Effects of peripheral beta blockers on isoprenaline-induced fear conditioned rats

Anxiety disorders are the most prominent mental illness in the United States, affecting 18 percent of the population. Aversive memories, such as traumatic events, are associated with unconditioned stimuli. Few studies have shown that cardiovascular dysfunctions can be associated with aversive contexts or cues. However, preliminary results demonstrate that the beta-adrenergic agonist isoprenaline can induce defensive reactions in rats, which can promote aversive learning to the odors. The purpose of this study was to investigate whether aversive associations were prompted by activation of peripheral receptors. To test this, beta-blockers were injected 15 minutes before isoprenaline to induce fear. Male wistar rats (280-350g) were trained using an olfactory fear conditioning paradigm (OFC), consisting of 5 minute training and test sessions. Isoprenaline was used to arouse fear (unconditioned stimulus) and the neutral odor amyl acetate was used as the conditioned stimulus in an acquisition chamber, 24 h after a 3 min familiarization session. In the first experiment (during the training session), rats were injected with either saline or isoprenaline 15 min before conditioning to investigate whether isoprenaline promoted defensive behaviors (crouch sniffing, freezing and stretch ahead). Once isoprenaline was confirmed to promote fear, the second experiment used a pre-treatment of -blockers nadolol (10 mg/Kg, a peripheral non-selective beta-blocker) or atenolol (10 mg/Kg and 20 mg/Kg, a peripheral selective beta-1 blocker), which was injected 15 minutes before the isoprenaline treatment. The fear association was analyzed 24h later during the test session within a different context (odor box) composed of an enclosed and roofed zone as opposed to an open compartment where the odor was released after a minute of habituation. Defensive behaviors, as well as total time active, approach time, hide time, and crossings were observed in the odor box. Veronica Go, Biochemistry, Cellular and Molecular Biology, University of Tennessee, Knoxville, TN 37916 USA. [email protected] Carol Ferraz Webber, Eloisa Pavesi, and Antonio de Padua Carobrez, Departamento de Farmacologia, CCB, Universidade Federal de Santa Catarina, Florianpolis, SC 88040-900, Brazil Our results showed that nadolol attenuated isoprenalineinduced fear, while atenolol rats continued to display signs of fear during the training session. During the test, isoprenaline promoted aversive memories to odor, which was seen by increased defensive time during the odor test, while nadolol impaired this aversive association. Conversely, atenolol did not block the OFC induced by isoprenaline. These results suggest that fear memory can be induced by the peripheral beta receptor activation. While the beta-1 blocker was not able to prevent the odorassociation, the peripheral non-selective blocker could impair cardiovascular mal-dysfunctions responsible in the fear mechanisms, suggesting a potential anxiolytic compound.