ELSEVIER Pharmacology Biochemistry and Behavior, Vol. 54, No. I, pp. 205-210, 1996 Copyright @1996 Elsevier Science Inc. Printed in the USA. All rights reserved 0091-3057/96 $15.00 + .OO SSDI zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA 0091-3057(95)02133-7 Stress-Induced Increase in Brain Neuroactive Steroids: Antagonism by Abecarnil MARIA L. BARBACCIA,*’ GIANNA ROSCETTI,* FRANCESCA BOLACCHI,* ALESSANDRA CONCAS,? MARIA C. MOSTALLINO,t ROBERT H. PURDYS AND GIOVANNI BIGGIOt *Department of Experimental Medicine, University of Rome “Tor Vergata, ” Edificio F-sud, Stanza 14, Via di Tor Vergata, 135-00133 Roma, Italy tDepartment of Experimental Biology, University of Cagliari, 09123 Cagliari, Italy SDepartment of Psychiatry, University of California, San Diego, CA BARBACCIA, M. L., G. ROSCETTI, F. BOLACCHI, A. CONCAS, M. C. MOSTALLINO, R. H. PURDY AND G. BIGGIO. zyxwvutsrqponmlkjihgfedcbaZYXWVUTSRQPONMLKJIHGFEDCBA Stress- induced increase in brain neuroactive steroids: Antagonism by abecarnil. PHARMACOL BIOCHEM BEHAV 54(l) 205-210, 1996. -Acute foot shock stress elicits a selective and time-dependent increase of neuroactive steroid (pregnenolone, progesterone, allotetrahydrodeoxycorticosterone) concentrations in rat brain cortex, accompanied by a marked increase of plasma corticosterone. The brain cortical neuroactive steroid levels peaked between 10 and 30 min poststress and returned to control values by 2 h. Abecarnil (0.3 mg/kg, IP), a beta-carboline derivative with anxiolytic properties, completely antagonized the effect of foot shock on brain cortical neuroactive steroids. A single administration of the anxiogenic beta-carboline FG 7142 (15 mg/kg, IP), in contrast, mimicked the effect of foot shock. These data support the hypothesis for the existence of a functional relationhip between brain neuroactive steroid concentrations and GABA, receptor function/emotional state of the animal. Neuroactive steroids 3,Alpha-21-dihydroxy-5alpha-pregnan-20-one (allotetrahydrodeoxycorticosterone, THDOC) Pregnenolone Progesterone Corticosterone Foot shock GABA, receptor Beta-Carboline Abecarnil FG 7142 PREGNENOLONE, progesterone, and some of their A-ring reduced metabolites can be produced by neural tissue, both in the central and peripheral nervous systems, and for this are referred to as neurosteroids (1,2,12,22,23,27,28,33,34). More- over, after in vivo administration or direct in vitro application to cells, neurosteroids have been shown to regulate important neuronal functions via genomic (35) and membrane-mediated actions, among others, via specific interactions with ligand- gated ionotropic receptors such as GABA, receptors (26,28, 3 1,37). For this they have also been referred to as neuroactive steroids (28). Among the different neuroactive steroids the 3alpha-hydroxy-5alpha reduced derivatives of progesterone and deoxycorticosterone, namely, 3alpha-OH,Salpha-pregnan- IO-one (allopregnanolone, AP) and 3,alpha,21-dihydroxy- Salpha-pregnan-20-one (allo-tetrahydrodeoxy-corticosterone, THDOC) are the most potent and efficacious known positive modulators of the GABAA receptors (28,31). These receptors have been suggested to play a pivotal role in the regulation of the animal’s emotional state (6). Accord- ingly, anxiety and/or proconflict promoting conditions, such I To whom requests for reprints should be addressed. as acute stress, alter brain GABAergic neurotransmission. De- creased GABA-mediated chloride ion fluxes and increased [“S]-TBPS binding have been reported after several acute stress paradigms (handling, CO2 inhalation, foot shock, swim stress) (6,14,19,21,36,38). These stress-induced biochemical alterations are accompanied by behavioral changes, i.e., a de- creased punished response in the Vogel’s test, an index of anxiety in the animal (8,15,16), and an increased sensitivity to both the anxiolytic action of benzodiazepines (10,20) and to the convulsant action of isoniazid, an inhibitor of GABA syn- thesis (39). These effects of acute stress on the GABAergic neurotransmission are mimicked by an acute administration of anxiogenic beta-carbolines, i.e., negative allosteric modula- tors of the GABA, receptor complex, and prevented by prior treatment of the animals with anxiolytics that act as positive allosteric modulators of the GABA, receptor complex (6,8). AP and THDOC also enhance in vitro GABA, receptor func- tion (26,28,31,33,37) and, when administered in vivo, show anxiolytic and/or anticonvulsant properties (5,9,24,28). While evidence is accumulating on the pharmacological actions of 205