PharmacologyBiochemistry and Behavior, Vol.42, pp. 437-444, 1992 0091-3057/92$5.00 + .00 Printedin the U.S.A. All rightsreserved. Copyright© 1992 Pergamon PressLtd. Impact of Psychological Dynamics of Stress on the Peripheral Benzodiazepine Receptor PHILIP V. HOLMES, ANNE P. STRINGER AND ROBERT C. DRUGAN 1 Schrier Research Laboratory, Department of Psychology, Brown University, Providence, RI 02912 Received 9 December 1991 HOLMES, P. V., A. P. STRINGER AND R. C. DRUGAN. Impact of psychological dynamics ofstress on theperiph- eral benzodiazepine receptor. PHARMACOL BIOCHEM BEHAV 42(3) 437-444, 1992.--In an attempt to dissociate the relative impact of psychological vs. physiological concomitants of stress on the peripheral benzodiazepine receptor (PBR), the influence of stressor controllability and predictability was investigated in rats. In addition, the effect of a purely psycholog- ical stressor, contextually conditioned fear, was examined. The response of the PBR in rats confronted with a naturalistic threat, a cat, was also tested. Various peripheral and CNS tissues were analyzed. Specific binding of [3H]Ro 5-4864 was significantly reduced in the kidneys of subjects receiving either controllable or uncontrollable shock. Similar changes were seen in the kidneys of subjects receiving either predictable or unpredictable shock. Mean [3H]Ro 5-4864 binding in lung was reduced following both predictable and unpredictable shock, but only the reduction in the predictable shock group reached significance. Controllability appeared to protect against the stress-induced reduction in [3H]Ro 5-4864 binding in lung. Contextually conditioned fear only affected PBR in the olfactory bulb, and exposure to a cat was without effect. These data suggest that the PBR responds only to potent stressors, and psychological influences on the PBR are tissue specific. Peripheral benzodiazepine receptor Stress Rats Controllability Predictability Conditioned fear THE central benzodiazepine receptor (CBR) is associated with the GABA type-A receptor/chloride ionophore. This macro- molecular complex has been extensively characterized in the CNS (12,14,32). The CBR mediates the anxiolytic, anticonvul- sant, muscle relaxant, and sedative actions of benzodiazepines through allosteric interactions with the GABAA receptor (11,42). That the function of the CBR involves the mediation of fear-related behaviors is supported by evidence of anxio- genic endogenous ligands (1,40) and experiments demonstrat- ing alterations in CBR density (Bm~) in rats exposed to various stressors (22,44). Certain benzodiazepines (e.g., valium), the endogenous peptide diazepam binding inhibitor (DBI), and fragments of DBI bind not only to the CBR but also to a distinct type of receptor expressed in a variety of tissues, the peripheral benzodiazepine receptor (PBR) (9,12,36). The PBR is situated primarily on the outer mitochondrial membrane in cells of both the CNS and some peripheral tissues (5). The cDNA encoding the PBR has been cloned, and the apparent transla- tional product of the deduced DNA sequence is a 17- to 18-kD protein (16,41). In the CNS, the PBR appears to be associated primarily with glia (8). The PBR reversibly binds the proto- typic ligands Ro 5-4864 and PK 11195 with high affinity (- 1 nM). High densities of PBR are found in olfactory bulb, pi- neal gland, and choroid plexus, as well as the adrenal gland, kidney, lung, and heart (7,8,11,15). Its distinctive subcellular and tissue-specific localization and physical structure have been well characterized, yet its physiological significance is poorly understood. Recent evidence links the PBR to steroid biosynthesis in adrenocortical and Leydig cells in vitro (9,33,36,37). PK 11195 and Ro 5-4864 are potent stimulators of steroidogenesis whereas lower-affinity PBR ligands such as diazepam are less potent and efficacious (33). Recent work has elucidated a spe- cific role for DBI and a 34 amino acid fragment of DBI, trialkontatetraneuropeptide (TTN), in stimulating steroido- genesis through specific interactions with the PBR (36). The PBR appears to be involved in the delivery of cholesterol through the outer mitochondrial membrane to the side-chain- cleavage enzyme cytochrome P-450 situated on the inner mem- brane (37,49). This process, in which cholesterol is converted to pregnenolone, is the rate-limiting step in steroidogenesis. The PBR has also been linked to adrenocorticotropin (ACTH) and corticotropin-releasing hormone (CRH) secre- tion in vivo and in vitro (13). The molecular mechanisms by which secretion of these peptide hormones is stimulated is unclear. Earlier experiments reported an inhibitory action of Ro 5-4864 on B-endorphin release in vitro, and an interaction i To whom requests for reprints should be addressed. 437