density of opiate receptors, which allows for manipulation of opiate neurotransmission with receptor antagonists. The goal of this study was to determine the role these regions play in opiate reinforcement, and whether dependence alters the reinforcing effects of opiates by examining the effect of local administration of the opiate receptor antagonist methylnaloxonium on heroin self-administration in dependent and nondependent rats. Previous studies revealed that blockade of the reinforcing effects of opiates with systemic administration of opiate receptor antagonists results in an increase in heroin self-administration in nondependent rats, and a greater increase in dependent rats. In the present study, methylnaloxonium dose-dependently suppressed heroin intake when injected into the bed nucleus of the stria terminalis and shell of the nucleus accumbens of dependent rats, and had no effect in nondependent rats. These results demonstrate that opiate receptors in parts of the extended amygdala may be responsible for the reinforcing effects of opiates in dependent animals and suggest that activity in this system may be recruited during the development of dependence. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Bed nucleus of the stria terminalis; Nucleus accumbens; Methylnaloxonium; Self-administration; Dependence; Heroin 1. Introduction In order to understand the biological basis of drug addiction, an understanding of how the brain is altered in w x addicted versus nonaddicted states is needed 20,27 . Drug addiction or substance dependence is characterized by a compulsion to take drugs, a loss of control of drug intake, and emergence of a negative affective state upon drug w x abstinence 18,24 . It is clear that there is a difference between occasional use and abuse of drugs, yet the respon- sible neurobiological mechanisms are still unknown. Of recent interest in drug dependence is the possible involvement of the extended amygdala which intercon- nects limbic brain structures and structures involved in w x motor function 3,23,25 . The extended amygdala is com- posed of several basal forebrain regions that share similar ) Corresponding author. Fax: q1-858-812-1584; e-mail: john_r.walker@nifg.novartis.com 1 Both authors contributed equally to this work. morphology, immunoreactivity, and connectivity. It is es- Ž . sentially continuous rostral-caudally from the medial shell Ž . portion of the nucleus accumbens AcbSh , through the Ž . bed nucleus of the stria terminalis BST , to the central Ž . nucleus of the amygdala ACE . Afferent inputs to these regions include various cortical structures, the hippocam- pal formation, basolateral amygdala, the ventral tegmental Ž . area VTA , thalamic nuclei, lateral hypothalamus, and lateral septum. Efferent connections include the sublenticu- lar ventral pallidum, medial VTA, reticular formation, w x central grey, and the lateral hypothalamus 2,9,14,22 . The extended amygdala therefore interconnects various brain structures hypothesized to be involved in the reinforcing w x effects of abused drugs 6,19,37 . Very low systemic doses of the opiate receptor antago- nist naloxone block heroin reinforcement to a greater degree in dependent than nondependent subjects, suggest- ing that the reinforcing effects of heroin become sensitized wx during dependence 7 . Of interest would be to determine which brain regions are responsible for this differential sensitivity to opiates brought about by dependence. 0006-8993r00r$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. Ž . PII: S0006-8993 99 02288-X