Pharmacology Biochemistry & Behavior, Vol. 28, pp. 21-27. ©Pergamon Journals Ltd.. 1987. Printed in the U.S.A. 0091-3057/87 $3.00 + .00 GABA-Benzodiazepine Modulation of Aversion in the Medial Hypothalamus of the Rat H. MILANI AND F. G. GRAEFF 1 Department of Pharmacology, School of Medicine Campus USP, 14049 Ribeirfto Preto, SP, Brazil Received 6 October 1986 MILANI, H. AND F. G. GRAEFF. GABA-benzodiazepine modulation of aversion in the medial hypothalamus of the rat. PHARMACOL BIOCHEM BEHAV 28(1) 21-27, 1987.--Earlier results indicate that the neurons of the midbrain central gray (CG) responsible for the elaboration and/or expression of aversive states are tonically inhibited by the GABA- benzodiazepine system. In the present study, chemitrodes were implanted in the medial hypothalamus (MH) of the rat, another aversive area of the brain deeply interrelated with the dorsal CG. Microinjection of the benzodiazepine receptor agonist midazolam raised the aversive threshold of electrical stimulation of the MH in a dose-dependent way, though in only about half of the animals tested. In the remaining rats, midazolam was ineffective. Similar antiaversive effects were caused by the GABA-A receptor agonist THIP. In contrast, mi'croinjection of the GABA-A receptor blocker bicuculline induced aversive-like behavioral and autonomic changes. The effects of bicuculline were antagonized by pretreatment with either THIP or midazolam, the latter being counteracted by the competitive benzodiazepine receptor blocker Ro 15-1788. These results extend to the MH, the hypothesis of GABA-benzodiazepine modulation of neurons integrating aversive motivational states. Aversion Medial hypothalamus Brain electrical stimulation Intracerebral injection Bicuculline Midazolam GABA Benzodiazepine receptors THIP EXPERIMENTAL evidence reviewed elsewhere [10] indi- cates that the medial hypothalamus (MH), the dorsal mid- brain central gray (CG) and parts of the amygdala constitute an integrated neural system responsible for the elaboration and/or expression of aversive states. Previously reported results have shown that microinjec- tion in the dorsal CG of two benzodiazepine anxiolytics, chlordiazepoxide and midazolam, of the sedative-hypnotic pentobarbital, as well as of the inhibitory neurotransmitter GABA and several direct GABA-A receptor agonists raises the aversive threshold of electrical stimulation of the same brain area [1, 2, 13]. The antiaversive effect of the ben- zodiazepine anxiolytics is likely to be mediated by ben- zodiazepine receptors since it was abolished by pretreatment with the competitive benzodiazepine receptor blocker Ro 15-1788 [15], also microinjected in the dorsal CG [1]. There- fore, increase of GABAergic activity in the dorsal CG at- tenuates the aversive effect of its electrical stimulation. Complementary results were obtained with drugs that im- pair GABAergic neurotransmission. Thus, the competitive GABA-A receptor blockers, bicuculline [4,27] and SR 95103 [25], the non-competitive GABA antagonist picrotoxin, and three different inhibitors of GABA synthesis have been shown to induce either aversive-like behaviors or neuroveg- etative changes characteristic of the defense reaction when microinjected into the dorsal CG of the rat [2, 3, 6, 23, 25, 26]. The above results led to the suggestion that the GABA- benzodiazepine system tonically inhibits neuronal groups in the dorsal CG, commanding aversive-defensive behaviors and elaborating negative motivational states [2, 6, 12, 13, 23]. The MH is anatomically interconnected with the dorsal CG [8, 9, 21, 28] and its electrical stimulation is similarly aversive [5, 7, 18, 29, 22, 24]. In addition, flight behavior has been described following microinjection of GABA-A recep- tor antagonists as well as of inhibitors of GABA synthesis in the MH of the rat, indicating that GABA modulates aversion in the MH in the same way as in the CG [3, 6, 25, 26]. In the present study, the role of the GABA-benzo- diazepine system in the MH was further explored. For this purpose, the effect of microinjections of the benzodiazepine receptor agonist midazolam [14] as well as of the GABA-A receptor agonist THIP [17] on the aversive threshold of elec- trical stimulation of the MH of the rat was measured. The behavioral and neurovegetative changes induced by intrahypothalamic injection of bicuculline were also as- sessed. In addition, the antagonism of bicuculline effects by 1Request for reprints should be addressed to F. G. Graeff, Laboratory of Psychobiology, FFCLRP, Campus USP, 14049 Ribeir~o Preto, SP, Brazil. 21